0А0АаАВVcd02117, NifH_like, This family contains the NifH (iron protein) of nitrogenase, L subunit (BchL/ChlL) of the protochlorophyllide reductase and the BchX subunit of the Chlorophyllide reductase. Members of this family use energey from ATP hydrolysis and transfer electrons through a Fe4-S4 cluster to other subunit for reduction of substrate.бА0АкА0АаАCDDбАаАе║вА0А0АаАВcd02120, PA_subtilisin_like, PA_subtilisin_like: Protease-associated domain containing subtilisin-like proteases. This group contains various PA domain-containing subtilisin-like proteases including melon cucumisin, Arabidopsis thaliana Ara12, a nodule specific serine protease from Alnus glutinosa ag12, members of the tomato P69 family, and tomato LeSBT2. These proteins belong to the peptidase S8 family. Cucumisin from the juice of melon fruits is a thermostable serine peptidase, with a broad substrate specificity for oligopeptides and proteins. A. thaliana Ara12 is a thermostable, extracellular serine protease, found chiefly in silique tissue and stem tissue. Ara12 is stimulated by Ca2+ ions. A. glutinosa ag12 is expressed at high levels in the nodules, and at low levels in the shoot tips; it is implicated in both symbiotic and non-symbiotic processes in plant development. The tomato P69 protease family is comprised of various protein isoforms of approximately 69KDa. These isoforms accumulate extracellularly. Some of the P69 genes are tightly regulated in a tissue specific fashion, and by environmental and developmental signals. For example: infection with avirulent bacteria activates transcription of the genes for the P69 B and C isoforms, the P69 E transcript was detected only in roots, and the P69F transcript only in hydathodes. The Tomato LeSBT2 subtilase transcript was not detected in flowers and roots, but was present in cotyledons and leaves. The significance of the PA domain to these proteins has not been ascertained. It may be a protein-protein interaction domain. At peptidase active sites, the PA domain may participate in substrate binding and/or promoting conformational changes, which influence the stability and accessibility of the site to substrate.бА0АкА0АаАCDDбАаАе╗вА0А0АаАВ─cd02121, PA_GCPII_like, PA_GCPII_like: Protease-associated domain containing protein, glutamate carboxypeptidase II (GCPII)-like. This group contains various PA domain-containing proteins similar to GCPII including, GCPIII (NAALADase2) and NAALADase L. These proteins belong to the peptidase M28 family. GCPII is also known N-acetylated-alpha-linked acidic dipeptidase (NAALDase1), folate hydrolase or prostate-specific membrane antigen (PSMA). GCPII is found in various human tissues including prostate, small intestine, and the central nervous system. In the brain, GCPII is known as NAALDase1, it functions as a NAALDase hydrolyzing the neuropeptide N-acetyl-L-aspartyl-L-glutamate (alpha-NAAG), to release free glutamate. In the small intestine, GCPII releases the terminal glutamate from poly-gamma-glutamated folates. GCPII (PSMA) is a useful cancer marker; its expression is markedly increased in prostate cancer and in tumor-associated neovasculature. GCPIII hydrolyzes alpha-NAAG with a lower efficiency than does GCPII; NAALADase L is not able to hydrolyze alpha-NAAG. The GCPII PA domain (referred to as the apical domain) participates in substrate binding and may act as a protein-protein interaction domain.бА0АкА0АаАCDDбАаАе╝вА0А0АаАВcd02122, PA_GRAIL_like, PA _GRAIL_like: Protease-associated (PA) domain GRAIL-like. This group includes PA domain containing E3 (ubiquitin ligases) similar to human GRAIL (gene related to anergy in lymphocytes) protein. Proteins in this group contain a C3H2C3 RING finger. E3 ubiquitin ligase is part of an enzymic cascade, the end result of which is the ubiquitination of proteins. In this cascade, E1 activates the ubiquitin, the activated ubiquitin is carried by E2, and E3 recognizes the acceptor protein as well as catalyzes the transfer of the activated ubiquitin from E2 to this acceptor. GRAIL, a transmembrane protein localized in the endosomes, controls the development of T cell clonal anergy, and may ubiquitinate membrane-associated targets for T cell activation. GRAIL1 is associated with, and regulated by, two isoforms of otubain 1 (the ubiquitin-specific protease). Additional E3s belonging to this group include human (h)Goliath and Xenopus GREUL1 (Goliath Related E3 Ubiquitin Ligase 1). hGoliath and GRAIL both have the property of self-ubiquitination. hGoliath is expressed in leukocytes; its expression and localization is not modified in leukemia. GREUL1 may play a role in the generation of anterior ectoderm. The significance of the PA domain to these proteins has not been ascertained. It may be a protein-protein interaction domain. At peptidase active sites, the PA domain may participate in substrate binding and/or promoting conformational changes, which influence the stability and accessibility of the site to substrate.бА0АкА0АаАCDDбАаАе╜вА0А0АаАВ cd02123, PA_C_RZF_like, PA_C-RZF_ like: Protease-associated (PA) domain C_RZF-like. This group includes various PA domain-containing proteins similar to C-RZF (chicken embryo RING zinc finger) protein. These proteins contain a C3H2C3 RING finger. C-RZF is expressed in embryo cells and is restricted mainly to brain and heart, it is localized to both the nucleus and endosomes. Additional C3H2C3 RING finger proteins belonging to this group, include Arabidopsis ReMembR-H2 protein and mouse sperizin. ReMembR-H2 is likely to be an integral membrane protein, and to traffic through the endosomal pathway. Sperizin is expressed in haploid germ cells and localized in the cytoplasm, it may participate in spermatogenesis. The significance of the PA domain to these proteins has not been ascertained. It may be a protein-protein interaction domain. At peptidase active sites, the PA domain may participate in substrate binding and/or promoting conformational changes, which influence the stability and accessibility of the site to substrate.бА0АкА0АаАCDDбАаАе╛вА0А0АаАВ╧cd02124, PA_PoS1_like, PA_PoS1_like: Protease-associated (PA) domain PoS1-like. This group includes various PA domain-containing proteins similar to Pleurotus ostreatus (Po)S1. PoSl, the main extracellular protease in P. ostreatus is a subtilisin-like serine protease belonging to the peptidase S8 family. Ca2+ and Mn2+ both stimulate the protease activity of (Po)S1. Ca2+ protects PoS1 from autolysis. PoS1 is a monomeric glycoprotein, which may play a role in the regulation of laccases in lignin formation. (Po)S1 participates in the degradation of POXA1b, and in the activation of POXA3, (POXA1b and POXA3 are laccase isoenzymes), but its effect may be indirect. The significance of the PA domain to PoS1 has not been ascertained. It may be a protein-protein interaction domain. At peptidase active sites, the PA domain may participate in substrate binding and/or promoting conformational changes, which influence the stability and accessibility of the site to substrate.бА0АкА0АаАCDDбАаАе┐вА0А0АаАВwcd02125, PA_VSR, PA_VSR: Protease-associated (PA) domain-containing plant vacuolar sorting receptor (VSR). This group includes various PA domain-containing VSRs such as garden pea BP-80, pumpkin PV72, and various Arabidopsis VSRs including AtVSR1. In contrast to most eukaryotes, which only have one or two VSRs, plants have several. This may in part be a reflection of having a more complex vacuolar system with both lytic vacuoles and storage vacuoles. The lytic vacuole is thought to be equivalent to the mammalian lysosome and the yeast vacuole. Pea BP-80 is a type 1 transmembrane protein, involved in the targeting of proteins to the lytic vacuole; it has been suggested that this protein also mediates targeting to the storage vacuole. PV72 and AtVSR1 may mediate transport of seed storage proteins to protein storage vacuoles. The significance of the PA domain to VSRs has not been ascertained. It may be a protein-protein interaction domain. At peptidase active sites, the PA domain may participate in substrate binding and/or promoting conformational changes, which influence the stability and accessibility of the site to substrate.бА0АкА0АаАCDDбАаАе└вА0А0АаАВScd02126, PA_EDEM3_like, PA_EDEM3_like: protease associated domain (PA) domain-containing EDEM3-like proteins. This group contains various PA domain-containing proteins similar to mouse EDEM3 (ER-degradation-enhancing mannosidase-like 3 protein). EDEM3 contains a region, similar to Class I alpha-mannosidases (gylcosyl hydrolase family 47), N-terminal to the PA domain. EDEM3 accelerates glycoprotein ERAD (ER-associated degradation). In transfected mammalian cells, overexpression of EDEM3 enhances the mannose trimming from the N-glycans, of a model misfolded protein [alpha1-antitrypsin null (Hong Kong)] as well as, from total glycoproteins. Mannose trimming appears to be involved in the selection of ERAD substrates. EDEM3 has a different specificity of trimming than ER alpha-mannosidase 1. The significance of the PA domain to EDEM3 has not been ascertained. It may be a protein-protein interaction domain. At peptidase active sites, the PA domain may participate in substrate binding and/or promoting conformational changes, which influence the stability and accessibility of the site to substrate.бА0АкА0АаАCDDбАаАе┴вА0А0АаАВКcd02127, PA_hPAP21_like, PA_hPAP21_like: Protease-associated domain containing proteins like the human secreted glycoprotein hPAP21 (human protease-associated domain-containing protein, 21kDa). This group contains various PA domain-containing proteins similar to hPAP21. Complex N-glycosylation may be required for the secretion of hPAP21. The significance of the PA domain to hPAP21 has not been ascertained. It may be a protein-protein interaction domain. At peptidase active sites, the PA domain may participate in substrate binding and/or promoting conformational changes, which influence the stability and accessibility of the site to substrate.бА0АкА0АаАCDDбАаАе┬вА0А0АаАВОcd02128, PA_TfR, PA_TfR: Protease-associated domain containing proteins like transferrin receptor (TfR). This group contains various PA domain-containing proteins similar to human TfR1 and TfR2. TfR1 and TfR2 are type II membrane proteins, belonging to the peptidase M28 family. TfR1 is homodimeric, widely expressed, and a key player in the uptake of iron-loaded transferrin (Tf) into cells. The TfR1 homodimer binds two molecules of Tf and this complex is internalized. In addition to its role in iron uptake, TfR1 may participate in cell growth and proliferation. TfR2 also binds Tf but with a significantly lower affinity than does TfR1. TfR2 is expressed chiefly in hepatocytes, hematopoietic cells, and duodenal crypt cells; its expression overlaps with that of hereditary hemochromatosis protein (HFE). TfR2 is involved in iron homeostasis. HFE and TfR2 interact in cells. By one model for serum iron sensing, at low or basal iron concentrations, HFE and TFR1 form a complex at the plasma membrane; at increased Tf, Tf competes with HFE for binding of TfR1, resulting in HFE disassociating from TfR1 and associating with TfR2 . The TfR1-TfR2 association might initiate a signal cascade leading to the induction of hepcidin (a small peptide hormone that controls systemic iron levels). Human mutations in TfR2 are associated with a form of hemochromatosis (HFE3). The significance of the PA domain to TfRs has not been ascertained. It may be a protein-protein interaction domain. At peptidase active sites, the PA domain may participate in substrate binding and/or promoting conformational changes, which influence the stability and accessibility of the site to substrate.бА0АкА0АаАCDDбАаАе├вА0А0АаАВCcd02129, PA_hSPPL_like, PA_hSPPL_like: Protease-associated domain containing human signal peptide peptidase-like (hSPPL)-like. This group contains various PA domain-containing proteins similar to hSPPL2a and 2b. These SPPLs are GxGD aspartic proteases. SPPL2a is sorted to the late endosomes, SPPL2b to the plasma membrane. In activated dendritic cells, hSPPL2a and 2b catalyze the intramembrane proteolysis of tumor necrosis factor alpha triggering IL-12 production. hSPPL2a and 2b may have a broad substrate spectrum. The significance of the PA domain to these SPPLs has not been ascertained. It may be a protein-protein interaction domain. At peptidase active sites, the PA domain may participate in substrate binding and/or promoting conformational changes, which influence the stability and accessibility of the site to substrate.бА0АкА0АаАCDDбАаАе─вА0А0АаАВcd02130, PA_ScAPY_like, PA_ScAPY_like: Protease-associated domain containing proteins like Saccharomyces cerevisiae aminopeptidase Y (ScAPY). This group contains various PA domain-containing proteins similar to the S. cerevisiae APY, including Trichophyton rubrum leucine aminopeptidase 1(LAP1). Proteins in this group belong to the peptidase M28 family. ScAPY hydrolyzes amino acid-4-methylcoumaryl-7-amides (MCAs). ScAPY more rapidly hydrolyzes dipeptidyl-MCAs. Hydrolysis of amino acid-MCAs or dipeptides is stimulated by Co2+ while the hydrolysis of dipeptidyl-MCAs, tripeptides, and longer peptides is inhibited by Co2+. ScAPY is vacuolar and is activated by proteolytic processing. LAP1 is a secreted leucine aminopeptidase. The significance of the PA domain to these proteins has not been ascertained. It may be a protein-protein interaction domain. At peptidase active sites, the PA domain may participate in substrate binding and/or promoting conformational changes, which influence the stability and accessibility of the site to substrate.бА0АкА0АаАCDDбАаАе┼вА0А0АаАВ┐cd02131, PA_hNAALADL2_like, PA_hNAALADL2_like: Protease-associated domain containing proteins like human N-acetylated alpha-linked acidic dipeptidase-like 2 protein (hNAALADL2). This group contains various PA domain-containing proteins similar to hNAALADL2. The function of hNAALADL2 is unknown. This gene has been mapped to a chromosomal region associated with Cornelia de Lange syndrome. The significance of the PA domain to hNAALADL2 has not been ascertained. It may be a protein-protein interaction domain. At peptidase active sites, the PA domain may participate in substrate binding and/or promoting conformational changes, which influence the stability and accessibility of the site to substrate.бА0АкА0АаАCDDбАаАе╞вА0А0АаАВўcd02132, PA_GO-like, PA_GO-like: Protease-associated domain containing proteins like Arabidopsis thaliana growth-on protein GRO10. This group contains various PA domain-containing proteins similar to the functionally uncharacterized Arabidopsis GRO10. The PA domain may be a protein-protein interaction domain. At peptidase active sites, the PA domain may participate in substrate binding and/or promoting conformational changes, which influence the stability and accessibility of the site to substrate.бА0АкА0АаАCDDбАаАе╟вА0А0АаАВMcd02133, PA_C5a_like, PA_C5a_like: Protease-associated domain containing proteins like Streptococcus pyogenes C5a peptidase. This group contains various PA domain-containing proteins similar to S. pyogenes C5a, including, i) Vpr, a minor extracellular serine protease from Bacillus subtilis, ii) a large molecular mass collagenolytic protease from Geobacillus collagenovorans MO-1, and iii) PrtS, a cell envelope protease from Streptococcus thermophilus CNRZ 385. Proteins in this group belong to the peptidase S8 family. C5a peptidase is a cell surface serine protease which specifically inactivates C5a [a chemotactic peptide, which attracts polymorphonuclear leukocytes (PMNs)], by cleaving it to release a 7-residue carboxy-terminal fragment which contains the PMN binding site. The significance of the PA domain to these proteins has not been ascertained. It may be a protein-protein interaction domain. At peptidase active sites, the PA domain may participate in substrate binding and/or promoting conformational changes, which influence the stability and accessibility of the site to substrate.бА0АкА0АаАCDDбАаАе╚вА0А0АаАВ╬cd02134, NusA_KH, NusA_K homology RNA-binding domain (KH). NusA is an essential multifunctional transcription elongation factor that is universally conserved among prokaryotes and archaea. NusA anti-termination function plays an important role in the expression of ribosomal rrn operons. During transcription of many other genes, NusA-induced RNAP pausing provides a mechanism for synchronizing transcription and translation . The N-terminal RNAP-binding domain (NTD) is connected through a flexible hinge helix to three globular domains, S1, KH1 and KH2. The KH motif is a beta-alpha-alpha-beta-beta unit that folds into an alpha-beta structure with a three stranded beta-sheet interupted by two contiguous helices.бА0АкА0АаАCDDбАаАе╔вА0А0АаАВMcd02135, Arsenite_oxidase, Nitroreductase-like family which includes NADH oxidase and arsenite oxidiase. NADH oxidase catalyses the oxidation of NAD(P)H and accepts a wide broad range of compounds as electron acceptors, such as nitrocompound. Arsenite oxidase in a beta-proteobacterial strain is able to oxidize arsenite to arsenate.бА0АкА0АаАCDDбАаАе╩вА0А0АаАВcd02136, Nitroreductase, Nitroreductase family. Members of this family utilize FMN as a cofactor and catalyze reduction of a variety of nitroaromatic compounds, including nitrofurans, nitrobenzens, nitrophenol, nitrobenzoate and quinones by using either NADH or NADPH as a source of reducing equivalents in an obligatory two-election transfer mechanism. The enzyme is typically a homodimer. Members of this family are also called NADH dehydrogenase, oxygen-insensitive NAD(P)H nitrogenase or dihydropteridine reductase.бА0АкА0АаАCDDбАаАе╦вА0А0АаАВ;cd02137, Nitroreductase_1, Nitroreductase-like family 1. A subfamily of the nitroreductase family containing uncharacterized proteins that are similar to nitroreductase. Nitroreductase catalyzes the reduction of nitroaromatic compounds such as nitrotoluenes, nitrofurans and nitroimidazoles. This process requires NAD(P)H as electron donor in an obligatory two-electron transfer and uses FMN as cofactor. The enzyme is typically a homodimer. Members of this family are also called NADH dehydrogenase, oxygen-insensitive NAD(P)H nitrogenase or dihydropteridine reductase.бА0АкА0АаАCDDбАаАе╠вА0А0АаАВ;cd02138, Nitroreductase_2, Nitroreductase-like family 2. A subfamily of the nitroreductase family containing uncharacterized proteins that are similar to nitroreductase. Nitroreductase catalyzes the reduction of nitroaromatic compounds such as nitrotoluenes, nitrofurans and nitroimidazoles. This process requires NAD(P)H as electron donor in an obligatory two-electron transfer and uses FMN as cofactor. The enzyme is typically a homodimer. Members of this family are also called NADH dehydrogenase, oxygen-insensitive NAD(P)H nitrogenase or dihydropteridine reductase.бА0АкА0АаАCDDбАаАе═вА0А0АаАВ;cd02139, Nitroreductase_3, Nitroreductase-like family 3. A subfamily of the nitroreductase family containing uncharacterized proteins that are similar to nitroreductase. Nitroreductase catalyzes the reduction of nitroaromatic compounds such as nitrotoluenes, nitrofurans and nitroimidazoles. This process requires NAD(P)H as electron donor in an obligatory two-electron transfer and uses FMN as cofactor. The enzyme is typically a homodimer. Members of this family are also called NADH dehydrogenase, oxygen-insensitive NAD(P)H nitrogenase or dihydropteridine reductase.бА0АкА0АаАCDDбАаАе╬вА0А0АаАВвА0А0АаАВScd02766, MopB_3, The MopB_3 CD includes a group of related uncharacterized bacterial and archaeal molybdopterin-binding oxidoreductase-like domains with a putative N-terminal iron-sulfur [4Fe-4S] cluster binding site and molybdopterin cofactor binding site. These members belong to the molybdopterin_binding (MopB) superfamily of proteins.бА0АкА0АаАCDDбАаАж?вА0А0АаАВcd02767, MopB_ydeP, The MopB_ydeP CD includes a group of related uncharacterized bacterial molybdopterin-binding oxidoreductase-like domains with a putative molybdopterin cofactor binding site. These members belong to the molybdopterin_binding (MopB) superfamily of proteins.бА0АкА0АаАCDDбАаАж@вА0А0АаАВ∙cd02768, MopB_NADH-Q-OR-NuoG2, MopB_NADH-Q-OR-NuoG2: The NuoG/Nad11/75-kDa subunit (second domain) of the NADH-quinone oxidoreductase (NADH-Q-OR)/respiratory complex I/NADH dehydrogenase-1 (NDH-1). The NADH-Q-OR is the first energy-transducting complex in the respiratory chains of many prokaryotes and eukaryotes. Mitochondrial complex I and its bacterial counterpart, NDH-1, function as a redox pump that uses the redox energy to translocate H+ ions across the membrane, resulting in a significant contribution to energy production. The atomic structure of complex I is not known and the mechanisms of electron transfer and proton pumping are not established. The nad11 gene codes for the largest (75-kDa) subunit of the mitochondrial NADH:ubiquinone oxidoreductase, it constitutes the electron input part of the enzyme, or the so-called NADH dehydrogenase fragment. In Escherichia coli, this subunit is encoded by the nuoG gene, and is part of the 14 distinct subunits constituting the 'minimal' functional enzyme. The nad11 gene is nuclear-encoded in animals, plants, and fungi, but is still encoded in the mitochondrial genome of some protists. The Nad11/NuoG subunit is made of two domains: the first contains three binding sites for FeS clusters (the fer2 domain), the second domain (this CD), is of unknown function or, as postulated, has lost an ancestral formate dehydrogenase activity that became redundant during the evolution of the complex I enzyme. Although only vestigial sequence evidence remains of a molybdopterin binding site, this protein domain family belongs to the molybdopterin_binding (MopB) superfamily of proteins. Bacterial type II NADH-quinone oxidoreductases and NQR-type sodium-motive NADH-quinone oxidoreductases are not homologs of this domain family.бА0АкА0АаАCDDбАаАжAвА0А0АаАВfcd02769, MopB_DMSOR-BSOR-TMAOR, The MopB_DMSOR-BSOR-TMAOR CD contains dimethylsulfoxide reductase (DMSOR), biotin sulfoxide reductase (BSOR), trimethylamine N-oxide reductase (TMAOR) and other related proteins. DMSOR always catalyzes the reduction of DMSO to dimethylsulfide, but its cellular location and oligomerization state are organism-dependent. For example, in Rhodobacter sphaeriodes and Rhodobacter capsulatus, it is an 82-kDa monomeric soluble protein found in the periplasmic space; in E. coli, it is membrane-bound and exists as a heterotrimer. BSOR catalyzes the reduction of biotin sulfixode to biotin, and is unique among Mo enzymes because no additional auxiliary proteins or cofactors are required. TMAOR is similar to DMSOR, but its only natural substrate is TMAO. Members of this CD belong to the molybdopterin_binding (MopB) superfamily of proteins.бА0АкА0АаАCDDбАаАжBвА0А0АаАВЦcd02770, MopB_DmsA-EC, This CD (MopB_DmsA-EC) includes the DmsA enzyme of the dmsABC operon encoding the anaerobic dimethylsulfoxide reductase (DMSOR) of Escherichia coli and other related DMSOR-like enzymes. Unlike other DMSOR-like enzymes, this group has a predicted N-terminal iron-sulfur [4Fe-4S] cluster binding site. These members belong to the molybdopterin_binding (MopB) superfamily of proteins.бА0АкА0АаАCDDбАаАжCвА0А0АаАВcd02771, MopB_NDH-1_NuoG2-N7, MopB_NDH-1_NuoG2-N7: The second domain of the NuoG subunit (with a [4Fe-4S] cluster, N7) of the NADH-quinone oxidoreductase/NADH dehydrogenase-1 (NDH-1) found in various bacteria. The NDH-1 is the first energy-transducting complex in the respiratory chain and functions as a redox pump that uses the redox energy to translocate H+ ions across the membrane, resulting in a significant contribution to energy production. In Escherichia coli NDH-1, the largest subunit is encoded by the nuoG gene, and is part of the 14 distinct subunits constituting the functional enzyme. The NuoG subunit is made of two domains: the first contains three binding sites for FeS clusters (the fer2 domain), the second domain (this CD), is of unknown function or, as postulated, has lost an ancestral formate dehydrogenase activity that became redundant during the evolution of the complex I enzyme. Unique to this group, compared to the other prokaryotic and eukaryotic groups in this domain protein family (NADH-Q-OR-NuoG2), is an N-terminal [4Fe-4S] cluster (N7/N1c) present in the second domain. Although only vestigial sequence evidence remains of a molybdopterin binding site, this protein domain belongs to the molybdopterin_binding (MopB) superfamily of proteins.бА0АкА0АаАCDDбАаАжDвА0А0АаАВ"cd02772, MopB_NDH-1_NuoG2, MopB_NDH-1_NuoG2: The second domain of the NuoG subunit of the NADH-quinone oxidoreductase/NADH dehydrogenase-1 (NDH-1), found in beta- and gammaproteobacteria. The NDH-1 is the first energy-transducting complex in the respiratory chain and functions as a redox pump that uses the redox energy to translocate H+ ions across the membrane, resulting in a significant contribution to energy production. In Escherichia coli NDH-1, the largest subunit is encoded by the nuoG gene, and is part of the 14 distinct subunits constituting the functional enzyme. The NuoG subunit is made of two domains: the first contains three binding sites for FeS clusters (the fer2 domain), the second domain (this CD), is of unknown function or, as postulated, has lost an ancestral formate dehydrogenase activity that became redundant during the evolution of the complex I enzyme. Although only vestigial sequence evidence remains of a molybdopterin binding site, this protein domain belongs to the molybdopterin_binding (MopB) superfamily of proteins.бА0АкА0АаАCDDбАаАжEвА0А0АаАВ▒cd02773, MopB_Res-Cmplx1_Nad11, MopB_Res_Cmplx1_Nad11: The second domain of the Nad11/75-kDa subunit of the NADH-quinone oxidoreductase/respiratory complex I/NADH dehydrogenase-1(NDH-1) of eukaryotes and the Nqo3/G subunit of alphaproteobacteria NDH-1. The NADH-quinone oxidoreductase is the first energy-transducting complex in the respiratory chains of many prokaryotes and eukaryotes. Mitochondrial complex I and its bacterial counterpart, NDH-1, function as a redox pump that uses the redox energy to translocate H+ ions across the membrane, resulting in a significant contribution to energy production. The nad11 gene codes for the largest (75 kDa) subunit of the mitochondrial NADH:ubiquinone oxidoreductase, it constitutes the electron input part of the enzyme, or the so-called NADH dehydrogenase fragment. In Paracoccus denitrificans, this subunit is encoded by the nqo3 gene, and is part of the 14 distinct subunits constituting the 'minimal' functional enzyme. The Nad11/Nqo3 subunit is made of two domains: the first contains three binding sites for FeS clusters (the fer2 domain), the second domain (this CD), is of unknown function or, as postulated, has lost an ancestral formate dehydrogenase activity that became redundant during the evolution of the complex I enzyme. Although only vestigial sequence evidence remains of a molybdopterin binding site, this protein domain belongs to the molybdopterin_binding (MopB) superfamily of proteins.бА0АкА0АаАCDDбАаАжFвА0А0АаАВqcd02774, MopB_Res-Cmplx1_Nad11-M, MopB_Res_Cmplx1_Nad11_M: Mitochondrial-encoded NADH-quinone oxidoreductase/respiratory complex I, the second domain of the Nad11/75-kDa subunit of some protists. NADH-quinone oxidoreductase is the first energy-transducting complex in the respiratory chain and functions as a redox pump that uses the redox energy to translocate H+ ions across the membrane, resulting in a significant contribution to energy production. The nad11 gene codes for the largest (75-kDa) subunit of the mitochondrial NADH-quinone oxidoreductase, it constitutes the electron input part of the enzyme, or the so-called NADH dehydrogenase fragment. The Nad11 subunit is made of two domains: the first contains three binding sites for FeS clusters (the fer2 domain), the second domain (this CD), is of unknown function or, as postulated, has lost an ancestral formate dehydrogenase activity that became redundant during the evolution of the complex I enzyme. Although only vestigial sequence evidence remains of a molybdopterin binding site, this protein domain belongs to the molybdopterin_binding (MopB) superfamily of proteins.бА0АкА0АаАCDDбАаАжGвА0А0АаАВ{cd02775, MopB_CT, Molybdopterin-Binding, C-terminal (MopB_CT) domain of the MopB superfamily of proteins, a large, diverse, heterogeneous superfamily of enzymes that, in general, bind molybdopterin as a cofactor. The MopB domain is found in a wide variety of molybdenum- and tungsten-containing enzymes, including formate dehydrogenase-H (Fdh-H) and -N (Fdh-N), several forms of nitrate reductase (Nap, Nas, NarG), dimethylsulfoxide reductase (DMSOR), thiosulfate reductase, formylmethanofuran dehydrogenase, and arsenite oxidase. Molybdenum is present in most of these enzymes in the form of molybdopterin, a modified pterin ring with a dithiolene side chain, which is responsible for ligating the Mo. In many bacterial and archaeal species, molybdopterin is in the form of a dinucleotide, with two molybdopterin dinucleotide units per molybdenum. These proteins can function as monomers, heterodimers, or heterotrimers, depending on the protein and organism. Also included in the MopB superfamily is the eukaryotic/eubacterial protein domain family of the 75-kDa subunit/Nad11/NuoG (second domain) of respiratory complex 1/NADH-quinone oxidoreductase which is postulated to have lost an ancestral formate dehydrogenase activity and only vestigial sequence evidence remains of a molybdopterin binding site. This hierarchy is of the conserved MopB_CT domain present in many, but not all, MopB homologs.бА0АкА0АаАCDDбАаАжHвА0А0АаАВ▒cd02776, MopB_CT_Nitrate-R-NarG-like, Respiratory nitrate reductase A (NarGHI), alpha chain (NarG) and related proteins. Under anaerobic conditions in the presence of nitrate, E. coli synthesizes the cytoplasmic membrane-bound quinol-nitrate oxidoreductase (NarGHI), which reduces nitrate to nitrite and forms part of a redox loop generating a proton-motive force. Found in prokaryotes and some archaea, NarGHI usually functions as a heterotrimer. The alpha chain contains the molybdenum cofactor-containing Mo-bisMGD catalytic subunit. This CD (MopB_CT_Nitrate-R-NarG-like) is of the conserved molybdopterin_binding C-terminal (MopB_CT) region present in many, but not all, MopB homologs.бА0АкА0АаАCDDбАаАжIвА0А0АаАВЁcd02777, MopB_CT_DMSOR-like, The MopB_CT_DMSOR-like CD contains dimethylsulfoxide reductase (DMSOR), biotin sulfoxide reductase (BSOR), trimethylamine N-oxide reductase (TMAOR) and other related proteins. DMSOR always catalyzes the reduction of DMSO to dimethylsulfide, but its cellular location and oligomerization state are organism-dependent. For example, in Rhodobacter sphaeriodes and Rhodobacter capsulatus, it is an 82-kDa monomeric soluble protein found in the periplasmic space; in E. coli, it is membrane-bound and exists as a heterotrimer. BSOR catalyzes the reduction of biotin sulfixode to biotin, and is unique among Mo enzymes because no additional auxiliary proteins or cofactors are required. TMAOR is similar to DMSOR, but its only natural substrate is TMAO. Also included in this group is the pyrogallol-phloroglucinol transhydroxylase from Pelobacter acidigallici. This CD is of the conserved molybdopterin_binding C-terminal (MopB_CT) region present in many, but not all, MopB homologs.бА0АкА0АаАCDDбАаАжJвА0А0АаАВ/cd02778, MopB_CT_Thiosulfate-R-like, The MopB_CT_Thiosulfate-R-like CD contains thiosulfate-, sulfur-, and polysulfide-reductases, and other related proteins. Thiosulfate reductase catalyzes the cleavage of sulfur-sulfur bonds in thiosulfate. Polysulfide reductase is a membrane-bound enzyme that catalyzes the reduction of polysulfide using either hydrogen or formate as the electron donor. Also included in this CD is the phenylacetyl-CoA:acceptor oxidoreductase, large subunit (PadB2), which has been characterized as a membrane-bound molybdenum-iron-sulfur enzyme involved in anaerobic metabolism of phenylalanine in the denitrifying bacterium Thauera aromatica. The MopB_CT_Thiosulfate-R-like CD is of the conserved molybdopterin_binding C-terminal (MopB_CT) region present in many, but not all, MopB homologs.бА0АкА0АаАCDDбАаАжKвА0А0АаАВocd02779, MopB_CT_Arsenite-Ox, This CD contains the molybdopterin_binding C-terminal (MopB_CT) region of Arsenite oxidase (Arsenite-Ox) and related proteins. Arsenite oxidase oxidizes arsenite to the less toxic arsenate; it transfers the electrons obtained from the oxidation of arsenite towards the soluble periplasmic electron carriers cytochrome c and/or amicyanin.бА0АкА0АаАCDDбАаАжLвА0А0АаАБ№cd02780, MopB_CT_Tetrathionate_Arsenate-R, This CD contains the molybdopterin_binding C-terminal (MopB_CT) region of tetrathionate reductase, subunit A, (TtrA); respiratory arsenate As(V) reductase, catalytic subunit (ArrA); and other related proteins.бА0АкА0АаАCDDбАаАжMвА0А0АаАВЩcd02781, MopB_CT_Acetylene-hydratase, The MopB_CT_Acetylene-hydratase CD contains acetylene hydratase (Ahy) and other related proteins. The acetylene hydratase of Pelobacter acetylenicus is a tungsten iron-sulfur protein involved in the fermentation of acetylene to ethanol and acetate. This CD is of the conserved molybdopterin_binding C-terminal (MopB_CT) region present in many, but not all, MopB homologs.бА0АкА0АаАCDDбАаАжNвА0А0АаАВucd02782, MopB_CT_1, The MopB_CT_1 CD includes a group of related uncharacterized bacterial molybdopterin-binding oxidoreductase-like domains with a putative N-terminal iron-sulfur [4Fe-4S] cluster binding site and molybdopterin cofactor binding site. This CD is of the conserved molybdopterin_binding C-terminal (MopB_CT) region present in many, but not all, MopB homologs.бА0АкА0АаАCDDбАаАжOвА0А0АаАВВcd02783, MopB_CT_2, The MopB_CT_2 CD includes a group of related uncharacterized bacterial and archaeal molybdopterin-binding oxidoreductase-like domains with a putative N-terminal iron-sulfur [4Fe-4S] cluster binding site and molybdopterin cofactor binding site. This CD is of the conserved molybdopterin_binding C-terminal (MopB_CT) region present in many, but not all, MopB homologs.бА0АкА0АаАCDDбАаАжPвА0А0АаАВвА0А0АаАВ┐cd02883, Nudix_Hydrolase, Nudix hydrolase is a superfamily of enzymes found in all three kingdoms of life, and it catalyzes the hydrolysis of NUcleoside DIphosphates linked to other moieties, X. Enzymes belonging to this superfamily require a divalent cation, such as Mg2+ or Mn2+ for their activity. Members of this family are recognized by a highly conserved 23-residue nudix motif (GX5EX7REUXEEXGU, where U = I, L or V), which forms a structural motif that functions as a metal binding and catalytic site. Substrates of nudix hydrolase include intact and oxidatively damaged nucleoside triphosphates, dinucleoside polyphosphates, nucleotide-sugars and dinucleotide enzymes. These substrates are metabolites or cell signaling molecules that require regulation during different stages of the cell cycle or during periods of stress. In general, the role of the nudix hydrolase is to sanitize the nucleotide pools and to maintain cell viability, thereby serving as surveillance and "house-cleaning" enzymes. Substrate specificity is used to define child families within the superfamily. Differences in substrate specificity are determined by the N-terminal extension or by residues in variable loop regions. Mechanistically, substrate hydrolysis occurs by a nucleophilic substitution reaction, with variation in the numbers and roles of divalent cations required. This superfamily consists of at least nine families: IPP (isopentenyl diphosphate) isomerase, ADP ribose pyrophosphatase, mutT pyrophosphohydrolase, coenzyme-A pyrophosphatase, MTH1-7,8-dihydro-8-oxoguanine-triphosphatase, diadenosine tetraphosphate hydrolase, NADH pyrophosphatase, GDP-mannose hydrolase and the c-terminal portion of the mutY adenine glycosylase.бА0АкА0АаАCDDбАаАжqвА0А0АаАВYcd02885, IPP_Isomerase, Isopentenyl diphosphate (IPP) isomerase, a member of the Nudix hydrolase superfamily, is a key enzyme in the isoprenoid biosynthetic pathway. Isoprenoids comprise a large family of natural products including sterols, carotenoids, dolichols and prenylated proteins. These compounds are synthesized from two precursors: isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP). IPP isomerase catalyzes the interconversion of IPP and DMAPP by a stereoselective antarafacial transposition of hydrogen. The enzyme requires one Mn2+ or Mg2+ ion in its active site to fold into an active conformation and also contains the Nudix motif, a highly conserved 23-residue block (GX5EX7REUXEEXGU, where U = I, L or V), that functions as a metal binding and catalytic site. The metal binding site is present within the active site and plays structural and catalytical roles. IPP isomerase is well represented in several bacteria, archaebacteria and eukaryotes, including fungi, mammals and plants. Despite sequence variations (mainly at the N-terminus), the core structure is highly conserved.бА0АкА0АаАCDDбАаАжrвА0А0АаАВПcd02888, RNR_II_dimer, Class II ribonucleotide reductase, dimeric form. Ribonucleotide reductase (RNR) catalyzes the reductive synthesis of deoxyribonucleotides from their corresponding ribonucleotides. It provides the precursors necessary for DNA synthesis. RNRs are separated into three classes based on their metallocofactor usage. Class I RNRs, found in eukaryotes, bacteria, and bacteriophage, use a diiron-tyrosyl radical. Class II RNRs, found in bacteria, bacteriophage, algae and archaea, use coenzyme B12 (adenosylcobalamin, AdoCbl). Class III RNRs, found in anaerobic bacteria, bacteriophage, and archaea, use an FeS cluster and S-adenosylmethionine to generate a glycyl radical. Many organisms have more than one class of RNR present in their genomes. All three RNRs have a ten-stranded alpha-beta barrel domain that is structurally similar to the domain of PFL (pyruvate formate lyase). Class II RNRs are found in bacteria that can live under both aerobic and anaerobic conditions. Many, but not all members of this class are found to be homodimers. Adenosylcobalamin interacts directly with an active site cysteine to form the reactive cysteine radical.бА0АкА0АаАCDDбАаАVвА0А0АаАВ┐cd02889, SQCY, Squalene cyclase (SQCY) domain; found in class II terpene cyclases that have an alpha 6 - alpha 6 barrel fold. Squalene cyclase (SQCY) and 2,3-oxidosqualene cyclase (OSQCY) are integral membrane proteins that catalyze a cationic cyclization cascade converting linear triterpenes to fused ring compounds. Bacterial SQCY catalyzes the convertion of squalene to hopene or diplopterol. Eukaryotic OSQCY transforms the 2,3-epoxide of squalene to compounds such as, lanosterol (a metabolic precursor of cholesterol and steroid hormones) in mammals and fungi or, cycloartenol in plants. Deletion of a single glycine residue of Alicyclobacillus acidocaldarius SQCY alters its substrate specificity into that of eukaryotic OSQCY. Both enzymes have a second minor domain, which forms an alpha-alpha barrel that is inserted into the major domain. This group also contains SQCY-like archael sequences and some bacterial SQCY's which lack this minor domain.бА0АкА0АаАCDDбАаАжsвА0А0АаАВўcd02890, PTase, Protein prenyltransferase (PTase) domain, beta subunit (alpha 6 - alpha 6 barrel fold). The protein prenyltransferase family of lipid-modifying enzymes includes protein farnesyltransferase (FTase) and geranylgeranyltransferase types I and II (GGTase-I and GGTase-II). They catalyze the carboxyl-terminal lipidation of Ras, Rab, and several other cellular signal transduction proteins, facilitating membrane associations and specific protein-protein interactions. Prenyltransferases employ a Zn2+ ion to alkylate a thiol group catalyzing the formation of thioether linkages between the C1 atom of farnesyl (15-carbon by FTase) or geranylgeranyl (20-carbon by GGTase-I, II) isoprenoid lipids and cysteine residues at or near the C-terminus of protein acceptors. FTase and GGTase-I prenylate the cysteine in the terminal sequence, "CAAX"; and GGTase-II prenylates both cysteines in the "CC" (or "CXC") terminal sequence. These enzymes are heterodimeric with both alpha and beta subunits required for catalytic activity. In contrast to other prenyltransferases, GGTase-II does not recognize its protein acceptor directly but requires Rab to complex with REP (Rab escort protein) before prenylation can occur. These enzymes are found exclusively in eukaryotes.бА0АкА0АаАCDDбАаАжtвА0А0АаАВсcd02891, A2M_like, Proteins similar to alpha2-macroglobulin (alpha (2)-M). Alpha (2)-M is a major carrier protein in serum. It is a broadly specific proteinase inhibitor. The structural thioester of alpha (2)-M, is involved in the immobilization and entrapment of proteases. This group contains another broadly specific proteinase inhibitor: pregnancy zone protein (PZP). PZP is a trace protein in the plasma of non-pregnant females and males which is elevated in pregnancy. Alpha (2)-M and PZ bind to placental protein-14 and may modulate its activity in T-cell growth and cytokine production thereby protecting the allogeneic fetus from attack by the maternal immune system. This group also contains C3, C4 and C5 of vertebrate complement. The vertebrate complement is an effector of both the acquired and innate immune systems The point of convergence of the classical, alternative and lectin pathways of the complement system is the proteolytic activation of C3. C4 plays a key role in propagating the classical and lectin pathways. C5 participates in the classical and alternative pathways. The thioester bond located within the structure of C3 and C4 is central to the function of complement. C5 does not contain an active thioester bond.бА0АкА0АаАCDDбАаАжuвА0А0АаАВGcd02892, SQCY_1, Squalene cyclase (SQCY) domain subgroup 1; found in class II terpene cyclases that have an alpha 6 - alpha 6 barrel fold. Squalene cyclase (SQCY) and 2,3-oxidosqualene cyclase (OSQCY) are integral membrane proteins that catalyze a cationic cyclization cascade converting linear triterpenes to fused ring compounds. This group contains bacterial SQCY which catalyzes the convertion of squalene to hopene or diplopterol and eukaryotic OSQCY which transforms the 2,3-epoxide of squalene to compounds such as, lanosterol in mammals and fungi or, cycloartenol in plants. Deletion of a single glycine residue of Alicyclobacillus acidocaldarius SQCY alters its substrate specificity into that of eukaryotic OSQCY. Both enzymes have a second minor domain, which forms an alpha-alpha barrel that is inserted into the major domain.бА0АкА0АаАCDDбАаАжvвА0А0АаАВtcd02893, FTase, Protein farnesyltransferase (FTase)_like proteins containing the protein prenyltransferase (PTase) domain, beta subunit (alpha 6 - alpha 6 barrel fold). FTases are a subgroup of PTase family of lipid-modifying enzymes. PTases catalyze the carboxyl-terminal lipidation of Ras, Rab, and several other cellular signal transduction proteins, facilitating membrane associations and specific protein-protein interactions. These proteins are heterodimers of alpha and beta subunits. Both subunits are required for catalytic activity. Prenyltransferases employ a Zn2+ ion to alkylate a thiol group catalyzing the formation of thioether linkages between cysteine residues at or near the C-terminus of protein acceptors and the C1 atom of isoprenoid lipids. Ftase attaches a 15-carbon farnesyl group to the cysteine within the C-terminal CaaX motif of substrate proteins when X is Ala, Met, Ser, Cys or Gln. Protein farnesylation has been shown to play critical roles in a variety of cellular processes including Ras/mitogen activated protein kinase signaling pathways in mammals and, abscisic acid signal transduction in Arabidopsis.бА0АкА0АаАCDDбАаАжwвА0А0АаАВФcd02894, GGTase-II, Geranylgeranyltransferase type II (GGTase-II)_like proteins containing the protein prenyltransferase (PTase) domain, beta subunit (alpha 6 - alpha 6 barrel fold). GGTase-IIs are a subgroup of the protein prenyltransferase family of lipid-modifying enzymes. PTases catalyze the carboxyl-terminal lipidation of Ras, Rab, and several other cellular signal transduction proteins, facilitating membrane associations and specific protein-protein interactions. Prenyltransferases employ a Zn2+ ion to alkylate a thiol group catalyzing the formation of thioether linkages between cysteine residues at or near the C-terminus of protein acceptors and the C1 atom of isoprenoid lipids (geranylgeranyl (20-carbon) in the case of GGTase-II ). GGTase-II catalyzes alkylation of both cysteine residues in Rab proteins containing carboxy-terminal "CC", "CXCX" or "CXC" motifs. PTases are heterodimeric with both alpha and beta subunits required for catalytic activity. In contrast to other prenyltransferases, GGTas-II requires an escort protein to bring the substrate protein to the catalytic heterodimer and to escort the geryanylgeranylated product to the membrane.бА0АкА0АаАCDDбАаАжxвА0А0АаАВ cd02895, GGTase-I, Geranylgeranyltransferase types I (GGTase-I)-like proteins containing the protein prenyltransferase (PTase) domain, beta subunit (alpha 6 - alpha 6 barrel fold). GGTase-I s are a subgroup of the protein prenyltransferase family of lipid-modifying enzymes PTases catalyze the carboxyl-terminal lipidation of Ras, Rab, and several other cellular signal transduction proteins, facilitating membrane associations and specific protein-protein interactions. Prenyltransferases employ a Zn2+ ion to alkylate a thiol group catalyzing the formation of thioether linkages between cysteine residues at or near the C-terminus of protein acceptors and the C1 atom of isoprenoid lipids (geranylgeranyl (20-carbon) in the case of GGTase-I ). GGTase-I prenylates the cysteine in the terminal sequence, "CAAX" when X is Leu or Phe. Substrates for GTTase-I include the gamma subunit of neural G-proteins and several Ras-related G-proteins. PTases are heterodimeric with both alpha and beta subunits required for catalytic activity.бА0АкА0АаАCDDбАаАжyвА0А0АаАВФcd02896, complement_C3_C4_C5, Proteins similar to C3, C4 and C5 of vertebrate complement. The vertebrate complement system, comprised of a large number of distinct plasma proteins, is an effector of both the acquired and innate immune systems. The point of convergence of the classical, alternative and lectin pathways of the complement system is the proteolytic activation of C3. C4 plays a key role in propagating the classical and lectin pathways. C5 participates in the classical and alternative pathways. The thioester bond located within the structure of C3 and C4 is central to the function of complement. C5 does not contain an active thioester bond.бА0АкА0АаАCDDбАаАжzвА0А0АаАВэcd02897, A2M_2, Proteins similar to alpha2-macroglobulin (alpha (2)-M). This group also contains the pregnancy zone protein (PZP). Alpha(2)-M and PZP are broadly specific proteinase inhibitors. Alpha (2)-M is a major carrier protein in serum. The structural thioester of alpha (2)-M, is involved in the immobilization and entrapment of proteases. PZP is a trace protein in the plasma of non-pregnant females and males which is elevated in pregnancy. Alpha (2)-M and PZ bind to placental protein-14 and may modulate its activity in T-cell growth and cytokine production contributing to fetal survival. It has been suggested that thioester bond cleavage promotes the binding of PZ and alpha (2)-M to the CD91 receptor clearing them from circulation.бА0АкА0АаАCDDбАаАж{вА0А0АаАВ"cd02899, PLAT_SR, Scavenger receptor protein. A subfamily of PLAT (Polycystin-1, Lipoxygenase, Alpha-Toxin) domain or LH2 (Lipoxygenase homology 2) domain. It consists of an eight stranded beta-barrel. The domain can be found in various domain architectures, in case of lipoxygenases, alpha toxin, lipases and polycystin, but also as a single domain or as repeats.The putative function of this domain is to facilitate access to sequestered membrane or micelle bound substrates. This subfamily contains Toxoplasma gondii Scavenger protein TgSR1.бА0АкА0АаАCDDбАаАж|вА0А0АаАВ}cd02900, Macro_Appr_pase, Macro domain, Appr-1"-pase family. The macro domain is a high-affinity ADP-ribose binding module found in a variety of proteins as a stand-alone domain or in combination with other domains like in histone macroH2A and some PARPs (poly ADP-ribose polymerases). Some macro domains recognize poly ADP-ribose as a ligand. The yeast protein Ymx7 and related proteins in this family contain a stand-alone macro domain and may be specific phosphatases catalyzing the conversion of ADP-ribose-1"-monophosphate (Appr-1"-p) to ADP-ribose. Appr-1"-p is an intermediate in a metabolic pathway involved in pre-tRNA splicing.бА0АкА0АаАCDDбАаАж}вА0А0АаАВОcd02901, Macro_Poa1p_like, Macro domain, Poa1p_like family. The macro domain is a high-affinity ADP-ribose binding module found in a variety of proteins as a stand-alone domain or in combination with other domains like in histone macroH2A and some PARPs (poly ADP-ribose polymerases). Some macro domains recognize poly ADP-ribose as a ligand. Previously identified as displaying an Appr-1"-p (ADP-ribose-1"-monophosphate) processing activity, the macro domain may play roles in distinct ADP-ribose pathways, such as the ADP-ribosylation of proteins, an important post-translational modification which occurs in DNA repair, transcription, chromatin biology, and long-term memory formation, among other processes. Members of this family show similarity to the yeast protein Poa1p, reported to be a phosphatase specific for Appr-1"-p, a tRNA splicing metabolite. Poa1p may play a role in tRNA splicing regulation.бА0АкА0АаАCDDбАаАж~вА0А0АаАВЯcd02903, Macro_BAL_like, Macro domain, BAL_like family. The macro domain is a high-affinity ADP-ribose binding module found in a variety of proteins as a stand-alone domain or in combination with other domains like in histone macroH2A and some PARPs (poly ADP-ribose polymerases). Some macro domains recognize poly ADP-ribose as a ligand. Previously identified as displaying an Appr-1"-p (ADP-ribose-1"-monophosphate) processing activity, the macro domain may play roles in distinct ADP-ribose pathways, such as the ADP-ribosylation of proteins, an important post-translational modification which occurs in DNA repair, transcription, chromatin biology, and long-term memory formation, among other processes. Members of this family show similarity to BAL (B-aggressive lymphoma) proteins, which contain one to three macro domains. Most BAL family macro domains belong to this family except for the most N-terminal domain in multiple-domain containing proteins. Most BAL proteins also contain a C-terminal PARP active site and are also named as PARPs. Human BAL1 (or PARP-9) was originally identified as a risk-related gene in diffuse large B-cell lymphoma that promotes malignant B-cell migration. Some BAL family proteins exhibit PARP activity. Poly (ADP-ribosyl)ation is an immediate DNA-damage-dependent post-translational modification of histones and other nuclear proteins. BAL proteins may also function as transcription repressors.бА0АкА0АаАCDDбАаАжвА0А0АаАВ.cd02904, Macro_H2A_like, Macro domain, Macro_H2A_like family. The macro domain is a high-affinity ADP-ribose binding module found in a variety of proteins as a stand-alone domain or in combination with other domains like in histone macroH2A and some PARPs (poly ADP-ribose polymerases). Some macro domains recognize poly ADP-ribose as a ligand. Previously identified as displaying an Appr-1"-p (ADP-ribose-1"-monophosphate) processing activity, the macro domain may play roles in distinct ADP-ribose pathways, such as the ADP-ribosylation of proteins, an important post-translational modification which occurs in DNA repair, transcription, chromatin biology, and long-term memory formation, among other processes. Members of this family are similar to macroH2A, a variant of the major-type core histone H2A, which contains an N-terminal H2A domain and a C-terminal nonhistone macro domain. Histone macroH2A is enriched on the inactive X chromosome of mammalian female cells. It does not bind poly ADP-ribose, but does bind the monomeric SirT1 metabolite O-acetyl-ADP-ribose (OAADPR) with high affinity through its macro domain. In addition, the macro domain of macroH2A associates with histone deacetylases and affects the acetylation status of nucleosomes. MacroH2A-containing nucleosomes are repressive toward transcription.бА0АкА0АаАCDDбАаАжАвА0А0АаАВ=cd02905, Macro_GDAP2_like, Macro domain, GDAP2_like family. The macro domain is a high-affinity ADP-ribose binding module found in a variety of proteins as a stand-alone domain or in combination with other domains like in histone macroH2A and some PARPs (poly ADP-ribose polymerases). Some macro domains recognize poly ADP-ribose as a ligand. Previously identified as displaying an Appr-1"-p (ADP-ribose-1"-monophosphate) processing activity, the macro domain may play roles in distinct ADP-ribose pathways, such as the ADP-ribosylation of proteins, an important post-translational modification which occurs in DNA repair, transcription, chromatin biology, and long-term memory formation, among other processes. This family contains proteins similar to human GDAP2, the ganglioside induced differentiation associated protein 2, whose gene is expressed at a higher level in differentiated Neuro2a cells compared with non-differentiated cells. GDAP2 contains an N-terminal macro domain and a C-terminal Sec14p-like lipid binding domain. It is specifically expressed in brain and testis.бА0АкА0АаАCDDбАаАжБвА0А0АаАВxcd02906, Macro_1, Macro domain, Unknown family 1. The macro domain is a high-affinity ADP-ribose binding module found in a variety of proteins as a stand-alone domain or in combination with other domains like in histone macroH2A and some PARPs (poly ADP-ribose polymerases). Some macro domains recognize poly ADP-ribose as a ligand. Previously identified as displaying an Appr-1"-p (ADP-ribose-1"-monophosphate) processing activity, the macro domain may play roles in distinct ADP-ribose pathways, such as the ADP-ribosylation of proteins, an important post-translational modification which occurs in DNA repair, transcription, chromatin biology, and long-term memory formation, among other processes. This family is composed of uncharacterized proteins containing a macro domain, either as a stand-alone domain or in addition to a C-terminal SIR2 (silent information regulator 2) domain.бА0АкА0АаАCDDбАаАжВвА0А0АаАВcd02907, Macro_Af1521_BAL_like, Macro domain, Af1521- and BAL-like family. The macro domain is a high-affinity ADP-ribose binding module found in a variety of proteins as a stand-alone domain or in combination with other domains like in histone macroH2A and some PARPs (poly ADP-ribose polymerases). Some macro domains recognize poly ADP-ribose as a ligand. Previously identified as an Appr-1"-p (ADP-ribose-1"-monophosphate) processing activity, the macro domain may play roles in distinct ADP-ribose pathways, such as the ADP-ribosylation of proteins, an important post-translational modification which occurs in DNA repair, transcription, chromatin biology, and long-term memory formation, among other processes. The macro domains in this family show similarity to Af1521, a protein from Archaeoglobus fulgidus containing a stand-alone macro domain. Af1521 binds ADP-ribose and exhibits phosphatase activity toward Appr-1"-p. Also included in this family are the N-terminal (or first) macro domains of BAL (B-aggressive lymphoma) proteins which contain multiple macro domains. Most BAL proteins also contain a C-terminal PARP active site and are also named as PARPs. Human BAL1 (or PARP-9) was originally identified as a risk-related gene in diffuse large B-cell lymphoma that promotes malignant B-cell migration. Some BAL family proteins exhibit PARP activity. Poly (ADP-ribosyl)ation is an immediate DNA-damage-dependent post-translational modification of histones and other nuclear proteins. BAL proteins may also function as transcription repressors.бА0АкА0АаАCDDбАаАжГвА0А0АаАВиcd02908, Macro_Appr_pase_like, Macro domain, Appr-1"-pase_like family. The macro domain is a high-affinity ADP-ribose binding module found in a variety of proteins as a stand-alone domain or in combination with other domains like in histone macroH2A and some PARPs (poly ADP-ribose polymerases). Some macro domains recognize poly ADP-ribose as a ligand. Previously identified as displaying an Appr-1"-p (ADP-ribose-1"-monophosphate) processing activity, the macro domain may play roles in distinct ADP-ribose pathways, such as the ADP-ribosylation of proteins, an important post-translational modification which occurs in DNA repair, transcription, chromatin biology, and long-term memory formation, among other processes. This family is composed of uncharacterized proteins that show similarity to Appr-1"-pase, containing conserved putative active site residues. Appr-1"-pase is a phosphatase specific for ADP-ribose-1"-monophosphate.бА0АкА0АаАCDDбАаАжДвА0А0АаАВМcd02911, arch_FMN, Archeal FMN-binding domain. This family of archaeal proteins are part of the NAD(P)H-dependent flavin oxidoreductase (oxidored) FMN-binding family that reduce a range of alternative electron acceptors. Most use FAD/FMN as a cofactor and NAD(P)H as electron donor. Some contain 4Fe-4S cluster to transfer electron from FAD to FMN. The specific function of this group is unknown.бА0АкА0АаАCDDбАаАжЕвА0А0АаАВ7cd02922, FCB2_FMN, Flavocytochrome b2 (FCB2) FMN-binding domain. FCB2 (AKA L-lactate:cytochrome c oxidoreductase) is a respiratory enzyme located in the intermembrane space of fungal mitochondria which catalyzes the oxidation of L-lactate to pyruvate. FCB2 also participates in a short electron-transport chain involving cytochrome c and cytochrome oxidase which ultimately directs the reducing equivalents gained from L-lactate oxidation to oxygen, yielding one molecule of ATP for every L-lactate molecule consumed. FCB2 is composed of 2 domains: a C-terminal flavin-binding domain, which includes the active site for lacate oxidation, and an N-terminal b2-cytochrome domain, required for efficient cytochrome c reduction. FCB2 is a homotetramer and contains two noncovalently bound cofactors, FMN and heme per subunit.бА0АкА0АаАCDDбАаАжЖвА0А0АаАВоcd02929, TMADH_HD_FMN, Trimethylamine dehydrogenase (TMADH) and histamine dehydrogenase (HD) FMN-binding domain. TMADH is an iron-sulfur flavoprotein that catalyzes the oxidative demethylation of trimethylamine to form dimethylamine and formaldehyde. The protein forms a symetrical dimer with each subunit containing one 4Fe-4S cluster and one FMN cofactor. It contains a unique flavin, in the form of a 6-S-cysteinyl FMN which is bent by ~25 degrees along the N5-N10 axis of the flavin isoalloxazine ring. This modification of the conformation of the flavin is thought to facilitate catalysis.The closely related histamine dehydrogenase catalyzes oxidative deamination of histamine.бА0АкА0АаАCDDбАаАжЗвА0А0АаАВЦcd02930, DCR_FMN, 2,4-dienoyl-CoA reductase (DCR) FMN-binding domain. DCR in E. coli is an iron-sulfur flavoenzyme which contains FMN, FAD, and a 4Fe-4S cluster. It is also a monomer, unlike that of its eukaryotic counterparts which form homotetramers and lack the flavin and iron-sulfur cofactors. Metabolism of unsaturated fatty acids requires auxiliary enzymes in addition to those used in b-oxidation. After a given number of cycles through the b-oxidation pathway, those unsaturated fatty acyl-CoAs with double bonds at even-numbered carbon positions contain 2-trans, 4-cis double bonds that can not be modified by enoyl-CoA hydratase. DCR utilizes NADPH to remove the C4-C5 double bond. DCR can catalyze the reduction of both natural fatty acids with cis double bonds, as well as substrates containing trans double bonds. The reaction is initiated by hybrid transfer from NADPH to FAD, which in turn transfers electrons, one at a time, to FMN via the 4Fe-4S cluster. The fully reduced FMN provides a hydrid ion to the C5 atom of substrate, and Tyr and His are proposed to form a catalytic dyad that protonates the C4 atom of the substrate and completes the reaction.бА0АкА0АаАCDDбАаАжИвА0А0АаАВОcd02931, ER_like_FMN, Enoate reductase (ER)-like FMN-binding domain. Enoate reductase catalyzes the NADH-dependent reduction of carbon-carbon double bonds of several molecules, including nonactivated 2-enoates, alpha,beta-unsaturated aldehydes, cyclic ketones, and methylketones. ERs are similar to 2,4-dienoyl-CoA reductase from E. coli and to the old yellow enzyme from Saccharomyces cerevisiae.бА0АкА0АаАCDDбАаАжЙвА0А0АаАВecd02932, OYE_YqiM_FMN, Old yellow enzyme (OYE) YqjM-like FMN binding domain. YqjM is involved in the oxidative stress response of Bacillus subtilis. Like the other OYE members, each monomer of YqjM contains FMN as a non-covalently bound cofactor and uses NADPH as a reducing agent. The YqjM enzyme exists as a homotetramer that is assembled as a dimer of catalytically dependent dimers, while other OYE members exist only as monomers or dimers. Moreover, the protein displays a shared active site architecture where an arginine finger at the COOH terminus of one monomer extends into the active site of the adjacent monomer and is directly involved in substrate recognition. Another remarkable difference in the binding of the ligand in YqjM is represented by the contribution of the NH2-terminal tyrosine instead of a COOH-terminal tyrosine in OYE and its homologs.бА0АкА0АаАCDDбАаАжКвА0А0АаАВ:cd02933, OYE_like_FMN, Old yellow enzyme (OYE)-like FMN binding domain. OYE was the first flavin-dependent enzyme identified, however its true physiological role remains elusive to this day. Each monomer of OYE contains FMN as a non-covalently bound cofactor, uses NADPH as a reducing agent with oxygens, quinones, and alpha,beta-unsaturated aldehydes and ketones, and can act as electron acceptors in the catalytic reaction. Members of OYE family include 12-oxophytodienoate reductase, pentaerythritol tetranitrate reductase, morphinone reductase, and related enzymes.бА0АкА0АаАCDDбАаАжЛвА0А0АаАВ╙cd02940, DHPD_FMN, Dihydropyrimidine dehydrogenase (DHPD) FMN-binding domain. DHPD catalyzes the first step in pyrimidine degradation: the NADPH-dependent reduction of uracil and thymine to the corresponding 5,6-dihydropyrimidines. DHPD contains two FAD, two FMN, and eight [4Fe-4S] clusters, arranged in two electron transfer chains that pass the dimer interface twice. Two of the Fe-S clusters show a hitherto unobserved coordination involving a glutamine residue.бА0АкА0АаАCDDбАаАжМвА0А0АаАВYcd02947, TRX_family, TRX family; composed of two groups: Group I, which includes proteins that exclusively encode a TRX domain; and Group II, which are composed of fusion proteins of TRX and additional domains. Group I TRX is a small ancient protein that alter the redox state of target proteins via the reversible oxidation of an active site dithiol, present in a CXXC motif, partially exposed at the protein's surface. TRX reduces protein disulfide bonds, resulting in a disulfide bond at its active site. Oxidized TRX is converted to the active form by TRX reductase, using reducing equivalents derived from either NADPH or ferredoxins. By altering their redox state, TRX regulates the functions of at least 30 target proteins, some of which are enzymes and transcription factors. It also plays an important role in the defense against oxidative stress by directly reducing hydrogen peroxide and certain radicals, and by serving as a reductant for peroxiredoxins. At least two major types of functional TRXs have been reported in most organisms; in eukaryotes, they are located in the cytoplasm and the mitochondria. Higher plants contain more types (at least 20 TRX genes have been detected in the genome of Arabidopsis thaliana), two of which (types f amd m) are located in the same compartment, the chloroplast. Also included in the alignment are TRX-like domains which show sequence homology to TRX but do not contain the redox active CXXC motif. Group II proteins, in addition to either a redox active TRX or a TRX-like domain, also contain additional domains, which may or may not possess homology to known proteins.бА0АкА0АаАCDDбАаАжНвА0А0АаАВcd02948, TRX_NDPK, TRX domain, TRX and NDP-kinase (NDPK) fusion protein family; most members of this group are fusion proteins which contain one redox active TRX domain containing a CXXC motif and three NDPK domains, and are characterized as intermediate chains (ICs) of axonemal outer arm dynein. Dyneins are molecular motors that generate force against microtubules to produce cellular movement, and are divided into two classes: axonemal and cytoplasmic. They are supramolecular complexes consisting of three protein groups classified according to size: dynein heavy, intermediate and light chains. Axonemal dyneins form two structures, the inner and outer arms, which are attached to doublet microtubules throughout the cilia and flagella. The human homolog is the sperm-specific Sptrx-2, presumed to be a component of the human sperm axoneme architecture. Included in this group is another human protein, TRX-like protein 2, a smaller fusion protein containing one TRX and one NDPK domain, which is also associated with microtubular structures. The other members of this group are hypothetical insect proteins containing a TRX domain and outer arm dynein light chains (14 and 16kDa) of Chlamydomonas reinhardtii. Using standard assays, the fusion proteins have shown no TRX enzymatic activity.бА0АкА0АаАCDDбАаАжОвА0А0АаАВкcd02949, TRX_NTR, TRX domain, novel NADPH thioredoxin reductase (NTR) family; composed of fusion proteins found only in oxygenic photosynthetic organisms containing both TRX and NTR domains. The TRX domain functions as a protein disulfide reductase via the reversible oxidation of an active center dithiol present in a CXXC motif, while the NTR domain functions as a reductant to oxidized TRX. The fusion protein is bifunctional, showing both TRX and NTR activities, but it is not an independent NTR/TRX system. In plants, the protein is found exclusively in shoots and mature leaves and is localized in the chloroplast. It is involved in plant protection against oxidative stress.бА0АкА0АаАCDDбАаАжПвА0А0АаАВЩcd02950, TxlA, TRX-like protein A (TxlA) family; TxlA was originally isolated from the cyanobacterium Synechococcus. It is found only in oxygenic photosynthetic organisms. TRX is a small enzyme that participate in redox reactions, via the reversible oxidation of an active site dithiol present in a CXXC motif. Disruption of the txlA gene suggests that the protein is involved in the redox regulation of the structure and function of photosynthetic apparatus. The plant homolog (designated as HCF164) is localized in the chloroplast and is involved in the assembly of the cytochrome b6f complex, which takes a central position in photosynthetic electron transport.бА0АкА0АаАCDDбАаАжРвА0А0АаАВAcd02951, SoxW, SoxW family; SoxW is a bacterial periplasmic TRX, containing a redox active CXXC motif, encoded by a genetic locus (sox operon) involved in thiosulfate oxidation. Sulfur bacteria oxidize sulfur compounds to provide reducing equivalents for carbon dioxide fixation during autotrophic growth and the respiratory electron transport chain. It is unclear what the role of SoxW is, since it has been found to be dispensable in the oxidation of thiosulfate to sulfate. SoxW is specifically kept in the reduced state by SoxV, which is essential in thiosulfate oxidation.бА0АкА0АаАCDDбАаАжСвА0А0АаАВ─cd02952, TRP14_like, Human TRX-related protein 14 (TRP14)-like family; composed of proteins similar to TRP14, a 14kD cytosolic protein that shows disulfide reductase activity in vitro with a different substrate specificity compared with another human cytosolic protein, TRX1. TRP14 catalyzes the reduction of small disulfide-containing peptides but does not reduce disulfides of ribonucleotide reductase, peroxiredoxin and methionine sulfoxide reductase, which are TRX1 substrates. TRP14 also plays a role in tumor necrosis factor (TNF)-alpha signaling pathways, distinct from that of TRX1. Its depletion promoted TNF-alpha induced activation of c-Jun N-terminal kinase and mitogen-activated protein kinases.бА0АкА0АаАCDDбАаАжТвА0А0АаАВrcd02953, DsbDgamma, DsbD gamma family; DsbD gamma is the C-terminal periplasmic domain of the bacterial protein DsbD. It contains a CXXC motif in a TRX fold and shuttles the reducing potential from the membrane domain (DsbD beta) to the N-terminal periplasmic domain (DsbD alpha). DsbD beta, a transmembrane domain comprising of eight helices, acquires its reducing potential from the cytoplasmic thioredoxin. DsbD alpha transfers the acquired reducing potential from DsbD gamma to target proteins such as the periplasmic protein disulphide isomerases, DsbC and DsbG. This flow of reducing potential from the cytoplasm through DsbD allows DsbC and DsbG to act as isomerases in the oxidizing environment of the bacterial periplasm. DsbD also transfers reducing potential from the cytoplasm to specific reductases in the periplasm which are involved in the maturation of cytochromes.бА0АкА0АаАCDDбАаАжУвА0А0АаАВcd02954, DIM1, Dim1 family; Dim1 is also referred to as U5 small nuclear ribonucleoprotein particle (snRNP)-specific 15kD protein. It is a component of U5 snRNP, which pre-assembles with U4/U6 snRNPs to form a [U4/U6:U5] tri-snRNP complex required for pre-mRNA splicing. Dim1 interacts with multiple splicing-associated proteins, suggesting that it functions at multiple control points in the splicing of pre-mRNA as part of a large spliceosomal complex involving many protein-protein interactions. U5 snRNP contains seven core proteins (common to all snRNPs) and nine U5-specific proteins, one of which is Dim1. Dim1 adopts a thioredoxin fold but does not contain the redox active CXXC motif. It is essential for G2/M phase transition, as a consequence to its role in pre-mRNA splicing.бА0АкА0АаАCDDбАаАжФвА0А0АаАВїcd02955, SSP411, TRX domain, SSP411 protein family; members of this family are highly conserved proteins present in eukaryotes, bacteria and archaea, about 600-800 amino acids in length, which contain a TRX domain with a redox active CXXC motif. The human/rat protein, called SSP411, is specifically expressed in the testis in an age-dependent manner. The SSP411 mRNA is increased during spermiogenesis and is localized in round and elongated spermatids, suggesting a function in fertility regulation.бА0АкА0АаАCDDбАаАжХвА0А0АаАБ└cd02956, ybbN, ybbN protein family; ybbN is a hypothetical protein containing a redox-inactive TRX-like domain. Its gene has been sequenced from several gammaproteobacteria and actinobacteria.бА0АкА0АаАCDDбАаАжЦвА0А0АаАВ│cd02957, Phd_like, Phosducin (Phd)-like family; composed of Phd and Phd-like proteins (PhLP), characterized as cytosolic regulators of G protein functions. Phd and PhLPs specifically bind G protein betagamma (Gbg)-subunits with high affinity, resulting in the solubilization of Gbg from the plasma membrane and impeding G protein-mediated signal transduction by inhibiting the formation of a functional G protein trimer (G protein alphabetagamma). Phd also inhibits the GTPase activity of G protein alpha. Phd can be phosphorylated by protein kinase A and G protein-coupled receptor kinase 2, leading to its inactivation. Phd was originally isolated from the retina, where it is highly expressed and has been implicated to play an important role in light adaptation. It is also found in the pineal gland, liver, spleen, striated muscle and the brain. The C-terminal domain of Phd adopts a thioredoxin fold, but it does not contain a CXXC motif. Phd interacts with G protein beta mostly through the N-terminal helical domain. Also included in this family is a PhLP characterized as a viral inhibitor of apoptosis (IAP)-associated factor, named VIAF, that functions in caspase activation during apoptosis.бА0АкА0АаАCDDбАаАжЧвА0А0АаАВwcd02958, UAS, UAS family; UAS is a domain of unknown function. Most members of this family are uncharacterized proteins with similarity to FAS-associated factor 1 (FAF1) and ETEA because of the presence of a UAS domain N-terminal to a ubiquitin-associated UBX domain. FAF1 is a longer protein, compared to the other members of this family, having additional N-terminal domains, a ubiquitin-associated UBA domain and a nuclear targeting domain. FAF1 is an apoptotic signaling molecule that acts downstream in the Fas signal transduction pathway. It interacts with the cytoplasmic domain of Fas, but not to a Fas mutant that is deficient in signal transduction. ETEA is the protein product of a highly expressed gene in T-cells and eosinophils of atopic dermatitis patients. The presence of the ubiquitin-associated UBX domain in the proteins of this family suggests the possibility of their involvement in ubiquitination. Recently, FAF1 has been shown to interact with valosin-containing protein (VCP), which is involved in the ubiquitin-proteosome pathway. Some members of this family are uncharacterized proteins containing only a UAS domain.бА0АкА0АаАCDDбАаАжШвА0А0АаАВЯcd02959, ERp19, Endoplasmic reticulum protein 19 (ERp19) family; ERp19 is also known as ERp18, a protein located in the ER containing one redox active TRX domain. Denaturation studies indicate that the reduced form is more stable than the oxidized form, suggesting that the protein is involved in disulfide bond formation. In vitro, ERp19 has been shown to possess thiol-disulfide oxidase activity which is dependent on the presence of both active site cysteines. Although described as protein disulfide isomerase (PDI)-like, the protein does not complement for PDI activity. ERp19 shows a wide tissue distribution but is most abundant in liver, testis, heart and kidney.бА0АкА0АаАCDDбАаАжЩвА0А0АаАВ╞cd02960, AGR, Anterior Gradient (AGR) family; members of this family are similar to secreted proteins encoded by the cement gland-specific genes XAG-1 and XAG-2, expressed in the anterior region of dorsal ectoderm of Xenopus. They are implicated in the formation of the cement gland and the induction of forebrain fate. The human homologs, hAG-2 and hAG-3, are secreted proteins associated with estrogen-positive breast tumors. Yeast two-hybrid studies identified the metastasis-associated C4.4a protein and dystroglycan as binding partners, indicating possible roles in the development and progression of breast cancer. hAG-2 has also been implicated in prostate cancer. Its gene was cloned as an androgen-inducible gene and it was shown to be overexpressed in prostate cancer cells at the mRNA and protein levels. AGR proteins contain one conserved cysteine corresponding to the first cysteine in the CXXC motif of TRX. They show high sequence similarity to ERp19.бА0АкА0АаАCDDбАаАжЪвА0А0АаАВїcd02961, PDI_a_family, Protein Disulfide Isomerase (PDIa) family, redox active TRX domains; composed of eukaryotic proteins involved in oxidative protein folding in the endoplasmic reticulum (ER) by acting as catalysts and folding assistants. Members of this family include PDI and PDI-related proteins like ERp72, ERp57 (or ERp60), ERp44, P5, PDIR, ERp46 and the transmembrane PDIs. PDI, ERp57, ERp72, P5, PDIR and ERp46 are all oxidases, catalyzing the formation of disulfide bonds of newly synthesized polypeptides in the ER. They also exhibit reductase activity in acting as isomerases to correct any non-native disulfide bonds, as well as chaperone activity to prevent protein aggregation and facilitate the folding of newly synthesized proteins. These proteins usually contain multiple copies of a redox active TRX (a) domain containing a CXXC motif, and may also contain one or more redox inactive TRX-like (b) domains. Only one a domain is required for the oxidase function but multiple copies are necessary for the isomerase function. The different types of PDIs may show different substrate specificities and tissue-specific expression, or may be induced by stress. PDIs are in their reduced form at steady state and are oxidized to the active form by Ero1, which is localized in the ER through ERp44. Some members of this family also contain a DnaJ domain in addition to the redox active a domains; examples are ERdj5 and Pfj2. Also included in the family is the redox inactive N-terminal TRX-like domain of ERp29.бА0АкА0АаАCDDбАаАжЫвА0А0АаАВscd02962, TMX2, TMX2 family; composed of proteins similar to human TMX2, a 372-amino acid TRX-related transmembrane protein, identified and characterized through the cloning of its cDNA from a human fetal library. It contains a TRX domain but the redox active CXXC motif is replaced with SXXC. Sequence analysis predicts that TMX2 may be a Type I membrane protein, with its C-terminal half protruding on the luminal side of the endoplasmic reticulum (ER). In addition to the TRX domain, transmembrane region and ER-retention signal, TMX2 also contains a Myb DNA-binding domain repeat signature and a dileucine motif in the tail.бА0АкА0АаАCDDбАаАжЬвА0А0АаАВ╬cd02963, TRX_DnaJ, TRX domain, DnaJ domain containing protein family; composed of uncharacterized proteins of about 500-800 amino acids, containing an N-terminal DnaJ domain followed by one redox active TRX domain. DnaJ is a member of the 40 kDa heat-shock protein (Hsp40) family of molecular chaperones, which regulate the activity of Hsp70s. TRX is involved in the redox regulation of many protein substrates through the reduction of disulfide bonds. TRX has been implicated to catalyse the reduction of Hsp33, a chaperone holdase that binds to unfolded protein intermediates. The presence of DnaJ and TRX domains in members of this family suggests that they could be involved in a redox-regulated chaperone network.бА0АкА0АаАCDDбАаАжЭвА0А0АаАВmcd02964, TryX_like_family, Tryparedoxin (TryX)-like family; composed of TryX and related proteins including nucleoredoxin (NRX), rod-derived cone viability factor (RdCVF) and the nematode homolog described as a 16-kD class of TRX. Most members of this family, except RdCVF, are protein disulfide oxidoreductases containing an active site CXXC motif, similar to TRX.бА0АкА0АаАCDDбАаАжЮвА0А0АаАВ▄cd02965, HyaE, HyaE family; HyaE is also called HupG and HoxO. They are proteins serving a critical role in the assembly of multimeric [NiFe] hydrogenases, the enzymes that catalyze the oxidation of molecular hydrogen to enable microorganisms to utilize hydrogen as the sole energy source. The E. coli HyaE protein is a chaperone that specifically interacts with the twin-arginine translocation (Tat) signal peptide of the [NiFe] hydrogenase-1 beta subunit precursor. Tat signal peptides target precursor proteins to the Tat protein export system, which facilitates the transport of fully folded proteins across the inner membrane. HyaE may be involved in regulating the traffic of [NiFe] hydrogenase-1 on the Tat transport pathway.бА0АкА0АаАCDDбАаАжЯвА0А0АаАВУcd02966, TlpA_like_family, TlpA-like family; composed of TlpA, ResA, DsbE and similar proteins. TlpA, ResA and DsbE are bacterial protein disulfide reductases with important roles in cytochrome maturation. They are membrane-anchored proteins with a soluble TRX domain containing a CXXC motif located in the periplasm. The TRX domains of this family contain an insert, approximately 25 residues in length, which correspond to an extra alpha helix and a beta strand when compared with TRX. TlpA catalyzes an essential reaction in the biogenesis of cytochrome aa3, while ResA and DsbE are essential proteins in cytochrome c maturation. Also included in this family are proteins containing a TlpA-like TRX domain with domain architectures similar to E. coli DipZ protein, and the N-terminal TRX domain of PilB protein from Neisseria which acts as a disulfide reductase that can recylce methionine sulfoxide reductases.бА0АкА0АаАCDDбАаАжавА0А0АаАВ╠cd02967, mauD, Methylamine utilization (mau) D family; mauD protein is the translation product of the mauD gene found in methylotrophic bacteria, which are able to use methylamine as a sole carbon source and a nitrogen source. mauD is an essential accessory protein for the biosynthesis of methylamine dehydrogenase (MADH), the enzyme that catalyzes the oxidation of methylamine and other primary amines. MADH possesses an alpha2beta2 subunit structure; the alpha subunit is also referred to as the large subunit. Each beta (small) subunit contains a tryptophan tryptophylquinone (TTQ) prosthetic group. Accessory proteins are essential for the proper transport of MADH to the periplasm, TTQ synthesis and the formation of several structural disulfide bonds. Bacterial mutants containing an insertion on the mauD gene were unable to grow on methylamine as a sole carbon source, were found to lack the MADH small subunit and had decreased amounts of the MADH large subunit.бА0АкА0АаАCDDбАаАжбвА0А0АаАВmcd02968, SCO, SCO (an acronym for Synthesis of Cytochrome c Oxidase) family; composed of proteins similar to Sco1, a membrane-anchored protein possessing a soluble domain with a TRX fold. Members of this family are required for the proper assembly of cytochrome c oxidase (COX). They contain a metal binding motif, typically CXXXC, which is located in a flexible loop. COX, the terminal enzyme in the respiratory chain, is imbedded in the inner mitochondrial membrane of all eukaryotes and in the plasma membrane of some prokaryotes. It is composed of two subunits, COX I and COX II. It has been proposed that Sco1 specifically delivers copper to the CuA site, a dinuclear copper center, of the COX II subunit. Mutations in human Sco1 and Sco2 cause fatal infantile hepatoencephalomyopathy and cardioencephalomyopathy, respectively. Both disorders are associated with severe COX deficiency in affected tissues. More recently, it has been argued that the redox sensitivity of the copper binding properties of Sco1 implies that it participates in signaling events rather than functioning as a chaperone that transfers copper to COX II.бА0АкА0АаАCDDбАаАжввА0А0АаАВцcd02969, PRX_like1, Peroxiredoxin (PRX)-like 1 family; hypothetical proteins that show sequence similarity to PRXs. Members of this group contain a conserved cysteine that aligns to the first cysteine in the CXXC motif of TRX. This does not correspond to the peroxidatic cysteine found in PRXs, which aligns to the second cysteine in the CXXC motif of TRX. In addition, these proteins do not contain the other two conserved residues of the catalytic triad of PRX. PRXs confer a protective antioxidant role in cells through their peroxidase activity in which hydrogen peroxide, peroxynitrate, and organic hydroperoxides are reduced and detoxified using reducing equivalents derived from either thioredoxin, glutathione, trypanothione and AhpF.бА0АкА0АаАCDDбАаАжгвА0А0АаАВ/cd02970, PRX_like2, Peroxiredoxin (PRX)-like 2 family; hypothetical proteins that show sequence similarity to PRXs. Members of this group contain a CXXC motif, similar to TRX. The second cysteine in the motif corresponds to the peroxidatic cysteine of PRX, however, these proteins do not contain the other two residues of the catalytic triad of PRX. PRXs confer a protective antioxidant role in cells through their peroxidase activity in which hydrogen peroxide, peroxynitrate, and organic hydroperoxides are reduced and detoxified using reducing equivalents derived from either thioredoxin, glutathione, trypanothione and AhpF. TRXs alter the redox state of target proteins by catalyzing the reduction of their disulfide bonds via the CXXC motif using reducing equivalents derived from either NADPH or ferredoxins.бА0АкА0АаАCDDбАаАждвА0А0АаАВРcd02971, PRX_family, Peroxiredoxin (PRX) family; composed of the different classes of PRXs including many proteins originally known as bacterioferritin comigratory proteins (BCP), based on their electrophoretic mobility before their function was identified. PRXs are thiol-specific antioxidant (TSA) proteins also known as TRX peroxidases and alkyl hydroperoxide reductase C22 (AhpC) proteins. They confer a protective antioxidant role in cells through their peroxidase activity in which hydrogen peroxide, peroxynitrate, and organic hydroperoxides are reduced and detoxified using reducing equivalents derived from either TRX, glutathione, trypanothione and AhpF. They are distinct from other peroxidases in that they have no cofactors such as metals or prosthetic groups. The first step of catalysis, common to all PRXs, is the nucleophilic attack by the catalytic cysteine (also known as the peroxidatic cysteine) on the peroxide leading to cleavage of the oxygen-oxygen bond and the formation of a cysteine sulfenic acid intermediate. The second step of the reaction, the resolution of the intermediate, distinguishes the different types of PRXs. The presence or absence of a second cysteine (the resolving cysteine) classifies PRXs as either belonging to the 2-cys or 1-cys type. The resolving cysteine of 2-cys PRXs is either on the same chain (atypical) or on the second chain (typical) of a functional homodimer. Structural and motif analysis of this growing family supports the need for a new classification system. The peroxidase activity of PRXs is regulated in vivo by irreversible cysteine over-oxidation into a sulfinic acid, phosphorylation and limited proteolysis.бА0АкА0АаАCDDбАаАжевА0А0АаАВhcd02972, DsbA_family, DsbA family; consists of DsbA and DsbA-like proteins, including DsbC, DsbG, glutathione (GSH) S-transferase kappa (GSTK), 2-hydroxychromene-2-carboxylate (HCCA) isomerase, an oxidoreductase (FrnE) presumed to be involved in frenolicin biosynthesis, a 27-kDa outer membrane protein, and similar proteins. Members of this family contain a redox active CXXC motif (except GSTK and HCCA isomerase) imbedded in a TRX fold, and an alpha helical insert of about 75 residues (shorter in DsbC and DsbG) relative to TRX. DsbA is involved in the oxidative protein folding pathway in prokaryotes, catalyzing disulfide bond formation of proteins secreted into the bacterial periplasm. DsbC and DsbG function as protein disulfide isomerases and chaperones to correct non-native disulfide bonds formed by DsbA and prevent aggregation of incorrectly folded proteins.бА0АкА0АаАCDDбАаАжжвА0А0АаАВTcd02973, TRX_GRX_like, Thioredoxin (TRX)-Glutaredoxin (GRX)-like family; composed of archaeal and bacterial proteins that show similarity to both TRX and GRX, including the C-terminal TRX-fold subdomain of Pyrococcus furiosus protein disulfide oxidoreductase (PfPDO). All members contain a redox-active CXXC motif and may function as PDOs. The archaeal proteins Mj0307 and Mt807 show structures more similar to GRX, but activities more similar to TRX. Some members of the family are similar to PfPDO in that they contain a second CXXC motif located in a second TRX-fold subdomain at the N-terminus; the superimposable N- and C-terminal TRX subdomains form a compact structure. PfPDO is postulated to be the archaeal counterpart of bacterial DsbA and eukaryotic protein disulfide isomerase (PDI). The C-terminal CXXC motif of PfPDO is required for its oxidase, reductase and isomerase activities. Also included in the family is the C-terminal TRX-fold subdomain of the N-terminal domain (NTD) of bacterial AhpF, which has a similar fold as PfPDO with two TRX-fold subdomains but without the second CXXC motif.бА0АкА0АаАCDDбАаАжзвА0А0АаАВ¤cd02974, AhpF_NTD_N, Alkyl hydroperoxide reductase F subunit (AhpF) N-terminal domain (NTD) family, N-terminal TRX-fold subdomain; AhpF is a homodimeric flavoenzyme which catalyzes the NADH-dependent reduction of the peroxiredoxin AhpC, which in turn catalyzes the reduction of hydrogen peroxide and organic hydroperoxides. AhpF contains an NTD forming two contiguous TRX-fold subdomain similar to Pyrococcus furiosus protein disulfide oxidoreductase (PfPDO). It also contains a catalytic core similar to TRX reductase containing FAD and NADH binding domains with an active site disulfide. The proposed mechanism of action of AhpF is similar to a TRX/TRX reductase system. The flow of reducing equivalents goes from NADH -> catalytic core of AhpF -> NTD of AhpF -> AhpC -> peroxide substrates. The N-terminal TRX-fold subdomain of AhpF NTD is redox inactive, but is proposed to contain an important residue that aids in the catalytic function of the redox-active CXXC motif contained in the C-terminal TRX-fold subdomain.бА0АкА0АаАCDDбАаАживА0А0АаАВ═cd02975, PfPDO_like_N, Pyrococcus furiosus protein disulfide oxidoreductase (PfPDO)-like family, N-terminal TRX-fold subdomain; composed of proteins with similarity to PfPDO, a redox active thermostable protein believed to be the archaeal counterpart of bacterial DsbA and eukaryotic protein disulfide isomerase (PDI), which are both involved in oxidative protein folding. PfPDO contains two redox active CXXC motifs in two contiguous TRX-fold subdomains. The active site in the N-terminal TRX-fold subdomain is required for isomerase but not for reductase activity of PfPDO. The exclusive presence of PfPDO-like proteins in extremophiles may suggest that they have a special role in adaptation to extreme conditions.бА0АкА0АаАCDDбАаАжйвА0А0АаАВ.cd02976, NrdH, NrdH-redoxin (NrdH) family; NrdH is a small monomeric protein with a conserved redox active CXXC motif within a TRX fold, characterized by a glutaredoxin (GRX)-like sequence and TRX-like activity profile. In vitro, it displays protein disulfide reductase activity that is dependent on TRX reductase, not glutathione (GSH). It is part of the NrdHIEF operon, where NrdEF codes for class Ib ribonucleotide reductase (RNR-Ib), an efficient enzyme at low oxygen levels. Under these conditions when GSH is mostly conjugated to spermidine, NrdH can still function and act as a hydrogen donor for RNR-Ib. It has been suggested that the NrdHEF system may be the oldest RNR reducing system, capable of functioning in a microaerophilic environment, where GSH was not yet available. NrdH from Corynebacterium ammoniagenes can form domain-swapped dimers, although it is unknown if this happens in vivo. Domain-swapped dimerization, which results in the blocking of the TRX reductase binding site, could be a mechanism for regulating the oxidation state of the protein.бА0АкА0АаАCDDбАаАжквА0А0АаАВ┌cd02977, ArsC_family, Arsenate Reductase (ArsC) family; composed of TRX-fold arsenic reductases and similar proteins including the transcriptional regulator, Spx. ArsC catalyzes the reduction of arsenate [As(V)] to arsenite [As(III)], using reducing equivalents derived from glutathione (GSH) via glutaredoxin (GRX), through a single catalytic cysteine. This family of predominantly bacterial enzymes is unrelated to two other families of arsenate reductases which show similarity to low-molecular-weight acid phosphatases and phosphotyrosyl phosphatases. Spx is a general regulator that exerts negative and positive control over transcription initiation by binding to the C-terminal domain of the alpha subunit of RNA polymerase.бА0АкА0АаАCDDбАаАжлвА0А0АаАВ(cd02978, KaiB_like, KaiB-like family; composed of the circadian clock proteins, KaiB and the N-terminal KaiB-like sensory domain of SasA. KaiB is an essential protein in maintaining circadian rhythm. It was originally discovered from the cyanobacterium Synechococcus as part of the circadian clock gene cluster, kaiABC. KaiB attenuates KaiA-enhanced KaiC autokinase activity by interacting with KaiA-KaiC complexes in a circadian fashion. KaiB is membrane-associated as well as cytosolic. The amount of membrane-associated protein peaks in the evening (at circadian time (CT) 12-16) while the cytosolic form peaks later (at CT 20). The rhythmic localization of KaiB may function in regulating the formation of Kai complexes. SasA is a sensory histidine kinase which associates with KaiC. Although it is not an essential oscillator component, it is important in enhancing kaiABC expression and is important in metabolic growth control under day/night cycle conditions. SasA contains an N-terminal sensory domain with a TRX fold which is involved in the SasA-KaiC interaction. This domain shows high sequence similarity with KaiB. However, the KaiB structure does not show a classical TRX fold. The N-terminal half of KaiB shares the same beta-alpha-beta topology as TRX, but the topology of its C-terminal half diverges.бА0АкА0АаАCDDбАаАжмвА0А0АаАВ5cd02979, PHOX_C, FAD-dependent Phenol hydoxylase (PHOX) family, C-terminal TRX-fold domain; composed of proteins similar to PHOX from the aerobic topsoil yeast Trichosporon cutaneum. PHOX is a flavoprotein monooxygenase that catalyzes the hydroxylation of phenol and simple phenol derivatives in the ortho position with the consumption of NADPH and oxygen. This is the first step in the biodegradation and detoxification of phenolic compounds. PHOX contains three domains. The substrate and FAD/NAD(P) binding sites are contained in the first two domains, which adopt a complicated folding pattern. The third or C-terminal domain contains a TRX fold and is involved in dimerization. The functional unit of PHOX is a dimer, although active tetramers of the recombinant enzyme can be isolated when overproduced in bacteria.бА0АкА0АаАCDDбАаАжнвА0А0АаАВucd02980, TRX_Fd_family, Thioredoxin (TRX)-like [2Fe-2S] Ferredoxin (Fd) family; composed of [2Fe-2S] Fds with a TRX fold (TRX-like Fds) and proteins containing domains similar to TRX-like Fd including formate dehydrogenases, NAD-reducing hydrogenases and the subunit E of NADH:ubiquinone oxidoreductase (NuoE). TRX-like Fds are soluble low-potential electron carriers containing a single [2Fe-2S] cluster. The exact role of TRX-like Fd is still unclear. It has been suggested that it may be involved in nitrogen fixation. Its homologous domains in large redox enzymes (such as Nuo and hydrogenases) function as electron carriers.бА0АкА0АаАCDDбАаАжовА0А0АаАВccd02981, PDI_b_family, Protein Disulfide Isomerase (PDIb) family, redox inactive TRX-like domain b; composed of eukaryotic proteins involved in oxidative protein folding in the endoplasmic reticulum (ER) by acting as catalysts and folding assistants. Members of this family include PDI, calsequestrin and other PDI-related proteins like ERp72, ERp57, ERp44 and PDIR. PDI, ERp57 (or ERp60), ERp72 and PDIR are all oxidases, catalyzing the formation of disulfide bonds of newly synthesized polypeptides in the ER. They also exhibit reductase activity in acting as isomerases to correct any non-native disulfide bonds, as well as chaperone activity to prevent protein aggregation and facilitate the folding of newly synthesized proteins. These proteins contain multiple copies of a redox active TRX (a) domain containing a CXXC motif, and one or more redox inactive TRX-like (b) domains. The molecular structure of PDI is abb'a'. Also included in this family is the PDI-related protein ERp27, which contains only redox-inactive TRX-like (b and b') domains. The redox inactive b domains are implicated in substrate recognition.бА0АкА0АаАCDDбАаАжпвА0А0АаАВЭcd02982, PDI_b'_family, Protein Disulfide Isomerase (PDIb') family, redox inactive TRX-like domain b'; composed of eukaryotic proteins involved in oxidative protein folding in the endoplasmic reticulum (ER) by acting as catalysts and folding assistants. Members of this family include PDI, calsequestrin and other PDI-related proteins like ERp72, ERp57 (or ERp60), ERp44, P5 and PDIR. PDI, ERp57, ERp72, P5 and PDIR are all oxidases, catalyzing the formation of disulfide bonds of newly synthesized polypeptides in the ER. They also exhibit reductase activity in acting as isomerases to correct any non-native disulfide bonds, as well as chaperone activity to prevent protein aggregation and facilitate the folding of newly synthesized proteins. These proteins contain multiple copies of a redox active TRX (a) domain containing a CXXC motif, and one or more redox inactive TRX-like (b) domains. The molecular structure of PDI is abb'a'. Also included in this family is the PDI-related protein ERp27, which contains only redox-inactive TRX-like (b and b') domains. The redox inactive domains are implicated in substrate recognition with the b' domain serving as the primary substrate binding site. Only the b' domain is necessary for the binding of small peptide substrates. In addition to the b' domain, other domains are required for the binding of larger polypeptide substrates. The b' domain is also implicated in chaperone activity.бА0АкА0АаАCDDбАаАж░вА0А0АаАВУcd02983, P5_C, P5 family, C-terminal redox inactive TRX-like domain; P5 is a protein disulfide isomerase (PDI)-related protein with a domain structure of aa'b (where a and a' are redox active TRX domains and b is a redox inactive TRX-like domain). Like PDI, P5 is located in the endoplasmic reticulum (ER) and displays both isomerase and chaperone activities, which are independent of each other. Compared to PDI, the isomerase and chaperone activities of P5 are lower. The first cysteine in the CXXC motif of both redox active domains in P5 is necessary for isomerase activity. The P5 gene was first isolated as an amplified gene from a hydroxyurea-resistant hamster cell line. The zebrafish P5 homolog has been implicated to play a critical role in establishing left/right asymmetries in the embryonic midline. The C-terminal domain is likely involved in substrate binding, similar to the b and b' domains of PDI.бА0АкА0АаАCDDбАаАж▒вА0А0АаАВ`cd02984, TRX_PICOT, TRX domain, PICOT (for PKC-interacting cousin of TRX) subfamily; PICOT is a protein that interacts with protein kinase C (PKC) theta, a calcium independent PKC isoform selectively expressed in skeletal muscle and T lymphocytes. PICOT contains an N-terminal TRX-like domain, which does not contain the catalytic CXXC motif, followed by one to three glutaredoxin domains. The TRX-like domain is required for interaction with PKC theta. PICOT inhibits the activation of c-Jun N-terminal kinase and the transcription factors, AP-1 and NF-kB, induced by PKC theta or T-cell activating stimuli.бА0АкА0АаАCDDбАаАж▓вА0А0АаАВKcd02985, TRX_CDSP32, TRX family, chloroplastic drought-induced stress protein of 32 kD (CDSP32); CDSP32 is composed of two TRX domains, a C-terminal TRX domain which contains a redox active CXXC motif and an N-terminal TRX-like domain which contains an SXXS sequence instead of the redox active motif. CDSP32 is a stress-inducible TRX, i.e., it acts as a TRX by reducing protein disulfides and is induced by environmental and oxidative stress conditions. It plays a critical role in plastid defense against oxidative damage, a role related to its function as a physiological electron donor to BAS1, a plastidic 2-cys peroxiredoxin. Plants lacking CDSP32 exhibit decreased photosystem II photochemical efficiencies and chlorophyll retention compared to WT controls, as well as an increased proportion of BAS1 in its overoxidized monomeric form.бА0АкА0АаАCDDбАаАж│вА0А0АаАВГcd02986, DLP, Dim1 family, Dim1-like protein (DLP) subfamily; DLP is a novel protein which shares 38% sequence identity to Dim1. Like Dim1, it is also implicated in pre-mRNA splicing and cell cycle progression. DLP is located in the nucleus and has been shown to interact with the U5 small nuclear ribonucleoprotein particle (snRNP)-specific 102kD protein (or Prp6). Dim1 protein, also known as U5 snRNP-specific 15kD protein is a component of U5 snRNP, which pre-assembles with U4/U6 snRNPs to form a [U4/U6:U5] tri-snRNP complex required for pre-mRNA splicing. Dim1 adopts a thioredoxin fold but does not contain the redox active CXXC motif.бА0АкА0АаАCDDбАаАж┤вА0А0АаАВ┘cd02987, Phd_like_Phd, Phosducin (Phd)-like family, Phd subfamily; Phd is a cytosolic regulator of G protein functions. It specifically binds G protein betagamma (Gbg)-subunits with high affinity, resulting in the solubilization of Gbg from the plasma membrane. This impedes the formation of a functional G protein trimer (G protein alphabetagamma), thereby inhibiting G protein-mediated signal transduction. Phd also inhibits the GTPase activity of G protein alpha. Phd can be phosphorylated by protein kinase A and G protein-coupled receptor kinase 2, leading to its inactivation. Phd was originally isolated from the retina, where it is highly expressed and has been implicated to play an important role in light adaptation. It is also found in the pineal gland, liver, spleen, striated muscle and the brain. The C-terminal domain of Phd adopts a thioredoxin fold, but it does not contain a CXXC motif. Phd interacts with G protein beta mostly through the N-terminal helical domain.бА0АкА0АаАCDDбАаАж╡вА0А0АаАВшcd02988, Phd_like_VIAF, Phosducin (Phd)-like family, Viral inhibitor of apoptosis (IAP)-associated factor (VIAF) subfamily; VIAF is a Phd-like protein that functions in caspase activation during apoptosis. It was identified as an IAP binding protein through a screen of a human B-cell library using a prototype IAP. VIAF lacks a consensus IAP binding motif and while it does not function as an IAP antagonist, it still plays a regulatory role in the complete activation of caspases. VIAF itself is a substrate for IAP-mediated ubiquitination, suggesting that it may be a target of IAPs in the prevention of cell death. The similarity of VIAF to Phd points to a potential role distinct from apoptosis regulation. Phd functions as a cytosolic regulator of G protein by specifically binding to G protein betagamma (Gbg)-subunits. The C-terminal domain of Phd adopts a thioredoxin fold, but it does not contain a CXXC motif. Phd interacts with G protein beta mostly through the N-terminal helical domain.бА0АкА0АаАCDDбАаАж╢вА0А0АаАВ╣cd02989, Phd_like_TxnDC9, Phosducin (Phd)-like family, Thioredoxin (TRX) domain containing protein 9 (TxnDC9) subfamily; composed of predominantly uncharacterized eukaryotic proteins, containing a TRX-like domain without the redox active CXXC motif. The gene name for the human protein is TxnDC9. The two characterized members are described as Phd-like proteins, PLP1 of Saccharomyces cerevisiae and PhLP3 of Dictyostelium discoideum. Gene disruption experiments show that both PLP1 and PhLP3 are non-essential proteins. Unlike Phd and most Phd-like proteins, members of this group do not contain the Phd N-terminal helical domain which is implicated in binding to the G protein betagamma subunit.бА0АкА0АаАCDDбАаАж╖вА0А0АаАВ~cd02990, UAS_FAF1, UAS family, FAS-associated factor 1 (FAF1) subfamily; FAF1 contains a UAS domain of unknown function N-terminal to a ubiquitin-associated UBX domain. FAF1 also contains ubiquitin-associated UBA and nuclear targeting domains, N-terminal to the UAS domain. FAF1 is an apoptotic signaling molecule that acts downstream in the Fas signal transduction pathway. It interacts with the cytoplasmic domain of Fas, but not to a Fas mutant that is deficient in signal transduction. It is widely expressed in adult and embryonic tissues, and in tumor cell lines, and is localized not only in the cytoplasm where it interacts with Fas, but also in the nucleus. FAF1 contains phosphorylation sites for protein kinase CK2 within the nuclear targeting domain. Phosphorylation influences nuclear localization of FAF1 but does not affect its potentiation of Fas-induced apoptosis. Other functions have also been attributed to FAF1. It inhibits nuclear factor-kB (NF-kB) by interfering with the nuclear translocation of the p65 subunit. FAF1 also interacts with valosin-containing protein (VCP), which is involved in the ubiquitin-proteosome pathway.бА0АкА0АаАCDDбАаАж╕вА0А0АаАВcd02991, UAS_ETEA, UAS family, ETEA subfamily; composed of proteins similar to human ETEA protein, the translation product of a highly expressed gene in the T-cells and eosinophils of atopic dermatitis patients compared with those of normal individuals. ETEA shows homology to Fas-associated factor 1 (FAF1); both containing UAS and UBX (ubiquitin-associated) domains. Compared to FAF1, however, ETEA lacks the ubiquitin-associated UBA domain and a nuclear targeting domain. The function of ETEA is still unknown. A yeast two-hybrid assay showed that it can interact with Fas. Because of its homology to FAF1, it is postulated that ETEA could be involved in modulating Fas-mediated apoptosis of T-cells and eosinophils of atopic dermatitis patients, making them more resistant to apoptosis.бА0АкА0АаАCDDбАаАж╣вА0А0АаАВXcd02992, PDI_a_QSOX, PDIa family, Quiescin-sulfhydryl oxidase (QSOX) subfamily; QSOX is a eukaryotic protein containing an N-terminal redox active TRX domain, similar to that of PDI, and a small C-terminal flavin adenine dinucleotide (FAD)-binding domain homologous to the yeast ERV1p protein. QSOX oxidizes thiol groups to disulfides like PDI, however, unlike PDI, this oxidation is accompanied by the reduction of oxygen to hydrogen peroxide. QSOX is localized in high concentrations in cells with heavy secretory load and prefers peptides and proteins as substrates, not monothiols like glutathione. Inside the cell, QSOX is found in the endoplasmic reticulum and Golgi. The flow of reducing equivalents in a QSOX-catalyzed reaction goes from the dithiol substrate -> dithiol of the QSOX TRX domain -> dithiols of the QSOX ERV1p domain -> FAD -> oxygen.бА0АкА0АаАCDDбАаАж║вА0А0АаАВ╬cd02993, PDI_a_APS_reductase, PDIa family, 5'-Adenylylsulfate (APS) reductase subfamily; composed of plant-type APS reductases containing a C-terminal redox active TRX domain and an N-terminal reductase domain which is part of a superfamily that includes N type ATP PPases. APS reductase catalyzes the reduction of activated sulfate to sulfite, a key step in the biosynthesis of sulfur-containing metabolites. Sulfate is first activated by ATP sulfurylase, forming APS, which can be phosphorylated to 3'-phosphoadenosine-5'-phosphosulfate (PAPS). Depending on the organism, either APS or PAPS can be used for sulfate reduction. Prokaryotes and fungi use PAPS, whereas plants use both APS and PAPS. Since plant-type APS reductase uses glutathione (GSH) as its electron donor, the C-terminal domain may function like glutaredoxin, a GSH-dependent member of the TRX superfamily. The flow of reducing equivalents goes from GSH -> C-terminal TRX domain -> N-terminal reductase domain -> APS. Plant-type APS reductase shows no homology to that of dissimilatory sulfate-reducing bacteria, which is an iron-sulfur flavoenzyme. Also included in the alignment is EYE2 from Chlamydomonas reinhardtii, a protein required for eyespot assembly.бА0АкА0АаАCDDбАаАж╗вА0А0АаАВ0cd02994, PDI_a_TMX, PDIa family, TMX subfamily; composed of proteins similar to the TRX-related human transmembrane protein, TMX. TMX is a type I integral membrane protein; the N-terminal redox active TRX domain is present in the endoplasmic reticulum (ER) lumen while the C-terminus is oriented towards the cytoplasm. It is expressed in many cell types and its active site motif (CPAC) is unique. In vitro, TMX reduces interchain disulfides of insulin and renatures inactive RNase containing incorrect disulfide bonds. The C. elegans homolog, DPY-11, is expressed only in the hypodermis and resides in the cytoplasm. It is required for body and sensory organ morphogeneis. Another uncharacterized TRX-related transmembrane protein, human TMX4, is included in the alignment. The active site sequence of TMX4 is CPSC.бА0АкА0АаАCDDбАаАж╝вА0А0АаАВ╛cd02995, PDI_a_PDI_a'_C, PDIa family, C-terminal TRX domain (a') subfamily; composed of the C-terminal redox active a' domains of PDI, ERp72, ERp57 (or ERp60) and EFP1. PDI, ERp72 and ERp57 are endoplasmic reticulum (ER)-resident eukaryotic proteins involved in oxidative protein folding. They are oxidases, catalyzing the formation of disulfide bonds of newly synthesized polypeptides in the ER. They also exhibit reductase activity in acting as isomerases to correct any non-native disulfide bonds, as well as chaperone activity to prevent protein aggregation and facilitate the folding of newly synthesized proteins. PDI and ERp57 have the abb'a' domain structure (where a and a' are redox active TRX domains while b and b' are redox inactive TRX-like domains). PDI also contains an acidic region (c domain) after the a' domain that is absent in ERp57. ERp72 has an additional a domain at the N-terminus (a"abb'a' domain structure). ERp57 interacts with the lectin chaperones, calnexin and calreticulin, and specifically promotes the oxidative folding of glycoproteins, while PDI shows a wider substrate specificity. ERp72 associates with several ER chaperones and folding factors to form complexes in the ER that bind nascent proteins. EFP1 is a binding partner protein of thyroid oxidase, which is responsible for the generation of hydrogen peroxide, a crucial substrate of thyroperoxidase, which functions to iodinate thyroglobulin and synthesize thyroid hormones.бА0АкА0АаАCDDбАаАж╜вА0А0АаАВxcd02996, PDI_a_ERp44, PDIa family, endoplasmic reticulum protein 44 (ERp44) subfamily; ERp44 is an ER-resident protein, induced during stress, involved in thiol-mediated ER retention. It contains an N-terminal TRX domain, similar to that of PDIa, with a CXFS motif followed by two redox inactive TRX-like domains, homologous to the b and b' domains of PDI. The CXFS motif in the N-terminal domain allows ERp44 to form stable reversible mixed disulfides with its substrates. Through this activity, ERp44 mediates the ER localization of Ero1alpha, a protein that oxidizes protein disulfide isomerases into their active form. ERp44 also prevents the secretion of unassembled cargo protein with unpaired cysteines. It also modulates the activity of inositol 1,4,5-triphosphate type I receptor (IP3R1), an intracellular channel protein that mediates calcium release from the ER to the cytosol.бА0АкА0АаАCDDбАаАж╛вА0А0АаАВъcd02997, PDI_a_PDIR, PDIa family, PDIR subfamily; composed of proteins similar to human PDIR (for Protein Disulfide Isomerase Related). PDIR is composed of three redox active TRX (a) domains and an N-terminal redox inactive TRX-like (b) domain. Similar to PDI, it is involved in oxidative protein folding in the endoplasmic reticulum (ER) through its isomerase and chaperone activities. These activities are lower compared to PDI, probably due to PDIR acting only on a subset of proteins. PDIR is preferentially expressed in cells actively secreting proteins and its expression is induced by stress. Similar to PDI, the isomerase and chaperone activities of PDIR are independent; CXXC mutants lacking isomerase activity retain chaperone activity.бА0АкА0АаАCDDбАаАж┐вА0А0АаАВ▓cd02998, PDI_a_ERp38, PDIa family, endoplasmic reticulum protein 38 (ERp38) subfamily; composed of proteins similar to the P5-like protein first isolated from alfalfa, which contains two redox active TRX (a) domains at the N-terminus, like human P5, and a C-terminal domain with homology to the C-terminal domain of ERp29, unlike human P5. The cDNA clone of this protein (named G1) was isolated from an alfalfa cDNA library by screening with human protein disulfide isomerase (PDI) cDNA. The G1 protein is constitutively expressed in all major organs of the plant and its expression is induced by treatment with tunicamycin, indicating that it may be a glucose-regulated protein. The G1 homolog in the eukaryotic social amoeba Dictyostelium discoideum is also described as a P5-like protein, which is located in the endoplasmic reticulum (ER) despite the absence of an ER-retrieval signal. G1 homologs from Aspergillus niger and Neurospora crassa have also been characterized, and are named TIGA and ERp38, respectively. Also included in the alignment is an atypical PDI from Leishmania donovani containing a single a domain, and the C-terminal a domain of a P5-like protein from Entamoeba histolytica.бА0АкА0АаАCDDбАаАж└вА0А0АаАВ?cd02999, PDI_a_ERp44_like, PDIa family, endoplasmic reticulum protein 44 (ERp44)-like subfamily; composed of uncharacterized PDI-like eukaryotic proteins containing only one redox active TRX (a) domain with a CXXS motif, similar to ERp44. CXXS is still a redox active motif; however, the mixed disulfide formed with the substrate is more stable than those formed by CXXC motif proteins. PDI-related proteins are usually involved in the oxidative protein folding in the ER by acting as catalysts and folding assistants. ERp44 is involved in thiol-mediated retention in the ER.бА0АкА0АаАCDDбАаАж┴вА0А0АаАВ cd03000, PDI_a_TMX3, PDIa family, TMX3 subfamily; composed of eukaryotic proteins similar to human TMX3, a TRX related transmembrane protein containing one redox active TRX domain at the N-terminus and a classical ER retrieval sequence for type I transmembrane proteins at the C-terminus. The TMX3 transcript is found in a variety of tissues with the highest levels detected in skeletal muscle and the heart. In vitro, TMX3 showed oxidase activity albeit slightly lower than that of protein disulfide isomerase.бА0АкА0АаАCDDбАаАж┬вА0А0АаАВЗcd03001, PDI_a_P5, PDIa family, P5 subfamily; composed of eukaryotic proteins similar to human P5, a PDI-related protein with a domain structure of aa'b (where a and a' are redox active TRX domains and b is a redox inactive TRX-like domain). Like PDI, P5 is located in the endoplasmic reticulum (ER) and displays both isomerase and chaperone activities, which are independent of each other. Compared to PDI, the isomerase and chaperone activities of P5 are lower. The first cysteine in the CXXC motif of both redox active domains in P5 is necessary for isomerase activity. The P5 gene was first isolated as an amplified gene from a hydroxyurea-resistant hamster cell line. The zebrafish P5 homolog has been implicated to play a critical role in establishing left/right asymmetries in the embryonic midline. Some members of this subfamily are P5-like proteins containing only one redox active TRX domain.бА0АкА0АаАCDDбАаАж├вА0А0АаАВcd03004, PDI_a_ERdj5_C, PDIa family, C-terminal ERdj5 subfamily; ERdj5, also known as JPDI and macrothioredoxin, is a protein containing an N-terminal DnaJ domain and four redox active TRX domains. This subfamily is composed of the three TRX domains located at the C-terminal half of the protein. ERdj5 is a ubiquitous protein localized in the endoplasmic reticulum (ER) and is abundant in secretory cells. It's transcription is induced during ER stress. It interacts with BiP through its DnaJ domain in an ATP-dependent manner. BiP, an ER-resident member of the Hsp70 chaperone family, functions in ER-associated degradation and protein translocation. Also included in the alignment is the single complete TRX domain of an uncharacterized protein from Tetraodon nigroviridis, which also contains a DnaJ domain at its N-terminus.бА0АкА0АаАCDDбАаАж╞вА0А0АаАВМcd03005, PDI_a_ERp46, PDIa family, endoplasmic reticulum protein 46 (ERp46) subfamily; ERp46 is an ER-resident protein containing three redox active TRX domains. Yeast complementation studies show that ERp46 can substitute for protein disulfide isomerase (PDI) function in vivo. It has been detected in many tissues, however, transcript and protein levels do not correlate in all tissues, suggesting regulation at a posttranscriptional level. An identical protein, named endoPDI, has been identified as an endothelial PDI that is highly expressed in the endothelium of tumors and hypoxic lesions. It has a protective effect on cells exposed to hypoxia.бА0АкА0АаАCDDбАаАж╟вА0А0АаАВиcd03006, PDI_a_EFP1_N, PDIa family, N-terminal EFP1 subfamily; EFP1 is a binding partner protein of thyroid oxidase (ThOX), also called Duox. ThOX proteins are responsible for the generation of hydrogen peroxide, a crucial substrate of thyroperoxidase, which functions to iodinate thyroglobulin and synthesize thyroid hormones. EFP1 was isolated through a yeast two-hybrid method using the EF-hand fragment of dog Duox1 as a bait. It could be one of the partners in the assembly of a multiprotein complex constituting the thyroid hydrogen peroxide generating system. EFP1 contains two TRX domains related to the redox active TRX domains of protein disulfide isomerase (PDI). This subfamily is composed of the N-terminal TRX domain of EFP1, which contains a CXXS sequence in place of the typical CXXC motif, similar to ERp44. The CXXS motif allows the formation of stable mixed disulfides, crucial for the ER-retention function of ERp44.бА0АкА0АаАCDDбАаАж╚вА0А0АаАВtcd03007, PDI_a_ERp29_N, PDIa family, endoplasmic reticulum protein 29 (ERp29) subfamily; ERp29 is a ubiquitous ER-resident protein expressed in high levels in secretory cells. It forms homodimers and higher oligomers in vitro and in vivo. It contains a redox inactive TRX-like domain at the N-terminus, which is homologous to the redox active TRX (a) domains of PDI, and a C-terminal helical domain similar to the C-terminal domain of P5. The expression profile of ERp29 suggests a role in secretory protein production distinct from that of PDI. It has also been identified as a member of the thyroglobulin folding complex. The Drosophila homolog, Wind, is the product of windbeutel, an essential gene in the development of dorsal-ventral patterning. Wind is required for correct targeting of Pipe, a Golgi-resident type II transmembrane protein with homology to 2-O-sulfotransferase.бА0АкА0АаАCDDбАаАж╔вА0А0АаАВcd03008, TryX_like_RdCVF, Tryparedoxin (TryX)-like family, Rod-derived cone viability factor (RdCVF) subfamily; RdCVF is a thioredoxin (TRX)-like protein specifically expressed in photoreceptors. RdCVF was isolated and identified as a factor that supports cone survival in retinal cultures. Cone photoreceptor loss is responsible for the visual handicap resulting from the inherited disease, retinitis pigmentosa. RdCVF shows 33% similarity to TRX but does not exhibit any detectable thiol oxidoreductase activity.бА0АкА0АаАCDDбАаАж╩вА0А0АаАВFcd03009, TryX_like_TryX_NRX, Tryparedoxin (TryX)-like family, TryX and nucleoredoxin (NRX) subfamily; TryX and NRX are thioredoxin (TRX)-like protein disulfide oxidoreductases that alter the redox state of target proteins via the reversible oxidation of an active center CXXC motif. TryX is involved in the regulation of oxidative stress in parasitic trypanosomatids by reducing TryX peroxidase, which in turn catalyzes the reduction of hydrogen peroxide and organic hydroperoxides. TryX derives reducing equivalents from reduced trypanothione, a polyamine peptide conjugate unique to trypanosomatids, which is regenerated by the NADPH-dependent flavoprotein trypanothione reductase. Vertebrate NRX is a 400-amino acid nuclear protein with one redox active TRX domain containing a CPPC active site motif followed by one redox inactive TRX-like domain. Mouse NRX transcripts are expressed in all adult tissues but is restricted to the nervous system and limb buds in embryos. Plant NRX, longer than the vertebrate NRX by about 100-200 amino acids, is a nuclear protein containing a redox inactive TRX-like domain between two redox active TRX domains. Both vertebrate and plant NRXs show thiol oxidoreductase activity in vitro. Their localization in the nucleus suggests a role in the redox regulation of nuclear proteins such as transcription factors.бА0АкА0АаАCDDбАаАж╦вА0А0АаАВScd03010, TlpA_like_DsbE, TlpA-like family, DsbE (also known as CcmG and CycY) subfamily; DsbE is a membrane-anchored, periplasmic TRX-like reductase containing a CXXC motif that specifically donates reducing equivalents to apocytochrome c via CcmH, another cytochrome c maturation (Ccm) factor with a redox active CXXC motif. Assembly of cytochrome c requires the ligation of heme to reduced thiols of the apocytochrome. In bacteria, this assembly occurs in the periplasm. The reductase activity of DsbE in the oxidizing environment of the periplasm is crucial in the maturation of cytochrome c.бА0АкА0АаАCDDбАаАж╠вА0А0АаАВ■cd03011, TlpA_like_ScsD_MtbDsbE, TlpA-like family, suppressor for copper sensitivity D protein (ScsD) and actinobacterial DsbE homolog subfamily; composed of ScsD, the DsbE homolog of Mycobacterium tuberculosis (MtbDsbE) and similar proteins, all containing a redox-active CXXC motif. The Salmonella typhimurium ScsD is a thioredoxin-like protein which confers copper tolerance to copper-sensitive mutants of E. coli. MtbDsbE has been characterized as an oxidase in vitro, catalyzing the disulfide bond formation of substrates like hirudin. The reduced form of MtbDsbE is more stable than its oxidized form, consistent with an oxidase function. This is in contrast to the function of DsbE from gram-negative bacteria which is a specific reductase of apocytochrome c.бА0АкА0АаАCDDбАаАж═вА0А0АаАВЧcd03012, TlpA_like_DipZ_like, TlpA-like family, DipZ-like subfamily; composed uncharacterized proteins containing a TlpA-like TRX domain. Some members show domain architectures similar to that of E. coli DipZ protein (also known as DsbD). The only eukaryotic members of the TlpA family belong to this subfamily. TlpA is a disulfide reductase known to have a crucial role in the biogenesis of cytochrome aa3.бА0АкА0АаАCDDбАаАж╬вА0А0АаАВ3cd03013, PRX5_like, Peroxiredoxin (PRX) family, PRX5-like subfamily; members are similar to the human protein, PRX5, a homodimeric TRX peroxidase, widely expressed in tissues and found cellularly in mitochondria, peroxisomes and the cytosol. The cellular location of PRX5 suggests that it may have an important antioxidant role in organelles that are major sources of reactive oxygen species (ROS), as well as a role in the control of signal transduction. PRX5 has been shown to reduce hydrogen peroxide, alkyl hydroperoxides and peroxynitrite. As with all other PRXs, the N-terminal peroxidatic cysteine of PRX5 is oxidized into a sulfenic acid intermediate upon reaction with peroxides. Human PRX5 is able to resolve this intermediate by forming an intramolecular disulfide bond with its C-terminal cysteine (the resolving cysteine), which can then be reduced by TRX, just like an atypical 2-cys PRX. This resolving cysteine, however, is not conserved in other members of the subfamily. In such cases, it is assumed that the oxidized cysteine is directly resolved by an external small-molecule or protein reductant, typical of a 1-cys PRX. In the case of the H. influenza PRX5 hybrid, the resolving glutaredoxin domain is on the same protein chain as PRX. PRX5 homodimers show an A-type interface, similar to atypical 2-cys PRXs.бА0АкА0АаАCDDбАаАж╧вА0А0АаАВRcd03014, PRX_Atyp2cys, Peroxiredoxin (PRX) family, Atypical 2-cys PRX subfamily; composed of PRXs containing peroxidatic and resolving cysteines, similar to the homodimeric thiol specific antioxidant (TSA) protein also known as TRX-dependent thiol peroxidase (Tpx). Tpx is a bacterial periplasmic peroxidase which differs from other PRXs in that it shows substrate specificity toward alkyl hydroperoxides over hydrogen peroxide. As with all other PRXs, the peroxidatic cysteine (N-terminal) of Tpx is oxidized into a sulfenic acid intermediate upon reaction with peroxides. Tpx is able to resolve this intermediate by forming an intramolecular disulfide bond with a conserved C-terminal cysteine (the resolving cysteine), which can then be reduced by thioredoxin. This differs from the typical 2-cys PRX which resolves the oxidized cysteine by forming an intermolecular disulfide bond with the resolving cysteine from the other subunit of the homodimer. Atypical 2-cys PRX homodimers have a loop-based interface (A-type for alternate), in contrast with the B-type interface of typical 2-cys and 1-cys PRXs.бА0АкА0АаАCDDбАаАж╨вА0А0АаАВscd03015, PRX_Typ2cys, Peroxiredoxin (PRX) family, Typical 2-Cys PRX subfamily; PRXs are thiol-specific antioxidant (TSA) proteins, which confer a protective role in cells through its peroxidase activity by reducing hydrogen peroxide, peroxynitrite, and organic hydroperoxides. The functional unit of typical 2-cys PRX is a homodimer. A unique intermolecular redox-active disulfide center is utilized for its activity. Upon reaction with peroxides, its peroxidatic cysteine is oxidized into a sulfenic acid intermediate which is resolved by bonding with the resolving cysteine from the other subunit of the homodimer. This intermolecular disulfide bond is then reduced by thioredoxin, tryparedoxin or AhpF. Typical 2-cys PRXs, like 1-cys PRXs, form decamers which are stabilized by reduction of the active site cysteine. Typical 2-cys PRX interacts through beta strands at one edge of the monomer (B-type interface) to form the functional homodimer, and uses an A-type interface (similar to the dimeric interface in atypical 2-cys PRX and PRX5) at the opposite end of the monomer to form the stable decameric (pentamer of dimers) structure.бА0АкА0АаАCDDбАаАж╤вА0А0АаАВscd03016, PRX_1cys, Peroxiredoxin (PRX) family, 1-cys PRX subfamily; composed of PRXs containing only one conserved cysteine, which serves as the peroxidatic cysteine. They are homodimeric thiol-specific antioxidant (TSA) proteins that confer a protective role in cells by reducing and detoxifying hydrogen peroxide, peroxynitrite, and organic hydroperoxides. As with all other PRXs, a cysteine sulfenic acid intermediate is formed upon reaction of 1-cys PRX with its substrates. Having no resolving cysteine, the oxidized enzyme is resolved by an external small-molecule or protein reductant such as thioredoxin or glutaredoxin. Similar to typical 2-cys PRX, 1-cys PRX forms a functional dimeric unit with a B-type interface, as well as a decameric structure which is stabilized in the reduced form of the enzyme. Other oligomeric forms, tetramers and hexamers, have also been reported. Mammalian 1-cys PRX is localized cellularly in the cytosol and is expressed at high levels in brain, eye, testes and lung. The seed-specific plant 1-cys PRXs protect tissues from reactive oxygen species during desiccation and are also called rehydrins.бА0АкА0АаАCDDбАаАж╥вА0А0АаАВ8cd03017, PRX_BCP, Peroxiredoxin (PRX) family, Bacterioferritin comigratory protein (BCP) subfamily; composed of thioredoxin-dependent thiol peroxidases, widely expressed in pathogenic bacteria, that protect cells against toxicity from reactive oxygen species by reducing and detoxifying hydroperoxides. The protein was named BCP based on its electrophoretic mobility before its function was known. BCP shows substrate selectivity toward fatty acid hydroperoxides rather than hydrogen peroxide or alkyl hydroperoxides. BCP contains the peroxidatic cysteine but appears not to possess a resolving cysteine (some sequences, not all, contain a second cysteine but its role is still unknown). Unlike other PRXs, BCP exists as a monomer. The plant homolog of BCP is PRX Q, which is expressed only in leaves and is cellularly localized in the chloroplasts and the guard cells of stomata. Also included in this subfamily is the fungal nuclear protein, Dot5p (for disrupter of telomere silencing protein 5), which functions as an alkyl-hydroperoxide reductase during post-diauxic growth.бА0АкА0АаАCDDбАаАж╙вА0А0АаАВщcd03018, PRX_AhpE_like, Peroxiredoxin (PRX) family, AhpE-like subfamily; composed of proteins similar to Mycobacterium tuberculosis AhpE. AhpE is described as a 1-cys PRX because of the absence of a resolving cysteine. The structure and sequence of AhpE, however, show greater similarity to 2-cys PRXs than 1-cys PRXs. PRXs are thiol-specific antioxidant (TSA) proteins that confer a protective role in cells through their peroxidase activity in which hydrogen peroxide, peroxynitrate, and organic hydroperoxides are reduced and detoxified using reducing equivalents derived from either thioredoxin, glutathione, trypanothione and AhpF. The first step of catalysis is the nucleophilic attack by the peroxidatic cysteine on the peroxide leading to the formation of a cysteine sulfenic acid intermediate. The absence of a resolving cysteine suggests that functional AhpE is regenerated by an external reductant. The solution behavior and crystal structure of AhpE show that it forms dimers and octamers.бА0АкА0АаАCDDбАаАж╘вА0А0АаАВ9cd03019, DsbA_DsbA, DsbA family, DsbA subfamily; DsbA is a monomeric thiol disulfide oxidoreductase protein containing a redox active CXXC motif imbedded in a TRX fold. It is involved in the oxidative protein folding pathway in prokaryotes, and is the strongest thiol oxidant known, due to the unusual stability of the thiolate anion form of the first cysteine in the CXXC motif. The highly unstable oxidized form of DsbA directly donates disulfide bonds to reduced proteins secreted into the bacterial periplasm. This rapid and unidirectional process helps to catalyze the folding of newly-synthesized polypeptides. To regain catalytic activity, reduced DsbA is then reoxidized by the membrane protein DsbB, which generates its disulfides from oxidized quinones, which in turn are reoxidized by the electron transport chain.бА0АкА0АаАCDDбАаАж╒вА0А0АаАВ▒cd03020, DsbA_DsbC_DsbG, DsbA family, DsbC and DsbG subfamily; V-shaped homodimeric proteins containing a redox active CXXC motif imbedded in a TRX fold. They function as protein disulfide isomerases and chaperones in the bacterial periplasm to correct non-native disulfide bonds formed by DsbA and prevent aggregation of incorrectly folded proteins. DsbC and DsbG are kept in their reduced state by the cytoplasmic membrane protein DsbD, which utilizes the TRX/TRX reductase system in the cytosol as a source of reducing equivalents. DsbG differ from DsbC in that it has a more limited substrate specificity, and it may preferentially act later in the folding process to catalyze disulfide rearrangements in folded or partially folded proteins. Also included in the alignment is the predicted protein TrbB, whose gene was sequenced from the enterohemorrhagic E. coli type IV pilus gene cluster, which is required for efficient plasmid transfer.бА0АкА0АаАCDDбАаАж╓вА0А0АаАВYcd03021, DsbA_GSTK, DsbA family, Glutathione (GSH) S-transferase Kappa (GSTK) subfamily; GSTK is a member of the GST family of enzymes which catalyzes the transfer of the thiol of GSH to electrophilic substrates. It is specifically located in the mitochondria and peroxisomes, unlike other members of the canonical GST family, which are mainly cytosolic. The biological substrates of GSTK are not yet known. It is presumed to have a protective role during respiration when large amounts of reactive oxygen species are generated. GSTK has the same general fold as DsbA, consisting of a thioredoxin domain interrupted by an alpha-helical domain and its biological unit is a homodimer. GSTK is closely related to the bacterial enzyme, 2-hydroxychromene-2-carboxylate (HCCA) isomerase. It shows little sequence similarity to the other members of the GST family.бА0АкА0АаАCDDбАаАж╫вА0А0АаАВecd03022, DsbA_HCCA_Iso, DsbA family, 2-hydroxychromene-2-carboxylate (HCCA) isomerase subfamily; HCCA isomerase is a glutathione (GSH) dependent enzyme involved in the naphthalene catabolic pathway. It converts HCCA, a hemiketal formed spontaneously after ring cleavage of 1,2-dihydroxynapthalene by a dioxygenase, into cis-o-hydroxybenzylidenepyruvate (cHBPA). This is the fourth reaction in a six-step pathway that converts napthalene into salicylate. HCCA isomerase is unique to bacteria that degrade polycyclic aromatic compounds. It is closely related to the eukaryotic protein, GSH transferase kappa (GSTK).бА0АкА0АаАCDDбАаАж╪вА0А0АаАВ█cd03023, DsbA_Com1_like, DsbA family, Com1-like subfamily; composed of proteins similar to Com1, a 27-kDa outer membrane-associated immunoreactive protein originally found in both acute and chronic disease strains of the pathogenic bacteria Coxiella burnetti. It contains a CXXC motif, assumed to be imbedded in a DsbA-like structure. Its homology to DsbA suggests that the protein is a protein disulfide oxidoreductase. The role of such a protein in pathogenesis is unknown.бА0АкА0АаАCDDбАаАж┘вА0А0АаАВ cd03024, DsbA_FrnE, DsbA family, FrnE subfamily; FrnE is a DsbA-like protein containing a CXXC motif. It is presumed to be a thiol oxidoreductase involved in polyketide biosynthesis, specifically in the production of the aromatic antibiotics frenolicin and nanaomycins.бА0АкА0АаАCDDбАаАж┌вА0А0АаАВCcd03025, DsbA_FrnE_like, DsbA family, FrnE-like subfamily; composed of uncharacterized proteins containing a CXXC motif with similarity to DsbA and FrnE. FrnE is presumed to be a thiol oxidoreductase involved in polyketide biosynthesis, specifically in the production of the aromatic antibiotics frenolicin and nanaomycins.бА0АкА0АаАCDDбАаАж█вА0А0АаАВycd03026, AhpF_NTD_C, TRX-GRX-like family, Alkyl hydroperoxide reductase F subunit (AhpF) N-terminal domain (NTD) subfamily, C-terminal TRX-fold subdomain; AhpF is a homodimeric flavoenzyme which catalyzes the NADH-dependent reduction of the peroxiredoxin AhpC, which then reduces hydrogen peroxide and organic hydroperoxides. AhpF contains an NTD containing two contiguous TRX-fold subdomains similar to Pyrococcus furiosus protein disulfide oxidoreductase (PfPDO). It also contains a catalytic core similar to TRX reductase containing FAD and NADH binding domains with an active site disulfide. The proposed mechanism of action of AhpF is similar to a TRX/TRX reductase system. The flow of reducing equivalents goes from NADH -> catalytic core of AhpF -> NTD of AhpF -> AhpC -> peroxide substrates. The catalytic CXXC motif of the NTD of AhpF is contained in its C-terminal TRX subdomain.бА0АкА0АаАCDDбАаАж▄вА0А0АаАВ8cd03027, GRX_DEP, Glutaredoxin (GRX) family, Dishevelled, Egl-10, and Pleckstrin (DEP) subfamily; composed of uncharacterized proteins containing a GRX domain and additional domains DEP and DUF547, both of which have unknown functions. GRX is a glutathione (GSH) dependent reductase containing a redox active CXXC motif in a TRX fold. It has preference for mixed GSH disulfide substrates, in which it uses a monothiol mechanism where only the N-terminal cysteine is required. By altering the redox state of target proteins, GRX is involved in many cellular functions.бА0АкА0АаАCDDбАаАж▌вА0А0АаАВ>cd03028, GRX_PICOT_like, Glutaredoxin (GRX) family, PKC-interacting cousin of TRX (PICOT)-like subfamily; composed of PICOT and GRX-PICOT-like proteins. The non-PICOT members of this family contain only the GRX-like domain, whereas PICOT contains an N-terminal TRX-like domain followed by one to three GRX-like domains. It is interesting to note that PICOT from plants contain three repeats of the GRX-like domain, metazoan proteins (except for insect) have two repeats, while fungal sequences contain only one copy of the domain. PICOT is a protein that interacts with protein kinase C (PKC) theta, a calcium independent PKC isoform selectively expressed in skeletal muscle and T lymphocytes. PICOT inhibits the activation of c-Jun N-terminal kinase and the transcription factors, AP-1 and NF-kB, induced by PKC theta or T-cell activating stimuli. Both GRX and TRX domains of PICOT are required for its activity. Characterized non-PICOT members of this family include CXIP1, a CAX-interacting protein in Arabidopsis thaliana, and PfGLP-1, a GRX-like protein from Plasmodium falciparum.бА0АкА0АаАCDDбАаАж▐вА0А0АаАВ╣cd03029, GRX_hybridPRX5, Glutaredoxin (GRX) family, PRX5 hybrid subfamily; composed of hybrid proteins containing peroxiredoxin (PRX) and GRX domains, which is found in some pathogenic bacteria and cyanobacteria. PRXs are thiol-specific antioxidant (TSA) proteins that confer a protective antioxidant role in cells through their peroxidase activity in which hydrogen peroxide, peroxynitrate, and organic hydroperoxides are reduced and detoxified using reducing equivalents derived from either thioredoxin, glutathione, trypanothione and AhpF. GRX is a glutathione (GSH) dependent reductase, catalyzing the disulfide reduction of target proteins. PRX-GRX hybrid proteins from Haemophilus influenza and Neisseria meningitis exhibit GSH-dependent peroxidase activity. The flow of reducing equivalents in the catalytic cycle of the hybrid protein goes from NADPH -> GSH reductase -> GSH -> GRX domain of hybrid -> PRX domain of hybrid -> peroxide substrate.бА0АкА0АаАCDDбАаАж▀вА0А0АаАВ{cd03030, GRX_SH3BGR, Glutaredoxin (GRX) family, SH3BGR (SH3 domain binding glutamic acid-rich protein) subfamily; a recently-identified subfamily composed of SH3BGR and similar proteins possessing significant sequence similarity to GRX, but without a redox active CXXC motif. The SH3BGR gene was cloned in an effort to identify genes mapping to chromosome 21, which could be involved in the pathogenesis of congenital heart disease affecting Down syndrome newborns. Several human SH3BGR-like (SH3BGRL) genes have been identified since, mapping to different locations in the chromosome. Of these, SH3BGRL3 was identified as a tumor necrosis factor (TNF) alpha inhibitory protein and was also named TIP-B1. Upregulation of expression of SH3BGRL3 is associated with differentiation. It has been suggested that it functions as a regulator of differentiation-related signal transduction pathways.бА0АкА0АаАCDDбАаАжрвА0А0АаАВрcd03031, GRX_GRX_like, Glutaredoxin (GRX) family, GRX-like domain containing protein subfamily; composed of uncharacterized eukaryotic proteins containing a GRX-like domain having only one conserved cysteine, aligning to the C-terminal cysteine of the CXXC motif of GRXs. This subfamily is predominantly composed of plant proteins. GRX is a glutathione (GSH) dependent reductase, catalyzing the disulfide reduction of target proteins via a redox active CXXC motif using a similar dithiol mechanism employed by TRXs. GRX has preference for mixed GSH disulfide substrates, in which it uses a monothiol mechanism where only the N-terminal cysteine is required. Proteins containing only the C-terminal cysteine are generally redox inactive.бА0АкА0АаАCDDбАаАжсвА0А0АаАВ╓cd03032, ArsC_Spx, Arsenate Reductase (ArsC) family, Spx subfamily; Spx is a unique RNA polymerase (RNAP)-binding protein present in bacilli and some mollicutes. It inhibits transcription by binding to the C-terminal domain of the alpha subunit of RNAP, disrupting complex formation between RNAP and certain transcriptional activator proteins like ResD and ComA. In response to oxidative stress, Spx can also activate transcription, making it a general regulator that exerts both positive and negative control over transcription initiation. Spx has been shown to exert redox-sensitive transcriptional control over genes like trxA (TRX) and trxB (TRX reductase), genes that function in thiol homeostasis. This redox-sensitive activity is dependent on the presence of a CXXC motif, present in some members of the Spx subfamily, that acts as a thiol/disulfide switch. Spx has also been shown to repress genes in a sulfate-dependent manner independent of the presence of the CXXC motif.бА0АкА0АаАCDDбАаАжтвА0А0АаАВAcd03033, ArsC_15kD, Arsenate Reductase (ArsC) family, 15kD protein subfamily; composed of proteins of unknown function with similarity to thioredoxin-fold arsenic reductases, ArsC. It is encoded by an ORF present in a gene cluster associated with nitrogen fixation that also encodes dinitrogenase reductase ADP-ribosyltransferase (DRAT) and dinitrogenase reductase activating glycohydrolase (DRAG). ArsC catalyzes the reduction of arsenate [As(V)] to arsenite [As(III)], using reducing equivalents derived from glutathione via glutaredoxin, through a single catalytic cysteine.бА0АкА0АаАCDDбАаАжувА0А0АаАВ·cd03034, ArsC_ArsC, Arsenate Reductase (ArsC) family, ArsC subfamily; arsenic reductases similar to that encoded by arsC on the R733 plasmid of Escherichia coli. E. coli ArsC catalyzes the reduction of arsenate [As(V)] to arsenite [As(III)], the first step in the detoxification of arsenic, using reducing equivalents derived from glutathione (GSH) via glutaredoxin (GRX). ArsC contains a single catalytic cysteine, within a thioredoxin fold, that forms a covalent thiolate-As(V) intermediate, which is reduced by GRX through a mixed GSH-arsenate intermediate. This family of predominantly bacterial enzymes is unrelated to two other families of arsenate reductases which show similarity to low-molecular-weight acid phosphatases and phosphotyrosyl phosphatases.бА0АкА0АаАCDDбАаАжфвА0А0АаАВcd03035, ArsC_Yffb, Arsenate Reductase (ArsC) family, Yffb subfamily; Yffb is an uncharacterized bacterial protein encoded by the yffb gene, related to the thioredoxin-fold arsenic reductases, ArsC. The structure of Yffb and the conservation of the catalytic cysteine suggest that it is likely to function as a glutathione (GSH)-dependent thiol reductase. ArsC catalyzes the reduction of arsenate [As(V)] to arsenite [As(III)], using reducing equivalents derived from GSH via glutaredoxin, through a single catalytic cysteine.бА0АкА0АаАCDDбАаАжхвА0А0АаАВIcd03036, ArsC_like, Arsenate Reductase (ArsC) family, unknown subfamily; uncharacterized proteins containing a CXXC motif with similarity to thioredoxin (TRX)-fold arsenic reductases, ArsC. Proteins containing a redox active CXXC motif like TRX and glutaredoxin (GRX) function as protein disulfide oxidoreductases, altering the redox state of target proteins via the reversible oxidation of the active site dithiol. ArsC catalyzes the reduction of arsenate [As(V)] to arsenite [As(III)], using reducing equivalents derived from glutathione via GRX, through a single catalytic cysteine.бА0АкА0АаАCDDбАаАжцвА0А0АаАВ┘cd03037, GST_N_GRX2, GST_N family, Glutaredoxin 2 (GRX2) subfamily; composed of bacterial proteins similar to E. coli GRX2, an atypical GRX with a molecular mass of about 24kD, compared with other GRXs which are 9-12kD in size. GRX2 adopts a GST fold containing an N-terminal thioredoxin-fold domain and a C-terminal alpha helical domain. It contains a redox active CXXC motif located in the N-terminal domain but is not able to reduce ribonucleotide reductase like other GRXs. However, it catalyzes GSH-dependent protein disulfide reduction of other substrates efficiently. GRX2 is thought to function primarily in catalyzing the reversible glutathionylation of proteins in cellular redox regulation including stress responses.бА0АкА0АаАCDDбАаАжчвА0А0АаАВNcd03038, GST_N_etherase_LigE, GST_N family, Beta etherase LigE subfamily; composed of proteins similar to Sphingomonas paucimobilis beta etherase, LigE, a GST-like protein that catalyzes the cleavage of the beta-aryl ether linkages present in low-moleculer weight lignins using GSH as the hydrogen donor. This reaction is an essential step in the degradation of lignin, a complex phenolic polymer that is the most abundant aromatic material in the biosphere. The beta etherase activity of LigE is enantioselective and it complements the activity of the other GST family beta etherase, LigF.бА0АкА0АаАCDDбАаАжшвА0А0АаАВ cd03039, GST_N_Sigma_like, GST_N family, Class Sigma_like; composed of GSTs belonging to class Sigma and similar proteins, including GSTs from class Mu, Pi and Alpha. GSTs are cytosolic dimeric proteins involved in cellular detoxification by catalyzing the conjugation of glutathione (GSH) with a wide range of endogenous and xenobiotic alkylating agents, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress. The GST fold contains an N-terminal TRX-fold domain and a C-terminal alpha helical domain, with an active site located in a cleft between the two domains. Vertebrate class Sigma GSTs are characterized as GSH-dependent hematopoietic prostaglandin (PG) D synthases and are responsible for the production of PGD2 by catalyzing the isomerization of PGH2. The functions of PGD2 include the maintenance of body temperature, inhibition of platelet aggregation, bronchoconstriction, vasodilation and mediation of allergy and inflammation. Other class Sigma members include the class II insect GSTs, S-crystallins from cephalopods and 28-kDa GSTs from parasitic flatworms. Drosophila GST2 is associated with indirect flight muscle and exhibits preference for catalyzing GSH conjugation to lipid peroxidation products, indicating an anti-oxidant role. S-crystallin constitutes the major lens protein in cephalopod eyes and is responsible for lens transparency and proper refractive index. The 28-kDa GST from Schistosoma is a multifunctional enzyme, exhibiting GSH transferase, GSH peroxidase and PGD2 synthase activities, and may play an important role in host-parasite interactions. Also members are novel GSTs from the fungus Cunninghamella elegans, designated as class Gamma, and from the protozoan Blepharisma japonicum, described as a light-inducible GST.бА0АкА0АаАCDDбАаАжщвА0А0АаАВ9cd03040, GST_N_mPGES2, GST_N family; microsomal Prostaglandin E synthase Type 2 (mPGES2) subfamily; mPGES2 is a membrane-anchored dimeric protein containing a CXXC motif which catalyzes the isomerization of PGH2 to PGE2. Unlike cytosolic PGE synthase (cPGES) and microsomal PGES Type 1 (mPGES1), mPGES2 does not require glutathione (GSH) for its activity, although its catalytic rate is increased two- to four-fold in the presence of DTT, GSH or other thiol compounds. PGE2 is widely distributed in various tissues and is implicated in the sleep/wake cycle, relaxation/contraction of smooth muscle, excretion of sodium ions, maintenance of body temperature and mediation of inflammation. mPGES2 contains an N-terminal hydrophobic domain which is membrane associated, and a C-terminal soluble domain with a GST-like structure.бА0АкА0АаАCDDбАаАжъвА0А0АаАВ╣cd03041, GST_N_2GST_N, GST_N family, 2 repeats of the N-terminal domain of soluble GSTs (2 GST_N) subfamily; composed of uncharacterized proteins. GSTs are cytosolic dimeric proteins involved in cellular detoxification by catalyzing the conjugation of glutathione (GSH) with a wide range of endogenous and xenobiotic alkylating agents, including carcinogens, therapeutic drugs, environmental toxins, and products of oxidative stress. GSTs also show GSH peroxidase activity and are involved in the synthesis of prostaglandins and leukotrienes. The GST fold contains an N-terminal TRX-fold domain and a C-terminal alpha helical domain, with an active site located in a cleft between the two domains.бА0АкА0АаАCDDбАаАжывА0А0АаАВ┼cd03042, GST_N_Zeta, GST_N family, Class Zeta subfamily; GSTs are cytosolic dimeric proteins involved in cellular detoxification by catalyzing the conjugation of glutathione (GSH) with a wide range of endogenous and xenobiotic alkylating agents, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress. The GST fold contains an N-terminal TRX-fold domain and a C-terminal alpha helical domain, with an active site located in a cleft between the two domains. Class Zeta GSTs, also known as maleylacetoacetate (MAA) isomerases, catalyze the isomerization of MAA to fumarylacetoacetate, the penultimate step in tyrosine/phenylalanine catabolism, using GSH as a cofactor. They show little GSH-conjugating activity towards traditional GST substrates but display modest GSH peroxidase activity. They are also implicated in the detoxification of the carcinogen dichloroacetic acid by catalyzing its dechlorination to glyoxylic acid.бА0АкА0АаАCDDбАаАжьвА0А0АаАВ╢cd03043, GST_N_1, GST_N family, unknown subfamily 1; composed of uncharacterized proteins, predominantly from bacteria, with similarity to GSTs. GSTs are cytosolic dimeric proteins involved in cellular detoxification by catalyzing the conjugation of glutathione (GSH) with a wide range of endogenous and xenobiotic alkylating agents, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress. GSTs also show GSH peroxidase activity and are involved in the synthesis of prostaglandins and leukotrienes. The GST fold contains an N-terminal TRX-fold domain and a C-terminal alpha helical domain, with an active site located in a cleft between the two domains.бА0АкА0АаАCDDбАаАжэвА0А0АаАВYcd03044, GST_N_EF1Bgamma, GST_N family, Gamma subunit of Elongation Factor 1B (EFB1gamma) subfamily; EF1Bgamma is part of the eukaryotic translation elongation factor-1 (EF1) complex which plays a central role in the elongation cycle during protein biosynthesis. EF1 consists of two functionally distinct units, EF1A and EF1B. EF1A catalyzes the GTP-dependent binding of aminoacyl-tRNA to the ribosomal A site concomitant with the hydrolysis of GTP. The resulting inactive EF1A:GDP complex is recycled to the active GTP form by the guanine-nucleotide exchange factor EF1B, a complex composed of at least two subunits, alpha and gamma. Metazoan EFB1 contain a third subunit, beta. The EF1B gamma subunit contains a GST fold consisting of an N-terminal TRX-fold domain and a C-terminal alpha helical domain. The GST-like domain of EF1Bgamma is believed to mediate the dimerization of the EF1 complex, which in yeast is a dimer of the heterotrimer EF1A:EF1Balpha:EF1Bgamma. In addition to its role in protein biosynthesis, EF1Bgamma may also display other functions. The recombinant rice protein has been shown to possess GSH conjugating activity. The yeast EF1Bgamma binds membranes in a calcium dependent manner and is also part of a complex that binds to the msrA (methionine sulfoxide reductase) promoter suggesting a function in the regulation of its gene expression.бА0АкА0АаАCDDбАаАжювА0А0АаАВ▐cd03045, GST_N_Delta_Epsilon, GST_N family, Class Delta and Epsilon subfamily; GSTs are cytosolic dimeric proteins involved in cellular detoxification by catalyzing the conjugation of glutathione (GSH) with a wide range of endogenous and xenobiotic alkylating agents, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress. GSTs also show GSH peroxidase activity and are involved in the synthesis of prostaglandins and leukotrienes. The GST fold contains an N-terminal TRX-fold domain and a C-terminal alpha helical domain, with an active site located in a cleft between the two domains. The class Delta and Epsilon subfamily is made up primarily of insect GSTs, which play major roles in insecticide resistance by facilitating reductive dehydrochlorination of insecticides or conjugating them with GSH to produce water-soluble metabolites that are easily excreted. They are also implicated in protection against cellular damage by oxidative stress.бА0АкА0АаАCDDбАаАжявА0А0АаАВ*cd03046, GST_N_GTT1_like, GST_N family, Saccharomyces cerevisiae GTT1-like subfamily; composed of predominantly uncharacterized proteins with similarity to the S. cerevisiae GST protein, GTT1, and the Schizosaccharomyces pombe GST-III. GSTs are cytosolic dimeric proteins involved in cellular detoxification by catalyzing the conjugation of glutathione (GSH) with a wide range of endogenous and xenobiotic alkylating agents, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress. GSTs also show GSH peroxidase activity and are involved in the synthesis of prostaglandins and leukotrienes. The GST fold contains an N-terminal TRX-fold domain and a C-terminal alpha helical domain, with an active site located in a cleft between the two domains. GTT1, a homodimer, exhibits GST activity with standard substrates and associates with the endoplasmic reticulum. Its expression is induced after diauxic shift and remains high throughout the stationary phase. S. pombe GST-III is implicated in the detoxification of various metals.бА0АкА0АаАCDDбАаАжЁвА0А0АаАВКcd03047, GST_N_2, GST_N family, unknown subfamily 2; composed of uncharacterized bacterial proteins with similarity to GSTs. GSTs are cytosolic dimeric proteins involved in cellular detoxification by catalyzing the conjugation of glutathione (GSH) with a wide range of endogenous and xenobiotic alkylating agents, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress. GSTs also show GSH peroxidase activity and are involved in the synthesis of prostaglandins and leukotrienes. The GST fold contains an N-terminal TRX-fold domain and a C-terminal alpha helical domain, with an active site located in a cleft between the two domains. The sequence from Burkholderia cepacia was identified as part of a gene cluster involved in the degradation of 2,4,5-trichlorophenoxyacetic acid. Some GSTs (e.g. Class Zeta and Delta) are known to catalyze dechlorination reactions.бА0АкА0АаАCDDбАаАжёвА0А0АаАВИcd03048, GST_N_Ure2p_like, GST_N family, Ure2p-like subfamily; composed of the Saccharomyces cerevisiae Ure2p and related GSTs. Ure2p is a regulator for nitrogen catabolism in yeast. It represses the expression of several gene products involved in the use of poor nitrogen sources when rich sources are available. A transmissible conformational change of Ure2p results in a prion called [Ure3], an inactive, self-propagating and infectious amyloid. Ure2p displays a GST fold containing an N-terminal TRX-fold domain and a C-terminal alpha helical domain, with an active site located in a cleft between the two domains. The N-terminal TRX-fold domain is sufficient to induce the [Ure3] phenotype and is also called the prion domain of Ure2p. In addition to its role in nitrogen regulation, Ure2p confers protection to cells against heavy metal ion and oxidant toxicity, and shows glutathione (GSH) peroxidase activity. Characterized GSTs in this subfamily include Aspergillus fumigatus GSTs 1 and 2, and Schizosaccharomyces pombe GST-I. GSTs are cytosolic dimeric proteins involved in cellular detoxification by catalyzing the conjugation of GSH with a wide range of endogenous and xenobiotic alkylating agents, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress. GSTs also show GSH peroxidase activity and are involved in the synthesis of prostaglandins and leukotrienes.бА0АкА0АаАCDDбАаАжЄвА0А0АаАВвcd03049, GST_N_3, GST_N family, unknown subfamily 3; composed of uncharacterized bacterial proteins with similarity to GSTs. GSTs are cytosolic dimeric proteins involved in cellular detoxification by catalyzing the conjugation of glutathione (GSH) with a wide range of endogenous and xenobiotic alkylating agents, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress. GSTs also show GSH peroxidase activity and are involved in the synthesis of prostaglandins and leukotrienes. The GST fold contains an N-terminal TRX-fold domain and a C-terminal alpha helical domain, with an active site located in a cleft between the two domains.бА0АкА0АаАCDDбАаАжєвА0А0АаАВDcd03050, GST_N_Theta, GST_N family, Class Theta subfamily; composed of eukaryotic class Theta GSTs and bacterial dichloromethane (DCM) dehalogenase. GSTs are cytosolic dimeric proteins involved in cellular detoxification by catalyzing the conjugation of glutathione (GSH) with a wide range of endogenous and xenobiotic alkylating agents, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress. The GST fold contains an N-terminal TRX-fold domain and a C-terminal alpha helical domain, with an active site located in a cleft between the two domains. Mammalian class Theta GSTs show poor GSH conjugating activity towards the standard substrates, CDNB and ethacrynic acid, differentiating them from other mammalian GSTs. GSTT1-1 shows similar cataytic activity as bacterial DCM dehalogenase, catalyzing the GSH-dependent hydrolytic dehalogenation of dihalomethanes. This is an essential process in methylotrophic bacteria to enable them to use chloromethane and DCM as sole carbon and energy sources. The presence of polymorphisms in human GSTT1-1 and its relationship to the onset of diseases including cancer is subject of many studies. Human GSTT2-2 exhibits a highly specific sulfatase activity, catalyzing the cleavage of sulfate ions from aralkyl sufate esters, but not from aryl or alkyl sulfate esters.бА0АкА0АаАCDDбАаАжЇвА0А0АаАВЕcd03051, GST_N_GTT2_like, GST_N family, Saccharomyces cerevisiae GTT2-like subfamily; composed of predominantly uncharacterized proteins with similarity to the S. cerevisiae GST protein, GTT2. GSTs are cytosolic dimeric proteins involved in cellular detoxification by catalyzing the conjugation of glutathione (GSH) with a wide range of endogenous and xenobiotic alkylating agents, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress. GSTs also show GSH peroxidase activity and are involved in the synthesis of prostaglandins and leukotrienes. The GST fold contains an N-terminal TRX-fold domain and a C-terminal alpha helical domain, with an active site located in a cleft between the two domains. GTT2, a homodimer, exhibits GST activity with standard substrates. Strains with deleted GTT2 genes are viable but exhibit increased sensitivity to heat shock.бА0АкА0АаАCDDбАаАжївА0А0АаАВ~cd03052, GST_N_GDAP1, GST_N family, Ganglioside-induced differentiation-associated protein 1 (GDAP1) subfamily; GDAP1 was originally identified as a highly expressed gene at the differentiated stage of GD3 synthase-transfected cells. More recently, mutations in GDAP1 have been reported to cause both axonal and demyelinating autosomal-recessive Charcot-Marie-Tooth (CMT) type 4A neuropathy. CMT is characterized by slow and progressive weakness and atrophy of muscles. Sequence analysis of GDAP1 shows similarities and differences with GSTs; it appears to contain both N-terminal TRX-fold and C-terminal alpha helical domains of GSTs, however, it also contains additional C-terminal transmembrane domains unlike GSTs. GDAP1 is mainly expressed in neuronal cells and is localized in the mitochondria through its transmembrane domains. It does not exhibit GST activity using standard substrates.бА0АкА0АаАCDDбАаАжЎвА0А0АаАВHcd03053, GST_N_Phi, GST_N family, Class Phi subfamily; composed of plant-specific class Phi GSTs and related fungal and bacterial proteins. GSTs are cytosolic dimeric proteins involved in cellular detoxification by catalyzing the conjugation of glutathione (GSH) with a wide range of endogenous and xenobiotic alkylating agents, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress. The GST fold contains an N-terminal TRX-fold domain and a C-terminal alpha helical domain, with an active site located in a cleft between the two domains. The class Phi GST subfamily has experience extensive gene duplication. The Arabidopsis and Oryza genomes contain 13 and 16 Phi GSTs, respectively. They are primarily responsible for herbicide detoxification together with class Tau GSTs, showing class specificity in substrate preference. Phi enzymes are highly reactive toward chloroacetanilide and thiocarbamate herbicides. Some Phi GSTs have other functions including transport of flavonoid pigments to the vacuole, shoot regeneration and GSH peroxidase activity.бА0АкА0АаАCDDбАаАжўвА0А0АаАВ└cd03054, GST_N_Metaxin, GST_N family, Metaxin subfamily; composed of metaxins and related proteins. Metaxin 1 is a component of a preprotein import complex of the mitochondrial outer membrane. It extends to the cytosol and is anchored to the mitochondrial membrane through its C-terminal domain. In mice, metaxin is required for embryonic development. In humans, alterations in the metaxin gene may be associated with Gaucher disease. Metaxin 2 binds to metaxin 1 and may also play a role in protein translocation into the mitochondria. Genome sequencing shows that a third metaxin gene also exists in zebrafish, Xenopus, chicken and mammals. Sequence analysis suggests that all three metaxins share a common ancestry and that they possess similarity to GSTs. Also included in the subfamily are uncharacterized proteins with similarity to metaxins, including a novel GST from Rhodococcus with toluene o-monooxygenase and glutamylcysteine synthetase activities.бА0АкА0АаАCDDбАаАж°вА0А0АаАВucd03055, GST_N_Omega, GST_N family, Class Omega subfamily; GSTs are cytosolic dimeric proteins involved in cellular detoxification by catalyzing the conjugation of glutathione (GSH) with a wide range of endogenous and xenobiotic alkylating agents, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress. The GST fold contains an N-terminal TRX-fold domain and a C-terminal alpha helical domain, with an active site located in a cleft between the two domains. Class Omega GSTs show little or no GSH-conjugating activity towards standard GST substrates. Instead, they catalyze the GSH dependent reduction of protein disulfides, dehydroascorbate and monomethylarsonate, activities which are more characteristic of glutaredoxins. They contain a conserved cysteine equivalent to the first cysteine in the CXXC motif of glutaredoxins, which is a redox active residue capable of reducing GSH mixed disulfides in a monothiol mechanism. Polymorphisms of the class Omega GST genes may be associated with the development of some types of cancer and the age-at-onset of both Alzheimer's and Parkinson's diseases.бА0АкА0АаАCDDбАаАж∙вА0А0АаАВвcd03056, GST_N_4, GST_N family, unknown subfamily 4; composed of uncharacterized bacterial proteins with similarity to GSTs. GSTs are cytosolic dimeric proteins involved in cellular detoxification by catalyzing the conjugation of glutathione (GSH) with a wide range of endogenous and xenobiotic alkylating agents, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress. GSTs also show GSH peroxidase activity and are involved in the synthesis of prostaglandins and leukotrienes. The GST fold contains an N-terminal TRX-fold domain and a C-terminal alpha helical domain, with an active site located in a cleft between the two domains.бА0АкА0АаАCDDбАаАж·вА0А0АаАВОcd03057, GST_N_Beta, GST_N family, Class Beta subfamily; GSTs are cytosolic dimeric proteins involved in cellular detoxification by catalyzing the conjugation of glutathione (GSH) with a wide range of endogenous and xenobiotic alkylating agents, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress. The GST fold contains an N-terminal TRX-fold domain and a C-terminal alpha helical domain, with an active site located in a cleft between the two domains. Unlike mammalian GSTs which detoxify a broad range of compounds, the bacterial class Beta GSTs exhibit limited GSH conjugating activity with a narrow range of substrates. In addition to GSH conjugation, they also bind antibiotics and reduce the antimicrobial activity of beta-lactam drugs. The structure of the Proteus mirabilis enzyme reveals that the cysteine in the active site forms a covalent bond with GSH.бА0АкА0АаАCDDбАаАж√вА0А0АаАВ3cd03058, GST_N_Tau, GST_N family, Class Tau subfamily; GSTs are cytosolic dimeric proteins involved in cellular detoxification by catalyzing the conjugation of glutathione (GSH) with a wide range of endogenous and xenobiotic alkylating agents, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress. The GST fold contains an N-terminal TRX-fold domain and a C-terminal alpha helical domain, with an active site located in a cleft between the two domains. The plant-specific class Tau GST subfamily has undergone extensive gene duplication. The Arabidopsis and Oryza genomes contain 28 and 40 Tau GSTs, respectively. They are primarily responsible for herbicide detoxification together with class Phi GSTs, showing class specificity in substrate preference. Tau enzymes are highly efficient in detoxifying diphenylether and aryloxyphenoxypropionate herbicides. In addition, Tau GSTs play important roles in intracellular signalling, biosynthesis of anthocyanin, responses to soil stresses and responses to auxin and cytokinin hormones.бА0АкА0АаАCDDбАаАж№вА0А0АаАВЦcd03059, GST_N_SspA, GST_N family, Stringent starvation protein A (SspA) subfamily; SspA is a RNA polymerase (RNAP)-associated protein required for the lytic development of phage P1 and for stationary phase-induced acid tolerance of E. coli. It is implicated in survival during nutrient starvation. SspA adopts the GST fold with an N-terminal TRX-fold domain and a C-terminal alpha helical domain, but it does not bind glutathione (GSH) and lacks GST activity. SspA is highly conserved among gram-negative bacteria. Related proteins found in Neisseria (called RegF), Francisella and Vibrio regulate the expression of virulence factors necessary for pathogenesis.бА0АкА0АаАCDDбАаАж¤вА0А0АаАВ@cd03060, GST_N_Omega_like, GST_N family, Omega-like subfamily; composed of uncharacterized proteins with similarity to class Omega GSTs. GSTs are cytosolic dimeric proteins involved in cellular detoxification by catalyzing the conjugation of glutathione (GSH) with a wide range of endogenous and xenobiotic alkylating agents, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress. The GST fold contains an N-terminal TRX-fold domain and a C-terminal alpha helical domain, with an active site located in a cleft between the two domains. Class Omega GSTs show little or no GSH-conjugating activity towards standard GST substrates. Instead, they catalyze the GSH dependent reduction of protein disulfides, dehydroascorbate and monomethylarsonate, activities which are more characteristic of glutaredoxins. Like Omega enzymes, proteins in this subfamily contain a conserved cysteine equivalent to the first cysteine in the CXXC motif of glutaredoxins, which is a redox active residue capable of reducing GSH mixed disulfides in a monothiol mechanism.бА0АкА0АаАCDDбАаАж■вА0А0АаАВ╦cd03061, GST_N_CLIC, GST_N family, Chloride Intracellular Channel (CLIC) subfamily; composed of CLIC1-5, p64, parchorin and similar proteins. They are auto-inserting, self-assembling intracellular anion channels involved in a wide variety of functions including regulated secretion, cell division and apoptosis. They can exist in both water-soluble and membrane-bound states, and are found in various vesicles and membranes. Biochemical studies of the C. elegans homolog, EXC-4, show that the membrane localization domain is present in the N-terminal part of the protein. The structure of soluble human CLIC1 reveals that it is monomeric and it adopts a fold similar to GSTs, containing an N-terminal domain with a TRX fold and a C-terminal alpha helical domain. Upon oxidation, the N-terminal domain of CLIC1 undergoes a structural change to form a non-covalent dimer stabilized by the formation of an intramolecular disulfide bond between two cysteines that are far apart in the reduced form. The CLIC1 dimer bears no similarity to GST dimers. The redox-controlled structural rearrangement exposes a large hydrophobic surface, which is masked by dimerization in vitro. In vivo, this surface may represent the docking interface of CLIC1 in its membrane-bound state. The two cysteines in CLIC1 that form the disulfide bond in oxidizing conditions are essential for dimerization and chloride channel activity, however, in other subfamily members, the second cysteine is not conserved.бА0АкА0АаАCDDбАаАж вА0А0АаАВ╜cd03062, TRX_Fd_Sucrase, TRX-like [2Fe-2S] Ferredoxin (Fd) family, Sucrase subfamily; composed of proteins with similarity to a novel plant enzyme, isolated from potato, which contains a Fd-like domain and exhibits sucrolytic activity. The putative active site of the Fd-like domain of the enzyme contains two cysteines and two histidines for possible binding to iron-sulfur clusters, compared to four cysteines present in the active site of Fd.бА0АкА0АаАCDDбАаАзвА0А0АаАВcd03063, TRX_Fd_FDH_beta, TRX-like [2Fe-2S] Ferredoxin (Fd) family, NAD-dependent formate dehydrogenase (FDH) beta subunit; composed of proteins similar to the beta subunit of NAD-linked FDH of Ralstonia eutropha, a soluble enzyme that catalyzes the irreversible oxidation of formate to carbon dioxide accompanied by the reduction of NAD to NADH. FDH is a heteromeric enzyme composed of four nonidentical subunits (alpha, beta, gamma and delta). The FDH beta subunit contains a NADH:ubiquinone oxidoreductase (Nuo) F domain C-terminal to a Fd-like domain without the active site cysteines. The absence of conserved metal-binding residues in the putative active site suggests that members of this subfamily have lost the ability to bind iron-sulfur clusters in the N-terminal Fd-like domain. The C-terminal NuoF domain is a component of Nuo, a multisubunit complex catalyzing the electron transfer of NADH to quinone coupled with the transfer of protons across the membrane. NuoF contains one [4Fe-4S] cluster and binds NADH and FMN.бА0АкА0АаАCDDбАаАзвА0А0АаАВcd03064, TRX_Fd_NuoE, TRX-like [2Fe-2S] Ferredoxin (Fd) family, NADH:ubiquinone oxidoreductase (Nuo) subunit E subfamily; Nuo, also called respiratory chain Complex 1, is the entry point for electrons into the respiratory chains of bacteria and the mitochondria of eukaryotes. It is a multisubunit complex with at least 14 core subunits. It catalyzes the electron transfer of NADH to quinone coupled with the transfer of protons across the membrane, providing the proton motive force required for energy-consuming processes. Electrons are transferred from NADH to quinone through a chain of iron-sulfur clusters in Nuo, including the [2Fe-2S] cluster present in NuoE core subunit, also called the 24 kD subunit of Complex 1. This subfamily also include formate dehydrogenases, NiFe hydrogenases and NAD-reducing hydrogenases, that contain a NuoE domain. A subset of these proteins contain both NuoE and NuoF in a single chain. NuoF, also called the 51 kD subunit of Complex 1, contains one [4Fe-4S] cluster and also binds the NADH substrate and FMN.бА0АкА0АаАCDDбАаАзвА0А0АаАВ`cd03065, PDI_b_Calsequestrin_N, PDIb family, Calsequestrin subfamily, N-terminal TRX-fold domain; Calsequestrin is the major calcium storage protein in the sarcoplasmic reticulum (SR) of skeletal and cardiac muscle. It stores calcium ions in sufficient quantities (up to 20 mM) to allow repetitive contractions and is essential to maintain movement, respiration and heart beat. A missense mutation in human cardiac calsequestrin is associated with catecholamine-induced polymorphic ventricular tachycardia (CPVT), a rare disease characterized by seizures or sudden death in response to physiologic or emotional stress. Calsequestrin is a highly acidic protein with up to 50 calcium binding sites formed simply by the clustering of two or more acidic residues. The monomer contains three redox inactive TRX-fold domains. Calsequestrin is condensed as a linear polymer in the SR lumen and is membrane-anchored through binding with intra-membrane proteins triadin, junctin and ryanodine receptor (RyR) Ca2+ release channel. In addition to its role as a calcium ion buffer, calsequestrin also regulates the activity of the RyR channel, coordinating the release of calcium ions from the SR with the loading of the calcium store. The N-terminal TRX-fold domain (or domain I) mediates front-to-front dimer interaction, an important feature in the formation of calsequestrin polymers.бА0АкА0АаАCDDбАаАзвА0А0АаАВ╚cd03066, PDI_b_Calsequestrin_middle, PDIb family, Calsequestrin subfamily, Middle TRX-fold domain; Calsequestrin is the major calcium storage protein in the sarcoplasmic reticulum (SR) of skeletal and cardiac muscle. It stores calcium ions in sufficient quantities (up to 20 mM) to allow repetitive contractions and is essential to maintain movement, respiration and heart beat. A missense mutation in human cardiac calsequestrin is associated with catecholamine-induced polymorphic ventricular tachycardia (CPVT), a rare disease characterized by seizures or sudden death in response to physiologic or emotional stress. Calsequestrin is a highly acidic protein with up to 50 calcium binding sites formed simply by the clustering of two or more acidic residues. The monomer contains three redox inactive TRX-fold domains. Calsequestrin is condensed as a linear polymer in the SR lumen and is membrane-anchored through binding with intra-membrane proteins triadin, junctin and ryanodine receptor (RyR) Ca2+ release channel. In addition to its role as a calcium ion buffer, calsequestrin also regulates the activity of the RyR channel, coordinating the release of calcium ions from the SR with the loading of the calcium store.бА0АкА0АаАCDDбАаАзвА0А0АаАВPcd03067, PDI_b_PDIR_N, PDIb family, PDIR subfamily, N-terminal TRX-like b domain; composed of proteins similar to human PDIR (for Protein Disulfide Isomerase Related). PDIR is composed of three redox active TRX (a) domains and an N-terminal redox inactive TRX-like (b) domain. Similar to PDI, it is involved in oxidative protein folding in the endoplasmic reticulum (ER) through its isomerase and chaperone activities. These activities are lower compared to PDI, probably due to PDIR acting only on a subset of proteins. PDIR is preferentially expressed in cells actively secreting proteins and its expression is induced by stress. Similar to PDI, the isomerase and chaperone activities of PDIR are independent; CXXC mutants lacking isomerase activity retain chaperone activity. The TRX-like b domain of PDIR is critical for its chaperone activity.бА0АкА0АаАCDDбАаАзвА0А0АаАВ8cd03068, PDI_b_ERp72, PDIb family, ERp72 subfamily, first redox inactive TRX-like domain b; ERp72 exhibits both disulfide oxidase and reductase functions like PDI, by catalyzing the formation of disulfide bonds of newly synthesized polypeptides in the ER and acting as isomerases to correct any non-native disulfide bonds. It also displays chaperone activity to prevent protein aggregation and facilitate the folding of newly synthesized proteins. ERp72 contains three redox-active TRX (a) domains and two redox inactive TRX-like (b) domains. Its molecular structure is a"abb'a', compared to the abb'a' structure of PDI. ERp72 associates with several ER chaperones and folding factors to form complexes in the ER that bind nascent proteins. Similar to PDI, the b domain of ERp72 is likely involved in binding to substrates.бА0АкА0АаАCDDбАаАзвА0А0АаАВЙcd03069, PDI_b_ERp57, PDIb family, ERp57 subfamily, first redox inactive TRX-like domain b; ERp57 (or ERp60) exhibits both disulfide oxidase and reductase functions like PDI, by catalyzing the formation of disulfide bonds of newly synthesized polypeptides in the ER and acting as isomerases to correct any non-native disulfide bonds. It also displays chaperone activity to prevent protein aggregation and facilitate the folding of newly synthesized proteins. ERp57 contains two redox-active TRX (a) domains and two redox inactive TRX-like (b) domains. It shares the same domain arrangement of abb'a' as PDI, but lacks the C-terminal acid-rich region (c domain) that is present in PDI. ERp57 interacts with the lectin chaperones, calnexin and calreticulin, and specifically promotes the oxidative folding of glycoproteins. Similar to PDI, the b domain of ERp57 is likely involved in binding to substrates.бА0АкА0АаАCDDбАаАзвА0А0АаАВ{cd03070, PDI_b_ERp44, PDIb family, ERp44 subfamily, first redox inactive TRX-like domain b; ERp44 is an endoplasmic reticulum (ER)-resident protein, induced during stress, involved in thiol-mediated ER retention. It contains an N-terminal TRX domain with a CXFS motif followed by two redox inactive TRX-like domains, homologous to the b and b' domains of PDI. Through the formation of reversible mixed disulfides, ERp44 mediates the ER localization of Ero1alpha, a protein that oxidizes protein disulfide isomerases into their active form. ERp44 also prevents the secretion of unassembled cargo protein with unpaired cysteines. ERp44 also modulates the activity of inositol 1,4,5-triphosphate type I receptor (IP3R1), an intracellular channel protein that mediates calcium release from the ER to the cytosol. Similar to PDI, the b domain of ERp44 is likely involved in binding to substrates.бА0АкА0АаАCDDбАаАзвА0А0АаАВ]cd03071, PDI_b'_NRX, PDIb' family, NRX subgroup, redox inactive TRX-like domain b'; composed of vertebrate nucleoredoxins (NRX). NRX is a 400-amino acid nuclear protein with one redox active TRX domain followed by one redox inactive TRX-like domain homologous to the b' domain of PDI. In vitro studies show that NRX has thiol oxidoreductase activity and that it may be involved in the redox regulation of transcription, in a manner different from that of TRX or glutaredoxin. NRX enhances the activation of NF-kB by TNFalpha, as well as PMA-1 induced AP-1 and FK-induced CREB activation. Mouse NRX transcripts are expressed in all adult tissues but is restricted to the nervous system and limb buds in embryos. The mouse NRX gene is implicated in streptozotocin-induced diabetes. Similar to PDI, the b' domain of NRX is likely involved in substrate recognition.бА0АкА0АаАCDDбАаАз вА0А0АаАВдcd03072, PDI_b'_ERp44, PDIb' family, ERp44 subfamily, second redox inactive TRX-like domain b'; ERp44 is an endoplasmic reticulum (ER)-resident protein, induced during stress, involved in thiol-mediated ER retention. It contains an N-terminal TRX domain with a CXFS motif followed by two redox inactive TRX-like domains, homologous to the b and b' domains of PDI. Through the formation of reversible mixed disulfides, ERp44 mediates the ER localization of Ero1alpha, a protein that oxidizes protein disulfide isomerases into their active form. ERp44 also prevents the secretion of unassembled cargo protein with unpaired cysteines. ERp44 also modulates the activity of inositol 1,4,5-triphosphate type I receptor (IP3R1), an intracellular channel protein that mediates calcium release from the ER to the cytosol. Similar to PDI, the b' domain of ERp44 is likely involved in substrate recognition and may be the primary binding site.бА0АкА0АаАCDDбАаАз вА0А0АаАВcd03073, PDI_b'_ERp72_ERp57, PDIb' family, ERp72 and ERp57 subfamily, second redox inactive TRX-like domain b'; ERp72 and ER57 are involved in oxidative protein folding in the ER, like PDI. They exhibit both disulfide oxidase and reductase functions, by catalyzing the formation of disulfide bonds of newly synthesized polypeptides and acting as isomerases to correct any non-native disulfide bonds. They also display chaperone activity to prevent protein aggregation and facilitate the folding of newly synthesized proteins. ERp57 contains two redox-active TRX (a) domains and two redox inactive TRX-like (b) domains. It shares the same domain arrangement of abb'a' as PDI, but lacks the C-terminal acid-rich region (c domain) that is present in PDI. ERp72 contains one additional redox-active TRX (a) domain at the N-terminus with a molecular structure of a"abb'a'. ERp57 interacts with the lectin chaperones, calnexin and calreticulin, and specifically promotes the oxidative folding of glycoproteins. ERp72 associates with several ER chaperones and folding factors to form complexes in the ER that bind nascent proteins. The b' domain of ERp57 is the primary binding site and is adapted for ER lectin association. Similarly, the b' domain of ERp72 is likely involved in substrate recognition.бА0АкА0АаАCDDбАаАзвА0А0АаАВ╠cd03074, PDI_b'_Calsequestrin_C, Protein Disulfide Isomerase (PDIb') family, Calsequestrin subfamily, C-terminal TRX-fold domain; Calsequestrin is the major calcium storage protein in the sarcoplasmic reticulum (SR) of skeletal and cardiac muscle. It stores calcium ions in sufficient quantities (up to 20 mM) to allow repetitive contractions and is essential to maintain movement, respiration and heart beat. A missense mutation in human cardiac calsequestrin is associated with catecholamine-induced polymorphic ventricular tachycardia (CPVT), a rare disease characterized by seizures or sudden death in response to physiologic or emotional stress. Calsequestrin is a highly acidic protein with up to 50 calcium binding sites formed simply by the clustering of two or more acidic residues. The monomer contains three redox inactive TRX-fold domains. Calsequestrin is condensed as a linear polymer in the SR lumen and is membrane-anchored through binding with intra-membrane proteins triadin, junctin and ryanodine receptor (RyR) Ca2+ release channel. In addition to its role as a calcium ion buffer, calsequestrin also regulates the activity of the RyR channel, coordinating the release of calcium ions from the SR with the loading of the calcium store. The C-terminal TRX-fold domain (or domain III) mediates back-to-back dimer interaction and also contriubutes to the front-to-front dimer interface, both of which are important features in the formation of calsequestrin polymers.бА0АкА0АаАCDDбАаАзвА0А0АаАВtcd03075, GST_N_Mu, GST_N family, Class Mu subfamily; GSTs are cytosolic dimeric proteins involved in cellular detoxification by catalyzing the conjugation of glutathione (GSH) with a wide range of endogenous and xenobiotic alkylating agents, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress. The GST fold contains an N-terminal TRX-fold domain and a C-terminal alpha helical domain, with an active site located in a cleft between the two domains. The class Mu subfamily is composed of eukaryotic GSTs. In rats, at least six distinct class Mu subunits have been identified, with homologous genes in humans for five of these subunits. Class Mu GSTs can form homodimers and heterodimers, giving a large number of possible isoenzymes that can be formed, all with overlapping activities but different substrate specificities. They are the most abundant GSTs in human liver, skeletal muscle and brain, and are believed to provide protection against diseases including cancer and neurodegenerative disorders. Some isoenzymes have additional specific functions. Human GST M1-1 acts as an endogenous inhibitor of ASK1 (apoptosis signal-regulating kinase 1), thereby suppressing ASK1-mediated cell death. Human GSTM2-2 and 3-3 have been identified as prostaglandin E2 synthases in the brain and may play crucial roles in temperature and sleep-wake regulation.бА0АкА0АаАCDDбАаАз вА0А0АаАВNcd03076, GST_N_Pi, GST_N family, Class Pi subfamily; GSTs are cytosolic dimeric proteins involved in cellular detoxification by catalyzing the conjugation of glutathione (GSH) with a wide range of endogenous and xenobiotic alkylating agents, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress. The GST fold contains an N-terminal TRX-fold domain and a C-terminal alpha helical domain, with an active site located in a cleft between the two domains. Class Pi GST is a homodimeric eukaryotic protein. The human GSTP1 is mainly found in erythrocytes, kidney, placenta and fetal liver. It is involved in stress responses and in cellular proliferation pathways as an inhibitor of JNK (c-Jun N-terminal kinase). Following oxidative stress, monomeric GSTP1 dissociates from JNK and dimerizes, losing its ability to bind JNK and causing an increase in JNK activity, thereby promoting apoptosis. GSTP1 is expressed in various tumors and is the predominant GST in a wide range of cancer cells. It has been implicated in the development of multidrug-resistant tumours.бА0АкА0АаАCDDбАаАзвА0А0АаАВcd03077, GST_N_Alpha, GST_N family, Class Alpha subfamily; GSTs are cytosolic dimeric proteins involved in cellular detoxification by catalyzing the conjugation of glutathione (GSH) with a wide range of endogenous and xenobiotic alkylating agents, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress. The GST fold contains an N-terminal TRX-fold domain and a C-terminal alpha helical domain, with an active site located in a cleft between the two domains. The class Alpha subfamily is composed of eukaryotic GSTs which can form homodimer and heterodimers. There are at least six types of class Alpha GST subunits in rats, four of which have human counterparts, resulting in many possible isoenzymes with different activities, tissue distribution and substrate specificities. Human GSTA1-1 and GSTA2-2 show high GSH peroxidase activity. GSTA3-3 catalyzes the isomerization of intermediates in steroid hormone biosynthesis. GSTA4-4 preferentially catalyzes the GSH conjugation of alkenals.бА0АкА0АаАCDDбАаАзвА0А0АаАВдcd03078, GST_N_Metaxin1_like, GST_N family, Metaxin subfamily, Metaxin 1-like proteins; composed of metaxins 1 and 3, and similar proteins including Tom37 from fungi. Mammalian metaxin (or metaxin 1) and the fungal protein Tom37 are components of preprotein import complexes of the mitochondrial outer membrane. Metaxin extends to the cytosol and is anchored to the mitochondrial membrane through its C-terminal domain. In mice, metaxin is required for embryonic development. Like the murine gene, the human metaxin gene is located downstream to the glucocerebrosidase (GBA) pseudogene and is convergently transcribed. Inherited deficiency of GBA results in Gaucher disease, which presents many diverse clinical phenotypes. Alterations in the metaxin gene, in addition to GBA mutations, may be associated with Gaucher disease. Genome sequencing shows that a third metaxin gene also exists in zebrafish, Xenopus, chicken and mammals.бА0АкА0АаАCDDбАаАзвА0А0АаАВ&cd03079, GST_N_Metaxin2, GST_N family, Metaxin subfamily, Metaxin 2; a metaxin 1 binding protein identified through a yeast two-hybrid system using metaxin 1 as the bait. Metaxin 2 shares sequence similarity with metaxin 1 but does not contain a C-terminal mitochondrial outer membrane signal-anchor domain. It associates with mitochondrial membranes through its interaction with metaxin 1, which is a component of the mitochondrial preprotein import complex of the outer membrane. The biological function of metaxin 2 is unknown. It is likely that it also plays a role in protein translocation into the mitochondria. However, this has not been experimentally validated. In a recent proteomics study, it has been shown that metaxin 2 is overexpressed in response to lipopolysaccharide-induced liver injury.бА0АкА0АаАCDDбАаАзвА0А0АаАВ╘cd03080, GST_N_Metaxin_like, GST_N family, Metaxin subfamily, Metaxin-like proteins; a heterogenous group of proteins, predominantly uncharacterized, with similarity to metaxins and GSTs. Metaxin 1 is a component of a preprotein import complex of the mitochondrial outer membrane. It extends to the cytosol and is anchored to the mitochondrial membrane through its C-terminal domain. In mice, metaxin is required for embryonic development. In humans, alterations in the metaxin gene may be associated with Gaucher disease. One characterized member of this subgroup is a novel GST from Rhodococcus with toluene o-monooxygenase and gamma-glutamylcysteine synthetase activities. Also members are the cadmium-inducible lysosomal protein CDR-1 and its homologs from C. elegans, and the failed axon connections (fax) protein from Drosophila. CDR-1 is an integral membrane protein that functions to protect against cadmium toxicity and may also have a role in osmoregulation to maintain salt balance in C. elegans. The fax gene of Drosophila was identified as a genetic modifier of Abelson (Abl) tyrosine kinase. The fax protein is localized in cellular membranes and is expressed in embryonic mesoderm and axons of the central nervous system.бА0АкА0АаАCDDбАаАзвА0А0АаАВ∙cd03081, TRX_Fd_NuoE_FDH_gamma, TRX-like [2Fe-2S] Ferredoxin (Fd) family, NADH:ubiquinone oxidoreductase (Nuo) subunit E subfamily, NAD-dependent formate dehydrogenase (FDH) gamma subunit; composed of proteins similar to the gamma subunit of NAD-linked FDH of Ralstonia eutropha, a soluble enzyme that catalyzes the irreversible oxidation of formate to carbon dioxide accompanied by the reduction of NAD+ to NADH. FDH is a heteromeric enzyme composed of four nonidentical subunits (alpha, beta, gamma and delta). The FDH gamma subunit is closely related to NuoE, which is part of a multisubunit complex (Nuo) catalyzing the electron transfer of NADH to quinone coupled with the transfer of protons across the membrane. Electrons are transferred from NADH to quinone through a chain of iron-sulfur clusters in Nuo, including the [2Fe-2S] cluster present in NuoE. Similarly, the FDH gamma subunit is hypothesized to be involved in an electron transport chain involving other FDH subunits, upon the oxidation of formate.бА0АкА0АаАCDDбАаАзвА0А0АаАВcd03082, TRX_Fd_NuoE_W_FDH_beta, TRX-like [2Fe-2S] Ferredoxin (Fd) family, NADH:ubiquinone oxidoreductase (Nuo) subunit E family, Tungsten-containing formate dehydrogenase (W-FDH) beta subunit; composed of proteins similar to the W-FDH beta subunit of Methylobacterium extorquens. W-FDH is a heterodimeric NAD-dependent enzyme catalyzing the conversion of formate to carbon dioxide. The beta subunit is a fusion protein containing an N-terminal NuoE domain and a C-terminal NuoF domain. NuoE and NuoF are components of Nuo, a multisubunit complex catalyzing the electron transfer of NADH to quinone coupled with the transfer of protons across the membrane. Electrons are transferred from NADH to quinone through a chain of iron-sulfur clusters in Nuo, including the [2Fe-2S] cluster in NuoE and the [4Fe-4S] cluster in NuoF. In addition, NuoF is also the NADH- and FMN-binding subunit. Similarly, the beta subunit of W-FDH is most likely involved in the electron transport chain during the NAD-dependent oxidation of formate.бА0АкА0АаАCDDбАаАзвА0А0АаАВ cd03083, TRX_Fd_NuoE_hoxF, TRX-like [2Fe-2S] Ferredoxin (Fd) family, NADH:ubiquinone oxidoreductase (Nuo) subunit E subfamily, hoxF; composed of proteins similar to the NAD-reducing hydrogenase (hoxS) alpha subunit of Alcaligenes eutrophus H16. HoxS is a cytoplasmic hydrogenase catalyzing the oxidation of molecular hydrogen accompanied by the reduction of NAD. It is composed of four structural subunits encoded by the genes hoxF, hoxU, hoxY and hoxH. The hoxF protein (or alpha subunit) is a fusion protein containing an N-terminal NuoE-like domain and a C-terminal NuoF domain. NuoE and NuoF are components of Nuo, a multisubunit complex catalyzing the electron transfer of NADH to quinone coupled with the transfer of protons across the membrane. Electrons are transferred from NADH to quinone through a chain of iron-sulfur clusters in Nuo, including the [2Fe-2S] cluster in NuoE and the [4Fe-4S] cluster in NuoF. In addition, NuoF is also the NADH- and FMN-binding subunit. HoxF may be involved in the electron transport chain during the NAD-dependent oxidation of hydrogen through its NuoF domain. The NuoE-like domain of hoxF contains only one conserved cysteine in its putative active site, compared to four cysteines in NuoE, and may have lost the ability to bind [2Fe-2S] clusters.бА0АкА0АаАCDDбАаАзвА0А0АаАВcd03084, phosphohexomutase, The alpha-D-phosphohexomutase superfamily includes several related enzymes that catalyze a reversible intramolecular phosphoryl transfer on their sugar substrates. Members of this family include the phosphoglucomutases (PGM1 and PGM2), phosphoglucosamine mutase (PNGM), phosphoacetylglucosamine mutase (PAGM), the bacterial phosphomannomutase ManB, the bacterial phosphoglucosamine mutase GlmM, and the bifunctional phosphomannomutase/phosphoglucomutase (PMM/PGM). These enzymes play important and diverse roles in carbohydrate metabolism in organisms from bacteria to humans. Each of these enzymes has four domains with a centrally located active site formed by four loops, one from each domain. All four domains are included in this alignment model.бА0АкА0АаАCDDбАаАЖЎвА0А0АаАВ╩cd03085, PGM1, Phosphoglucomutase 1 (PGM1) catalyzes the bidirectional interconversion of glucose-1-phosphate (G-1-P) and glucose-6-phosphate (G-6-P) via a glucose 1,6-diphosphate intermediate, an important metabolic step in prokaryotes and eukaryotes. In one direction, G-1-P produced from sucrose catabolism is converted to G-6-P, the first intermediate in glycolysis. In the other direction, conversion of G-6-P to G-1-P generates a substrate for synthesis of UDP-glucose which is required for synthesis of a variety of cellular constituents including cell wall polymers and glycoproteins. The PGM1 family also includes a non-enzymatic PGM-related protein (PGM-RP) thought to play a structural role in eukaryotes, as well as pp63/parafusin, a phosphoglycoprotein that plays an important role in calcium-regulated exocytosis in ciliated protozoans. PGM1 belongs to the alpha-D-phosphohexomutase superfamily which includes several related enzymes that catalyze a reversible intramolecular phosphoryl transfer on their sugar substrates. Other members of this superfamily include phosphoglucosamine mutase (PNGM), phosphoacetylglucosamine mutase (PAGM), the bacterial phosphomannomutase ManB, the bacterial phosphoglucosamine mutase GlmM, and the bifunctional phosphomannomutase/phosphoglucomutase (PMM/PGM). Each of these enzymes has four domains with a centrally located active site formed by four loops, one from each domain. All four domains are included in this alignment model.бА0АкА0АаАCDDбАаАЖўвА0А0АаАВ cd03086, PGM3, PGM3 (phosphoglucomutase 3), also known as PAGM (phosphoacetylglucosamine mutase) and AGM1 (N-acetylglucosamine-phosphate mutase), is an essential enzyme found in eukaryotes that reversibly catalyzes the conversion of GlcNAc-6-phosphate into GlcNAc-1-phosphate as part of the UDP-N-acetylglucosamine (UDP-GlcNAc) biosynthetic pathway. UDP-GlcNAc is an essential metabolite that serves as the biosynthetic precursor of many glycoproteins and mucopolysaccharides. AGM1 is a member of the alpha-D-phosphohexomutase superfamily, which catalyzes the intramolecular phosphoryl transfer of sugar substrates. The alpha-D-phosphohexomutases have four domains with a centrally located active site formed by four loops, one from each domain. All four domains are included in this alignment model.бА0АкА0АаАCDDбАаАЖ°вА0А0АаАВОcd03087, PGM_like1, This archaeal PGM-like (phosphoglucomutase-like) protein of unknown function belongs to the alpha-D-phosphohexomutase superfamily which includes several related enzymes that catalyze a reversible intramolecular phosphoryl transfer on their sugar substrates. The alpha-D-phosphohexomutases include several related enzymes that catalyze a reversible intramolecular phosphoryl transfer on their sugar substrates. Members of this superfamily include the phosphoglucomutases (PGM1 and PGM2), phosphoglucosamine mutase (PNGM), phosphoacetylglucosamine mutase (PAGM), the bacterial phosphomannomutase ManB, the bacterial phosphoglucosamine mutase GlmM, and the bifunctional phosphomannomutase/phosphoglucomutase (PMM/PGM). Each of these enzymes has four domains with a centrally located active site formed by four loops, one from each domain. All four domains are included in this alignment model.бА0АкА0АаАCDDбАаАЖ∙вА0А0АаАВbcd03088, ManB, ManB is a bacterial phosphomannomutase (PMM) that catalyzes the conversion of mannose 6-phosphate to mannose-1-phosphate in the second of three steps in the GDP-mannose pathway, in which GDP-D-mannose is synthesized from fructose-6-phosphate. In Mycobacterium tuberculosis, the causative agent of tuberculosis, PMM is involved in the biosynthesis of mannosylated lipoglycans that participate in the association of mycobacteria with host macrophage phagocytic receptors. ManB belongs to the the alpha-D-phosphohexomutase superfamily which includes several related enzymes that catalyze a reversible intramolecular phosphoryl transfer on their sugar substrates. Other members of this superfamily include the phosphoglucomutases (PGM1 and PGM2), phosphoglucosamine mutase (PNGM), phosphoacetylglucosamine mutase (PAGM), the bacterial phosphoglucosamine mutase GlmM, and the bifunctional phosphomannomutase/phosphoglucomutase (PMM/PGM). Each of these enzymes has four domains with a centrally located active site formed by four loops, one from each domain. All four domains are included in this alignment model.бА0АкА0АаАCDDбАаАЖ·вА0А0АаАВГcd03089, PMM_PGM, The phosphomannomutase/phosphoglucomutase (PMM/PGM) bifunctional enzyme catalyzes the reversible conversion of 1-phospho to 6-phospho-sugars (e.g. between mannose-1-phosphate and mannose-6-phosphate or glucose-1-phosphate and glucose-6-phosphate) via a bisphosphorylated sugar intermediate. The reaction involves two phosphoryl transfers, with an intervening 180 degree reorientation of the reaction intermediate during catalysis. Reorientation of the intermediate occurs without dissociation from the active site of the enzyme and is thus, a simple example of processivity, as defined by multiple rounds of catalysis without release of substrate. Glucose-6-phosphate and glucose-1-phosphate are known to be utilized for energy metabolism and cell surface construction, respectively. PMM/PGM belongs to the alpha-D-phosphohexomutase superfamily which includes several related enzymes that catalyze a reversible intramolecular phosphoryl transfer on their sugar substrates. Other members of this superfamily include phosphoglucosamine mutase (PNGM), phosphoacetylglucosamine mutase (PAGM), the bacterial phosphomannomutase ManB, the bacterial phosphoglucosamine mutase GlmM, and the phosphoglucomutases (PGM1 and PGM2). Each of these enzymes has four domains with a centrally located active site formed by four loops, one from each domain. All four domains are included in this alignment model.бА0АкА0АаАCDDбАаАЖ√вА0А0АаАВcd03108, AdSS, Adenylosuccinate synthetase (AdSS) catalyzes the first step in the de novo biosynthesis of AMP. IMP and L-aspartate are conjugated in a two-step reaction accompanied by the hydrolysis of GTP to GDP in the presence of Mg2+. In the first step, the r-phosphate group of GTP is transferred to the 6-oxygen atom of IMP. An aspartate then displaces this 6-phosphate group to form the product adenylosuccinate. Because of its critical role in purine biosynthesis, AdSS is a target of antibiotics, herbicides and antitumor drugs.бА0АкА0АаАCDDбАаАзвА0А0АаАВзcd03109, DTBS, Dethiobiotin synthetase (DTBS) is the penultimate enzyme in the biotin biosynthesis pathway in Escherichia coli and other microorganisms. The enzyme catalyzes formation of the ureido ring of dethiobiotin from (7R,8S)-7,8-diaminononanoic acid (DAPA) and carbon dioxide. The enzyme utilizes carbon dioxide instead of hydrogen carbonate as substrate and is dependent on ATP and divalent metal ions as cofactors.бА0АкА0АаАCDDбАаАзвА0А0АаАБвcd03110, Fer4_NifH_child, This protein family's function is unkown. It contains nucleotide binding site. It uses NTP as energy source to transfer electron or ion.бА0АкА0АаАCDDбАаАзвА0А0АаАВzcd03111, CpaE_like, This protein family consists of proteins similar to the cpaE protein of the Caulobacter pilus assembly and the orf4 protein of Actinobacillus pilus formation gene cluster. The function of these proteins are unkown. The Caulobacter pilus assembly contains 7 genes: pilA, cpaA, cpaB, cpaC, cpaD, cpaE and cpaF. These genes are clustered together on chromosome.бА0АкА0АаАCDDбАаАзвА0А0АаАВБcd03112, CobW_like, The function of this protein family is unkown. The amino acid sequence of YjiA protein in E. coli contains several conserved motifs that characterizes it as a P-loop GTPase. YijA gene is among the genes significantly induced in response to DNA-damage caused by mitomycin. YijA gene is a homologue of the CobW gene which encodes the cobalamin synthesis protein/P47K.бА0АкА0АаАCDDбАаАзвА0А0АаАВEcd03113, CTGs, CTP synthetase (CTPs) is a two-domain protein, which consists of an N-terminal synthetase domain and C-terminal glutaminase domain. The enzymes hydrolyze the amide bond of glutamine to ammonia and glutamate at the glutaminase domains and transfer nascent ammonia to the acceptor substrate at the synthetase domain to form an aminated product. Glutaminase domains have evolved from the same ancestor, whereas the synthetase domains are evolutionarily unrelated and have different functions. This protein family is classified based on the N-terminal synthetase domain.бА0АкА0АаАCDDбАаАзвА0А0АаАВ]cd03114, ArgK-like, The function of this protein family is unkown. The protein sequences are similar to the ArgK protein in E. coli. ArgK protein is a membrane ATPase which is required for transporting arginine, ornithine and lysine into the cells by the arginine and ornithine (AO system) and lysine, arginine and ornithine (LAO) transport systems.бА0АкА0АаАCDDбАаАзвА0А0АаАВуcd03115, SRP, The signal recognition particle (SRP) mediates the transport to or across the plasma membrane in bacteria and the endoplasmic reticulum in eukaryotes. SRP recognizes N-terminal sighnal sequences of newly synthesized polypeptides at the ribosome. The SRP-polypeptide complex is then targeted to the membrane by an interaction between SRP and its cognated receptor (SR). In mammals, SRP consists of six protein subunits and a 7SL RNA. One of these subunits is a 54 kd protein (SRP54), which is a GTP-binding protein that interacts with the signal sequence when it emerges from the ribosome. SRP54 is a multidomain protein that consists of an N-terminal domain, followed by a central G (GTPase) domain and a C-terminal M domain.бА0АкА0АаАCDDбАаАзвА0А0АаАВЩcd03116, MobB, Molybdenum is an essential trace element in the form of molybdenum cofactor (Moco) which is associated with the metabolism of nitrogen, carbon and sulfur by redox active enzymes. In E. coli, the synthesis of Moco involves genes from several loci: moa, mob, mod, moe and mog. The mob locus contains mobA and mobB genes. MobB catalyzes the attachment of the guanine dinucleotide to molybdopterin.бА0АкА0АаАCDDбАаАзвА0А0АаАВнcd03117, alpha_CA_IV_XV_like, Carbonic anhydrase alpha, CA_IV, CA_XV, like isozymes. Carbonic anhydrases (CAs) are zinc-containing enzymes that catalyze the reversible hydration of carbon dioxide in a two-step mechanism: a nucleophilic attack of a zinc-bound hydroxide ion on carbon dioxide, followed by the regeneration of the active site by ionization of the zinc-bound water molecule and removal of a proton from the active site. They are ubiquitous enzymes involved in fundamental processes like photosynthesis, respiration, pH homeostasis and ion transport. There are three evolutionary distinct groups - alpha, beta and gamma carbonic anhydrases - which show no significant sequence identity or structural similarity. Most alpha CAs are monomeric enzymes. The zinc ion is complexed by three histidine residues. This subgroup, restricted to animals, contains isozyme IV and similar proteins such as mouse CA XV. Isozymes IV is attached to membranes via a glycosylphosphatidylinositol (GPI) tail. In mammals, Isozyme IV plays crucial roles in kidney and lung function, amongst others. This subgroup also contains the dual domain CA from the giant clam, Tridacna gigas. T. gigas CA plays a role in the movement of inorganic carbon from the surrounding seawater to the symbiotic algae found in the clam's tissues. CA XV is expressed in several species but not in humans or chimps. Similar to isozyme CA IV, CA XV attaches to membranes via a GPI tail.бА0АкА0АаАCDDбАаАзвА0А0АаАВ*cd03118, alpha_CA_V, Carbonic anhydrase alpha, CA isozyme V_like subgroup. Carbonic anhydrases (CAs) are zinc-containing enzymes that catalyze the reversible hydration of carbon dioxide in a two-step mechanism: a nucleophilic attack of a zinc-bound hydroxide ion on carbon dioxide, followed by the regeneration of the active site by ionization of the zinc-bound water molecule and removal of a proton from the active site. They are ubiquitous enzymes involved in fundamental processes like photosynthesis, respiration, pH homeostasis and ion transport. Most alpha CAs are monomeric enzymes. The zinc ion is complexed by three histidines. This vertebrate subgroup comprises isozyme V. CA V is the mitochondrial isozyme, which may play a role in gluconeogenesis and ureagenesis and possibly also in lipogenesis.бА0АкА0АаАCDDбАаАз вА0А0АаАВПcd03119, alpha_CA_I_II_III_XIII, Carbonic anhydrase alpha, isozymes I, II, and III and XIII. Carbonic anhydrases (CAs) are zinc-containing enzymes that catalyze the reversible hydration of carbon dioxide in a two-step mechanism: a nucleophilic attack of a zinc-bound hydroxide ion on carbon dioxide, followed by the regeneration of the active site by ionization of the zinc-bound water molecule and removal of a proton from the active site. They are ubiquitous enzymes involved in fundamental processes like photosynthesis, respiration, pH homeostasis and ion transport. Most alpha CAs are monomeric enzymes. The zinc ion is complexed by three histidines. This vertebrate subgroup comprises isozymes I, II, and III, which are cytoplasmic enzymes. CA I, for example, is expressed in erythrocyes of many vertebrates; CA II is the most active cytosolic isozyme; while it is being expressed nearly ubiquitously, it comprises 95% of the renal carbonic anhydrase and is required for renal acidification; CA III has been implicated in protection from the damaging effect of oxidizing agents in hepatocytes. CAXIII may play important physiological roles in several organs.бА0АкА0АаАCDDбАаАз!вА0А0АаАВkcd03120, alpha_CARP_VIII, Carbonic anhydrase alpha related protein, group VIII. Carbonic anhydrase related proteins (CARPs) are sequence similar to carbonic anhydrases. Carbonic anhydrases are zinc-containing enzymes that catalyze the reversible hydration of carbon dioxide in a two-step mechanism. CARPs have lost conserved histidines involved in zinc binding and consequently their catalytic activity. CARP VIII may play roles in various biological processes of the central nervous system, and could be involved in protein-protein interactions. CARP VIII has been shown to bind inositol 1,4,5-triphosphate (IP3) receptor type I (IP3RI), reducing the affinity of the receptor for IP3. IP3RI is an intracellular IP3-gated Ca2+ channel located on intracellular Ca2+ stores. IP3RI converts IP3 signaling into Ca2+ signaling thereby participating in a variety of cell functions.бА0АкА0АаАCDDбАаАз"вА0А0АаАВ|cd03121, alpha_CARP_X_XI_like, Carbonic anhydrase alpha related protein: groups X, XI and related proteins. This subgroup contains carbonic anhydrase related proteins (CARPs) X and XI, which have been implicated in various biological processes of the central nervous system. CARPs are sequence similar to carbonic anhydrases. Carbonic anhydrases are zinc-containing enzymes that catalyze the reversible hydration of carbon dioxide in a two-step mechanism. CARPs have lost conserved histidines involved in zinc binding and consequently their catalytic activity. CARP XI plays a role in the development of gastrointestinal stromal tumors.бА0АкА0АаАCDDбАаАз#вА0А0АаАВ)cd03122, alpha_CARP_receptor_like, Carbonic anhydrase alpha related protein, receptor_like subfamily. Carbonic anhydrase related proteins (CARPs) are sequence similar to carbonic anhydrases. Carbonic anhydrases are zinc-containing enzymes that catalyze the reversible hydration of carbon dioxide in a two-step mechanism. CARPs have lost conserved histidines involved in zinc binding and consequently their catalytic activity. This sub-family of carbonic anhydrase-related domains found in tyrosine phosphatase receptors may play a role in cell adhesion.бА0АкА0АаАCDDбАаАз$вА0А0АаАВ║cd03123, alpha_CA_VI_IX_XII_XIV, Carbonic anhydrase alpha, isozymes VI, IX, XII and XIV. Carbonic anhydrases (CAs) are zinc-containing enzymes that catalyze the reversible hydration of carbon dioxide in a two-step mechanism: a nucleophilic attack of a zinc-bound hydroxide ion on carbon dioxide, followed by the regeneration of the active site by ionization of the zinc-bound water molecule and removal of a proton from the active site. They are ubiquitous enzymes involved in fundamental processes like photosynthesis, respiration, pH homeostasis and ion transport. There are three evolutionary distinct groups - alpha, beta and gamma carbonic anhydrases - which show no significant sequence identity or structural similarity. Alpha CAs are mostly monomeric enzymes. The zinc ion is complexed by three histidine residues. This sub-family comprises the secreted CA VI, which is found in saliva, for example, and the membrane proteins CA IX, XII, and XIV.бА0АкА0АаАCDDбАаАз%вА0А0АаАВЪcd03124, alpha_CA_prokaryotic_like, Carbonic anhydrase alpha, prokaryotic-like subfamily. Carbonic anhydrases (CAs) are zinc-containing enzymes that catalyze the reversible hydration of carbon dioxide in a two-step mechanism: a nucleophilic attack of a zinc-bound hydroxide ion on carbon dioxide, followed by the regeneration of the active site by ionization of the zinc-bound water molecule and removal of a proton from the active site. They are ubiquitous enzymes involved in fundamental processes like photosynthesis, respiration, pH homeostasis and ion transport. Most alpha CAs are monomeric enzymes. The zinc ion is complexed by three histidines. This sub-family includes bacterial carbonic anhydrase alpha, as well as plant enzymes such as tobacco nectarin III and yam dioscorin and, carbonic anhydrases from molluscs, such as nacrein, which are part of the organic matrix layer in shells. Other members of this family may be involved in maintaining pH balance, in facilitating transport of carbon dioxide or carbonic acid, or in sensing carbon dioxide levels in the environment. Dioscorin is the major storage protein of yam tubers and may play a role as an antioxidant. Tobacco Nectarin may play a role in the maintenace of pH and oxidative balance in nectar. Mollusc nacrein may participate in calcium carbonate crystal formation of the nacreous layer. This subfamily also includes three alpha carbonic anhydrases from Chlamydomonas reinhardtii (CAH 1-3). CAHs1-2 are localized in the periplasmic space. CAH1 faciliates the movement of carbon dioxide across the plasma membrane when the medium is alkaline. CAH3 is localized to the thylakoid lumen and provides CO2 to Rubisco.бА0АкА0АаАCDDбАаАз&вА0А0АаАВ`cd03125, alpha_CA_VI, Carbonic anhydrase alpha, isozyme VI. Carbonic anhydrases (CAs) are zinc-containing enzymes that catalyze the reversible hydration of carbon dioxide in a two-step mechanism: a nucleophilic attack of a zinc-bound hydroxide ion on carbon dioxide, followed by the regeneration of the active site by ionization of the zinc-bound water molecule and removal of a proton from the active site. They are ubiquitous enzymes involved in fundamental processes like photosynthesis, respiration, pH homeostasis and ion transport. There are three evolutionary distinct groups - alpha, beta and gamma carbonic anhydrases - which show no significant sequence identity or structural similarity. Most alpha CAs are monomeric enzymes. The zinc ion is complexed by three histidine residues. This sub-family comprises the secreted CA VI, which is found in saliva.бА0АкА0АаАCDDбАаАз'вА0А0АаАВfcd03126, alpha_CA_XII_XIV, Carbonic anhydrase alpha, isozymes XII and XIV. Carbonic anhydrases (CAs) are zinc-containing enzymes that catalyze the reversible hydration of carbon dioxide in a two-step mechanism: a nucleophilic attack of a zinc-bound hydroxide ion on carbon dioxide, followed by the regeneration of the active site by ionization of the zinc-bound water molecule and removal of a proton from the active site. They are ubiquitous enzymes involved in fundamental processes like photosynthesis, respiration, pH homeostasis and ion transport. There are three evolutionary distinct groups - alpha, beta and gamma carbonic anhydrases - which show no significant sequence identity or structural similarity. Most alpha CAs are monomeric enzymes. The zinc ion is complexed by three histidine residues. This sub-family comprises the membrane proteins CA XII and XIV.бА0АкА0АаАCDDбАаАз(вА0А0АаАВюcd03127, tetraspanin_LEL, Tetraspanin, extracellular domain or large extracellular loop (LEL). Tetraspanins are trans-membrane proteins with 4 trans-membrane segments. Both the N- and C-termini lie on the intracellular side of the membrane. This alignment model spans the extracellular domain between the 3rd and 4th trans-membrane segment. The tetraspanin family contains CD9, CD63, CD37, CD53, CD82, CD151, and CD81, amongst others. Tetraspanins are involved in diverse processes such as cell activation and proliferation, adhesion and motility, differentiation, cancer, and others. Their various functions may relate to their ability to act as molecular facilitators, grouping specific cell-surface proteins and affecting formation and stability of signaling complexes. Tetraspanins associate laterally with one another and cluster dynamically with numerous parnter domains in membrane microdomains, forming a network of multimolecular complexes, the "tetraspanin web", which may also include integrins.бА0АкА0АаАCDDбАаАз)вА0А0АаАВ°cd03128, GAT_1, Type 1 glutamine amidotransferase (GATase1)-like domain. Type 1 glutamine amidotransferase (GATase1)-like domain. This group contains proteins similar to Class I glutamine amidotransferases, the intracellular PH1704 from Pyrococcus horikoshii, the C-terminal of the large catalase: Escherichia coli HP-II, Sinorhizobium meliloti Rm1021 ThuA, the A4 beta-galactosidase middle domain and peptidase E. The majority of proteins in this group have a reactive Cys found in the sharp turn between a beta strand and an alpha helix termed the nucleophile elbow. For Class I glutamine amidotransferases proteins which transfer ammonia from the amide side chain of glutamine to an acceptor substrate, this Cys forms a Cys-His-Glu catalytic triad in the active site. Glutamine amidotransferases activity can be found in a range of biosynthetic enzymes included in this cd: glutamine amidotransferase, formylglycinamide ribonucleotide, GMP synthetase, anthranilate synthase component II, glutamine-dependent carbamoyl phosphate synthase (CPSase), cytidine triphosphate synthetase, gamma-glutamyl hydrolase, imidazole glycerol phosphate synthase and, cobyric acid synthase. For Pyrococcus horikoshii PH1704, the Cys of the nucleophile elbow together with a different His and, a Glu from an adjacent monomer form a catalytic triad different from the typical GATase1 triad. Peptidase E is believed to be a serine peptidase having a Ser-His-Glu catalytic triad which differs from the Cys-His-Glu catalytic triad of typical GATase1 domains, by having a Ser in place of the reactive Cys at the nucleophile elbow. The E. coli HP-II C-terminal domain, S. meliloti Rm1021 ThuA and the A4 beta-galactosidase middle domain lack the catalytic triad typical GATaseI domains. GATase1-like domains can occur either as single polypeptides, as in Class I glutamine amidotransferases, or as domains in a much larger multifunctional synthase protein, such as CPSase. Peptidase E has a circular permutation in the common core of a typical GTAse1 domain.бА0АкА0АаАCDDбАаАVЖвА0А0АаАВcd03129, GAT1_Peptidase_E_like, Type 1 glutamine amidotransferase (GATase1)-like domain found in peptidase E_like proteins. Type 1 glutamine amidotransferase (GATase1)-like domain found in peptidase E_like proteins. This group contains proteins similar to the aspartyl dipeptidases Salmonella typhimurium peptidase E and Xenopus laevis peptidase E and, extracellular cyanophycinases from Pseudomonas anguilliseptica BI (CphE) and Synechocystis sp. PCC 6803 CphB. In bacteria peptidase E is believed to play a role in degrading peptides generated by intracellular protein breakdown or imported into the cell as nutrient sources. Peptidase E uniquely hydrolyses only Asp-X dipeptides (where X is any amino acid), and one tripeptide Asp-Gly-Gly. Cyanophycinases are intracellular exopeptidases which hydrolyze the polymer cyanophycin (multi L-arginyl-poly-L-aspartic acid) to the dipeptide beta-Asp-Arg. Peptidase E and cyanophycinases are thought to have a Ser-His-Glu catalytic triad which differs from the Cys-His-Glu catalytic triad typical of GATase1 domains by having a Ser in place of the reactive Cys at the nucleophile elbow. Xenopus peptidase E is developmentally regulated in response to thyroid hormone and, it is thought to play a role in apoptosis during tail reabsorption.бА0АкА0АаАCDDбАаАVЗвА0А0АаАВfcd03130, GATase1_CobB, Type 1 glutamine amidotransferase (GATase1) domain found in Cobyrinic Acid a,c-Diamide Synthase. Type 1 glutamine amidotransferase (GATase1) domain found in Cobyrinic Acid a,c-Diamide Synthase. CobB plays a role in cobalamin biosythesis catalyzing the conversion of cobyrinic acid to cobyrinic acid a,c-diamide. CobB belongs to the triad family of amidotransferases. Two of the three residues of the catalytic triad that are involved in glutamine binding, hydrolysis and transfer of the resulting ammonia to the acceptor substrate in other triad aminodotransferases are conserved in CobB.бА0АкА0АаАCDDбАаАVИвА0А0АаАВПcd03131, GATase1_HTS, Type 1 glutamine amidotransferase (GATase1)-like domain found in homoserine trans-succinylase (HTS). Type 1 glutamine amidotransferase (GATase1)-like domain found in homoserine trans-succinylase (HTS). HTS, the first enzyme in methionine biosynthesis in Escherichia coli, transfers a succinyl group from succinyl-CoA to homoserine forming succinyl homoserine. It has been suggested that the succinyl group of succinyl-CoA is initially transferred to an enzyme nucleophile before subsequent transfer to homoserine. The catalytic triad typical of GATase1 domains is not conserved in this GATase1-like domain. However, in common with GATase1 domains a reactive cys residue is found in the sharp turn between a beta strand and an alpha helix termed the nucleophile elbow. It has been proposed that this cys is in the active site of the molecule. However, as succinyl has been found bound to a conserved lysine residue, this conserved cys may play a role in dimer formation. HTS activity is tightly regulated by several mechanisms including feedback inhibition and proteolysis. It represents a critical control point for cell growth and viability.бА0АкА0АаАCDDбАаАVЙвА0А0АаАВ√cd03132, GATase1_catalase, Type 1 glutamine amidotransferase (GATase1)-like domain found in at the C-terminal of several large catalases. Type 1 glutamine amidotransferase (GATase1)-like domain found in at the C-terminal of several large catalases. Catalase catalyzes the dismutation of hydrogen peroxide (H2O2) to water and oxygen. This group includes the large catalases: Neurospora crassa Catalase-1 and Catalase-3 and, Escherichia coli HP-II. This GATase1-like domain has an essential role in HP-II catalase activity. However, it lacks enzymatic activity and the catalytic triad typical of GATase1 domains. Catalase-1 and -3 are homotetrameric, HP-II is homohexameric. It has been proposed that this domain may facilitate the folding and oligomerization process. The interface between this GATase1-like domain of HP-II and the core of the subunit forms part of a channel which provides access to the deeply buried catalase active sites of HPII. Catalase-1 is associated with non-growing cells; Catalase-3 is associated with growing conditions. HP-II is produced in stationary phase. Catalase-1 is induced by ethanol and heat shock. Catalase-3 is induced under stress conditions such a hydrogen peroxide, paraquat, cadmium, heat shock, uric acid and nitrate treatment.бА0АкА0АаАCDDбАаАVКвА0А0АаАВ∙cd03133, GATase1_ES1, Type 1 glutamine amidotransferase (GATase1)-like domain found in zebrafish ES1. Type 1 glutamine amidotransferase (GATase1)-like domain found in zebrafish ES1. This group includes, proteins similar to ES1, Escherichia coli enhancing lycopene biosynthesis protein 2, Azospirillum brasilense iaaC and, human HES1. The catalytic triad typical of GATase1domains is not conserved in this GATase1-like domain. However, in common with GATase1domains a reactive cys residue is found in the sharp turn between a beta strand and an alpha helix termed the nucleophile elbow. Zebrafish ES1 is expressed specifically in adult photoreceptor cells and appears to be a cytoplasmic protein. A. brasilense iaaC is involved in controlling IAA biosynthesis.бА0АкА0АаАCDDбАаАVЛвА0А0АаАВеcd03134, GATase1_PfpI_like, A type 1 glutamine amidotransferase (GATase1)-like domain found in PfpI from Pyrococcus furiosus. A type 1 glutamine amidotransferase (GATase1)-like domain found in PfpI from Pyrococcus furiosus. This group includes proteins similar to PfpI from P. furiosus. and PH1704 from Pyrococcus horikoshii. These enzymes are ATP-independent intracellular proteases and may hydrolyze small peptides to provide a nutritional source. Only Cys of the catalytic triad typical of GATase1 domains is conserved in this group. This Cys residue is found in the sharp turn between a beta strand and an alpha helix termed the nucleophile elbow. For PH1704, it is believed that this Cys together with a different His in one monomer and Glu (from an adjacent monomer) forms a different catalytic triad from the typical GATase1domain. PfpI is homooligomeric. Protease activity is only found for oligomeric forms of PH1704.бА0АкА0АаАCDDбАаАVМвА0А0АаАВ░cd03135, GATase1_DJ-1, Type 1 glutamine amidotransferase (GATase1)-like domain found in Human DJ-1. Type 1 glutamine amidotransferase (GATase1)-like domain found in Human DJ-1. DJ-1 is involved in multiple physiological processes including cancer, Parkinson's disease and male fertility. It is unclear how DJ-1 functions in these. DJ-1 has been shown to possess chaperone activity. DJ-1 is preferentially expressed in the testis and moderately in other tissues; it is induced together with genes involved in oxidative stress response. The Drosophila homologue (DJ-1A) plays an essential role in oxidative stress response and neuronal maintenance. Inhibition of DJ-1A function through RNAi, results in the cellular accumulation of reactive oxygen species, organismal hypersensitivity to oxidative stress, and dysfunction and degeneration of dopaminergic and photoreceptor neurons. DJ-1 has lacks enzymatic activity and the catalytic triad of typical GATase1 domains, however it does contain the highly conserved cysteine located at the nucelophile elbow region typical of these domains. This cysteine been proposed to be a site of regulation of DJ-1 activity by oxidation. DJ-1 is a dimeric enzyme.бА0АкА0АаАCDDбАаАVНвА0А0АаАВ+cd03136, GATase1_AraC_ArgR_like, AraC transcriptional regulators having an N-terminal Type 1 glutamine amidotransferase (GATase1)-like domain. A subgroup of AraC transcriptional regulators having an N-terminal Type 1 glutamine amidotransferase (GATase1)-like domain. This group contains proteins similar to the Pseudomonas aeruginosa ArgR regulator. ArgR functions in the control of expression of certain genes of arginine biosynthesis and catabolism. AraC regulators are defined by a AraC-type helix-turn-helix DNA binding domain at their C-terminal. AraC family transcriptional regulators are widespread among bacteria and are involved in regulating diverse and important biological functions, including carbon metabolism, stress responses and virulence in different microorganisms. The catalytic triad typical of GATase1 domains is not conserved in this GATase1-like domain. However, in common with typical GATase1domains a reactive cys residue is found in some sequences in the sharp turn between a beta strand and an alpha helix termed the nucleophile elbow.бА0АкА0АаАCDDбАаАVОвА0А0АаАВ?cd03137, GATase1_AraC_1, AraC transcriptional regulators having a Type 1 glutamine amidotransferase (GATase1)-like domain. A subgroup of AraC transcriptional regulators having a Type 1 glutamine amidotransferase (GATase1)-like domain. AraC regulators are defined by a AraC-type helix-turn-helix DNA binding domain at their C-terminal. AraC family transcriptional regulators are widespread among bacteria and are involved in regulating diverse and important biological functions, including carbon metabolism, stress responses and virulence in different microorganisms. The catalytic triad typical of GATase1 domains is not conserved in this GATase1-like domain. However, in common with typical GATase1domains a reactive cys residue is found in the sharp turn between a beta strand and an alpha helix termed the nucleophile elbow.бА0АкА0АаАCDDбАаАVПвА0А0АаАВ?cd03138, GATase1_AraC_2, AraC transcriptional regulators having a Type 1 glutamine amidotransferase (GATase1)-like domain. A subgroup of AraC transcriptional regulators having a Type 1 glutamine amidotransferase (GATase1)-like domain. AraC regulators are defined by a AraC-type helix-turn-helix DNA binding domain at their C-terminal. AraC family transcriptional regulators are widespread among bacteria and are involved in regulating diverse and important biological functions, including carbon metabolism, stress responses and virulence in different microorganisms. The catalytic triad typical of GATase1 domains is not conserved in this GATase1-like domain. However, in common with typical GATase1domains a reactive cys residue is found in the sharp turn between a beta strand and an alpha helix termed the nucleophile elbow.бА0АкА0АаАCDDбАаАVРвА0А0АаАВacd03139, GATase1_PfpI_2, Type 1 glutamine amidotransferase (GATase1)-like domain found in a subgroup of proteins similar to PfpI from Pyrococcus furiosus. Type 1 glutamine amidotransferase (GATase1)-like domain found in a subgroup of proteins similar to PfpI from Pyrococcus furiosus. PfpI is an ATP-independent intracellular proteases which may hydrolyze small peptides to provide a nutritional source. Only Cys of the catalytic triad typical of GATase1 domains is conserved in this group. This Cys residue is found in the sharp turn between a beta strand and an alpha helix termed the nucleophile elbow.бА0АкА0АаАCDDбАаАVСвА0А0АаАВacd03140, GATase1_PfpI_3, Type 1 glutamine amidotransferase (GATase1)-like domain found in a subgroup of proteins similar to PfpI from Pyrococcus furiosus. Type 1 glutamine amidotransferase (GATase1)-like domain found in a subgroup of proteins similar to PfpI from Pyrococcus furiosus. PfpI is an ATP-independent intracellular proteases which may hydrolyze small peptides to provide a nutritional source. Only Cys of the catalytic triad typical of GATase1 domains is conserved in this group. This Cys residue is found in the sharp turn between a beta strand and an alpha helix termed the nucleophile elbow.бА0АкА0АаАCDDбАаАVТвА0А0АаАВ╤cd03141, GATase1_Hsp31_like, Type 1 glutamine amidotransferase (GATase1)-like domain found in proteins similar to Escherichia coli Hsp31 protein. Type 1 glutamine amidotransferase (GATase1)-like domain found in proteins similar to Escherichia coli Hsp31 protein (EcHsp31). This group includes EcHsp31 and Saccharomyces cerevisiae Ydr533c protein. EcHsp31 has chaperone activity. Ydr533c is upregulated in response to various stress conditions along with the heat shock family. EcHsp31 coordinates a metal ion using a 2-His-1-carboxylate motif present in various ions that use iron as a cofactor such as Carboxypeptidase A. The catalytic triad typical of GATase1 domains is not conserved in this GATase1-like domain. However, in common with a typical GATase1 domain, a reactive Cys residue is found in the sharp turn between a beta strand and an alpha helix termed the nucleophile elbow. For EcHsp31, this Cys together with a different His and, an Asp (rather than a Glu) residue form a different catalytic triad from the typical GATase1 domain. For Ydr533c a catalytic triad forms from the conserved Cys together with a different His and Glu from that of the typical GATase1domain. Ydr533c protein and EcHsp31 are homodimers.бА0АкА0АаАCDDбАаАVУвА0А0АаАВrcd03142, GATase1_ThuA, Type 1 glutamine amidotransferase (GATase1)-like domain found in Sinorhizobium meliloti Rm1021 ThuA (SmThuA). Type 1 glutamine amidotransferase (GATase1)-like domain found in Sinorhizobium meliloti Rm1021 ThuA (SmThuA). This group includes proteins similar to SmThuA which plays a role in a major pathway for trehalose catabolism. SmThuA is induced by trehalose but not by related structurally similar disaccharides like sucrose or maltose. Proteins in this group lack the catalytic triad of typical GATase1 domains: a His replaces the reactive Cys found in the sharp turn between a beta strand and an alpha helix termed the nucleophile elbow. S. meliloti Rm1021 thuA mutants are impaired in competitive colonization of Medicago sativa roots but are more competitive than the wild-type Rml021 in infecting alfalfa roots and forming nitrogen-fixing nodules.бА0АкА0АаАCDDбАаАVФвА0А0АаАВ8cd03143, A4_beta-galactosidase_middle_domain, A4 beta-galactosidase middle domain: a type 1 glutamine amidotransferase (GATase1)-like domain. A4 beta-galactosidase middle domain: a type 1 glutamine amidotransferase (GATase1)-like domain. This group includes proteins similar to beta-galactosidase from Thermus thermophilus. Beta-Galactosidase hydrolyzes the beta-1,4-D-galactosidic linkage of lactose, as well as those of related chromogens, o-nitrophenyl-beta-D-galactopyranoside (ONP-Gal) and 5-bromo-4-chloro-3-indolyl-beta-D-galactoside (X-gal). This A4 beta-galactosidase middle domain lacks the catalytic triad of typical GATase1 domains. The reactive Cys residue found in the sharp turn between a beta strand and an alpha helix termed the nucleophile elbow in typical GATase1 domains is not conserved in this group.бА0АкА0АаАCDDбАаАVХвА0А0АаАВ╓cd03144, GATase1_ScBLP_like, Type 1 glutamine amidotransferase (GATase1)-like domain found in proteins similar to Saccharomyces cerevisiae biotin-apoprotein ligase (ScBLP). Type 1 glutamine amidotransferase (GATase1)-like domain found in proteins similar to Saccharomyces cerevisiae biotin-apoprotein ligase (ScBLP). Biotin-apoprotein ligase modifies proteins by covalently attaching biotin. ScBLP is known to biotinylate acety-CoA carboxylase and pyruvate carboxylase. The catalytic triad typical of GATase1 domains is not conserved in this GATase1-like domain. However, the Cys residue found in the sharp turn between a beta strand and an alpha helix termed the nucleophile elbow in a typical GATase1 domain is conserved.бА0АкА0АаАCDDбАаАVЦвА0А0АаАВяcd03145, GAT1_cyanophycinase, Type 1 glutamine amidotransferase (GATase1)-like domain found in cyanophycinase. Type 1 glutamine amidotransferase (GATase1)-like domain found in cyanophycinase. This group contains proteins similar to the extracellular cyanophycinases from Pseudomonas anguilliseptica BI (CphE) and Synechocystis sp. PCC 6803 CphB. Cyanophycinases are intracellular exopeptidases which hydrolyze the polymer cyanophycin (multi L-arginyl-poly-L-aspartic acid) to the dipeptide beta-Asp-Arg. Cyanophycinase is believed to be a serine-type exopeptidase having a Ser-His-Glu catalytic triad which differs from the Cys-His-Glu catalytic triad typical of GATase1 domains by having a Ser in place of the reactive Cys at the nucleophile elbow.бА0АкА0АаАCDDбАаАVЧвА0А0АаАВ╙cd03146, GAT1_Peptidase_E, Type 1 glutamine amidotransferase (GATase1)-like domain found in peptidase E. Type 1 glutamine amidotransferase (GATase1)-like domain found in peptidase E. This group contains proteins similar to the aspartyl dipeptidases Salmonella typhimurium peptidase E and Xenopus laevis peptidase E. In bacteria peptidase E is believed to play a role in degrading peptides generated by intracellular protein breakdown or imported into the cell as nutrient sources. Peptidase E uniquely hydrolyses only Asp-X dipeptides (where X is any amino acid), and one tripeptide Asp-Gly-Gly. Peptidase E is believed to be a serine peptidase having a Ser-His-Glu catalytic triad which differs from the Cys-His-Glu catalytic triad typical of GATase1 domains by having a Ser in place of the reactive Cys at the nucleophile elbow. Xenopus PepE is developmentally regulated in response to thyroid hormone and, it is thought to play a role in apoptosis during tail reabsorption.бА0АкА0АаАCDDбАаАVШвА0А0АаАВ8cd03147, GATase1_Ydr533c_like, Type 1 glutamine amidotransferase (GATase1)-like domain found in Saccharomyces cerevisiae Ydr533c protein. Type 1 glutamine amidotransferase (GATase1)-like domain found in Saccharomyces cerevisiae Ydr533c protein. This group includes proteins similar to S. cerevisiae Ydr533c. Ydr533c is upregulated in response to various stress conditions along with the heat shock family. The catalytic triad typical of GATase1domains is not conserved in this GATase1-like domain. However, in common with a typical GATase1domain, a reactive Cys residue is found in the sharp turn between a beta strand and an alpha helix termed the nucleophile elbow. This Cys together with a different His and Glu residue form a different catalytic triad from the typical GATase1domain. Ydr533c protein is a homodimer.бА0АкА0АаАCDDбАаАVЩвА0А0АаАВОcd03148, GATase1_EcHsp31_like, Type 1 glutamine amidotransferase (GATase1)-like domain found in Escherichia coli Hsp31 protein (EcHsp31). Type 1 glutamine amidotransferase (GATase1)-like domain found in Escherichia coli Hsp31 protein (EcHsp31). This group includes proteins similar to EcHsp31. EcHsp31 has chaperone activity. EcHsp31 coordinates a metal ion using a 2-His-1-carboxylate motif present in various ions that use iron as a cofactor such as Carboxypeptidase A. The catalytic triad typical of GATase1 domains is not conserved in this GATase1-like domain. However, in common with a typical GATase1domain, a reactive Cys residue is found in the sharp turn between a beta strand and an alpha helix termed the nucleophile elbow. This Cys together with a different His and, an Asp (rather than a Glu) residue form a different catalytic triad from the typical GATase1 domain. EcHsp31 is a homodimer.бА0АкА0АаАCDDбАаАVЪвА0А0АаАВ[cd03149, alpha_CA_VII, Carbonic anhydrase alpha, CA isozyme VII_like subgroup. Carbonic anhydrases (CAs) are zinc-containing enzymes that catalyze the reversible hydration of carbon dioxide in a two-step mechanism: a nucleophilic attack of a zinc-bound hydroxide ion on carbon dioxide, followed by the regeneration of the active site by ionization of the zinc-bound water molecule and removal of a proton from the active site. They are ubiquitous enzymes involved in fundamental processes like photosynthesis, respiration, pH homeostasis and ion transport. Most alpha CAs are monomeric enzymes. The zinc ion is complexed by three histidines. This vertebrate subgroup comprises isozyme VII. CA VII is the most active cytosolic enzyme after CA II, and may be highly expressed in the brain. Human CA VII may be a target of antiepileptic sulfonamides/sulfamates.бА0АкА0АаАCDDбАаАз*вА0А0АаАВ¤cd03150, alpha_CA_IX, Carbonic anhydrase alpha, isozyme IX. Carbonic anhydrases (CAs) are zinc-containing enzymes that catalyze the reversible hydration of carbon dioxide in a two-step mechanism: a nucleophilic attack of a zinc-bound hydroxide ion on carbon dioxide, followed by the regeneration of the active site by ionization of the zinc-bound water molecule and removal of a proton from the active site. They are ubiquitous enzymes involved in fundamental processes like photosynthesis, respiration, pH homeostasis and ion transport. There are three evolutionary distinct groups - alpha, beta and gamma carbonic anhydrases - which show no significant sequence identity or structural similarity. Alpha CAs are strictly monomeric enzymes. The zinc ion is complexed by three histidine residues. This sub-family comprises the membrane protein CA IX. CA IX is functionally implicated in tumor growth and survival. CA IX is mainly present in solid tumors and its expression in normal tissues is limited to the mucosa of alimentary tract. CA IX is a transmembrane protein with two extracellular domains: carbonic anhydrase and, a proteoglycan-like segment mediating cell-cell adhesion. There is evidence for an involvement of the MAPK pathway in the regulation of CA9 expression.бА0АкА0АаАCDDбАаАз+вА0А0АаАВ█cd03151, CD81_like_LEL, Tetraspanin, extracellular domain or large extracellular loop (LEL), CD81_like subfamily. Tetraspanins are trans-membrane proteins with 4 trans-membrane segments. Both the N- and C-termini lie on the intracellular side of the membrane. This alignment model spans the extracellular domain between the 3rd and 4th trans-membrane segment. Tetraspanins are involved in diverse processes and their various functions may relate to their ability to act as molecular facilitators. Tetraspanins associate laterally with one another and cluster dynamically with numerous parnter domains in membrane microdomains, forming a network of multimolecular complexes, the "tetraspanin web". CD81, also referred to as Target for anti-proliferative antigen-1, TAPA-1, is found in virtually all tissues, may be involved in regulation of cell growth and has been described as a member of the CD19/CD21/Leu-13 signal transduction complex identified on B cells (the B-Cell co-receptor).бА0АкА0АаАCDDбАаАз,вА0А0АаАВcd03152, CD9_LEL, Tetraspanin, extracellular domain or large extracellular loop (LEL), CD9 family. Tetraspanins are trans-membrane proteins with 4 trans-membrane segments. Both the N- and C-termini lie on the intracellular side of the membrane. This alignment model spans the extracellular domain between the 3rd and 4th trans-membrane segment. Tetraspanins are involved in diverse processes and their various functions may relate to their ability to act as molecular facilitators. Tetraspanins associate laterally with one another and cluster dynamically with numerous parnter domains in membrane microdomains, forming a network of multimolecular complexes, the "tetraspanin web". CD9 is found in virtually all tissues and is potentially involved in developmental processes. It associates with the tetraspanins CD81 and CD63, as well as with some integrin, and has been shown to be involved in a variety of activation, adhesion, and cell motility functions, as well as cell-cell interactions - such as during fertilization.бА0АкА0АаАCDDбАаАз-вА0А0АаАВcd03153, PHEMX_like_LEL, Tetraspanin, extracellular domain or large extracellular loop (LEL), PHEMX_like family. Tetraspanins are trans-membrane proteins with 4 trans-membrane segments. Both the N- and C-termini lie on the intracellular side of the membrane. This alignment model spans the extracellular domain between the 3rd and 4th trans-membrane segment. Tetraspanins are involved in diverse processes and their various functions may relate to their ability to act as molecular facilitators. Tetraspanins associate laterally with one another and cluster dynamically with numerous parnter domains in membrane microdomains, forming a network of multimolecular complexes, the "tetraspanin web". Phemx (pan hematopoietic expression) or TSSC6 may play a role in hematopoietic cell function.бА0АкА0АаАCDDбАаАз.вА0А0АаАВгcd03154, TM4SF3_like_LEL, Tetraspanin, extracellular domain or large extracellular loop (LEL), TM4SF3_like subfamily. Tetraspanins are trans-membrane proteins with 4 trans-membrane segments. Both the N- and C-termini lie on the intracellular side of the membrane. This alignment model spans the extracellular domain between the 3rd and 4th trans-membrane segment. Tetraspanins are involved in diverse processes and their various functions may relate to their ability to act as molecular facilitators. Tetraspanins associate laterally with one another and cluster dynamically with numerous parnter domains in membrane microdomains, forming a network of multimolecular complexes, the "tetraspanin web". This subfamily contaions transmembrane 4 superfamily 3 (TM4SF3) or D6.1a and related proteins. D6.1a associates with alpha6beta4 integrin and supports cell motility, it has been ascribed a role in tumor progression and metastasis.бА0АкА0АаАCDDбАаАз/вА0А0АаАВpcd03155, CD151_like_LEL, Tetraspanin, extracellular domain or large extracellular loop (LEL), CD151_Like family. Tetraspanins are trans-membrane proteins with 4 trans-membrane segments. Both the N- and C-termini lie on the intracellular side of the membrane. This alignment model spans the extracellular domain between the 3rd and 4th trans-membrane segment. Tetraspanins are involved in diverse processes and their various functions may relate to their ability to act as molecular facilitators. Tetraspanins associate laterally with one another and cluster dynamically with numerous parnter domains in membrane microdomains, forming a network of multimolecular complexes, the "tetraspanin web". CD151strongly associates with integrins, especially alpha3beta1, alpha6beta1, alpha7beta1, and alpha6beta4; it may play roles in cell-cell adhesion, cell migration, platelet aggregation, and angiogenesis. For example, CD151 is is involved in regulation of migration of neutrophils, endothelial cells, and various tumor cell lines; it associates specifically with laminin-binding integrins and strengthens alpha6beta1 integrin-mediated adhesion to laminin-1; CD151 also specifically attenuates adhesion-dependent activation of Ras and correspdonding downstream effects, and is involved in epithelial cell-cell adhesion as a modulator of PKC- and Cdc42-dependent actin cytoskeletal reorganization.бА0АкА0АаАCDDбАаАз0вА0А0АаАВ╚cd03156, uroplakin_I_like_LEL, Tetraspanin, extracellular domain or large extracellular loop (LEL), uroplakin_I_like family. Tetraspanins are trans-membrane proteins with 4 trans-membrane segments. Both the N- and C-termini lie on the intracellular side of the membrane. This alignment model spans the extracellular domain between the 3rd and 4th trans-membrane segment. Tetraspanins are involved in diverse processes and their various functions may relate to their ability to act as molecular facilitators. Tetraspanins associate laterally with one another and cluster dynamically with numerous parnter domains in membrane microdomains, forming a network of multimolecular complexes, the "tetraspanin web". Uroplakin Ia and Ib are components of the 16nm protein particles, which are packed hexagonally to form 2D crystals of asymmetric unit membranes, and cover the apical surface of mammalian urothelium, contributing to the urinay bladder's permeability barrier function. Uroplakins Ia and Ib are maturation facilitators. They trigger conformational changes in their single-transmembrane-domain binding partner proteins uroplakin II and IIIa, which in turn may lead to ER-exit, stabilization, and cell-surface expression.бА0АкА0АаАCDDбАаАз1вА0А0АаАВcd03157, TM4SF12_like_LEL, Tetraspanin, extracellular domain or large extracellular loop (LEL), TM4SF12_like family. Tetraspanins are trans-membrane proteins with 4 trans-membrane segments. Both the N- and C-termini lie on the intracellular side of the membrane. This alignment model spans the extracellular domain between the 3rd and 4th trans-membrane segment. Tetraspanins are involved in diverse processes and their various functions may relate to their ability to act as molecular facilitators. Tetraspanins associate laterally with one another and cluster dynamically with numerous parnter domains in membrane microdomains, forming a network of multimolecular complexes, the "tetraspanin web". This sub-family contains proteins similar to human transmembrane 4 superfamily member 12 (TM4SF12).бА0АкА0АаАCDDбАаАз2вА0А0АаАВ-cd03158, penumbra_like_LEL, Tetraspanin, extracellular domain or large extracellular loop (LEL), penumbra_like family. Tetraspanins are trans-membrane proteins with 4 trans-membrane segments. Both the N- and C-termini lie on the intracellular side of the membrane. This alignment model spans the extracellular domain between the 3rd and 4th trans-membrane segment. Tetraspanins are involved in diverse processes and their various functions may relate to their ability to act as molecular facilitators. Tetraspanins associate laterally with one another and cluster dynamically with numerous parnter domains in membrane microdomains, forming a network of multimolecular complexes, the "tetraspanin web". Human Penumbra exhibits growth-suppressive activity in vitro and has been associated with myeloid malignancies.бА0АкА0АаАCDDбАаАз3вА0А0АаАВщcd03159, TM4SF9_like_LEL, Tetraspanin, extracellular domain or large extracellular loop (LEL), TM4SF9_like subfamily. Tetraspanins are trans-membrane proteins with 4 trans-membrane segments. Both the N- and C-termini lie on the intracellular side of the membrane. This alignment model spans the extracellular domain between the 3rd and 4th trans-membrane segment. Tetraspanins are involved in diverse processes and their various functions may relate to their ability to act as molecular facilitators. Tetraspanins associate laterally with one another and cluster dynamically with numerous parnter domains in membrane microdomains, forming a network of multimolecular complexes, the "tetraspanin web". This subfamily contaions transmembrane 4 superfamily 9 (TM4SF9) or Tetraspanin-5 and related proteins. TM4SF9 is strongly expressed witin the central nervous system, and expression levels appear to correlate with differentiation status of particular neurons, hinting at a role in neuronal maturation.бА0АкА0АаАCDDбАаАз4вА0А0АаАВcd03160, CD37_CD82_like_LEL, Tetraspanin, extracellular domain or large extracellular loop (LEL), CD37_CD82_Like family. Tetraspanins are trans-membrane proteins with 4 trans-membrane segments. Both the N- and C-termini lie on the intracellular side of the membrane. This alignment model spans the extracellular domain between the 3rd and 4th trans-membrane segment. Tetraspanins are involved in diverse processes and their various functions may relate to their ability to act as molecular facilitators. Tetraspanins associate laterally with one another and cluster dynamically with numerous parnter domains in membrane microdomains, forming a network of multimolecular complexes, the "tetraspanin web". CD37 is a leukocyte-specific protein, and its restricted expression pattern suggests a role in the immune system. A regulatory role in T-cell proliferation has been suggested. CD82 is a metastasis suppressor implicated in biological processes ranging from fusion, adhesion, and migration to apoptosis and alterations of cell morphology.бА0АкА0АаАCDDбАаАз5вА0А0АаАВкcd03161, TM4SF2_6_like_LEL, Tetraspanin, extracellular domain or large extracellular loop (LEL), TM4SF2_6_like subfamily. Tetraspanins are trans-membrane proteins with 4 trans-membrane segments. Both the N- and C-termini lie on the intracellular side of the membrane. This alignment model spans the extracellular domain between the 3rd and 4th trans-membrane segment. Tetraspanins are involved in diverse processes and their various functions may relate to their ability to act as molecular facilitators. Tetraspanins associate laterally with one another and cluster dynamically with numerous parnter domains in membrane microdomains, forming a network of multimolecular complexes, the "tetraspanin web". This subfamily contaions transmembrane 4 superfamily 2 (TM4SF2) or Tspan-7, transmembrane 4 superfamily 6 (TM4SF6) or Tspan-6, and related proteins. TM4SF2 has been identified as involved in some forms of X-linked mental retardation.бА0АкА0АаАCDDбАаАз6вА0А0АаАВ:cd03162, peripherin_like_LEL, Tetraspanin, extracellular domain or large extracellular loop (LEL), peripherin_like family. Tetraspanins are trans-membrane proteins with 4 trans-membrane segments. Both the N- and C-termini lie on the intracellular side of the membrane. This alignment model spans the extracellular domain between the 3rd and 4th trans-membrane segment. Tetraspanins are involved in diverse processes and their various functions may relate to their ability to act as molecular facilitators. Tetraspanins associate laterally with one another and cluster dynamically with numerous parnter domains in membrane microdomains, forming a network of multimolecular complexes, the "tetraspanin web". Peripherin, or RDS (retinal degradation slow) is a glycoprotein expressed in vertebrate photoreceptors, located at the rim of the disc membranes of the photoreceptor outer segments. RDS is thought to play a major role in folding and stacking of the discs. Mutations in RDS have been linked to hereditary retinal dystrophies, which typically exhibit a wide phenotypic spectrum.бА0АкА0АаАCDDбАаАз7вА0А0АаАВ╖cd03163, TM4SF8_like_LEL, Tetraspanin, extracellular domain or large extracellular loop (LEL), TM4SF8_like subfamily. Tetraspanins are trans-membrane proteins with 4 trans-membrane segments. Both the N- and C-termini lie on the intracellular side of the membrane. This alignment model spans the extracellular domain between the 3rd and 4th trans-membrane segment. Tetraspanins are involved in diverse processes and their various functions may relate to their ability to act as molecular facilitators. Tetraspanins associate laterally with one another and cluster dynamically with numerous parnter domains in membrane microdomains, forming a network of multimolecular complexes, the "tetraspanin web". This subfamily contaions transmembrane 4 superfamily 8 (TM4SF8) or Tspan-3 and related proteins. Tspan-3 has been reported to form a complex with integrin beta1 and OSP/claudin-11, which may be involved in oligodendrocyte proliferation and migration.бА0АкА0АаАCDDбАаАз8вА0А0АаАВ┤cd03164, CD53_like_LEL, Tetraspanin, extracellular domain or large extracellular loop (LEL), CD53_Like family. Tetraspanins are trans-membrane proteins with 4 trans-membrane segments. Both the N- and C-termini lie on the intracellular side of the membrane. This alignment model spans the extracellular domain between the 3rd and 4th trans-membrane segment. Tetraspanins are involved in diverse processes and their various functions may relate to their ability to act as molecular facilitators. Tetraspanins associate laterally with one another and cluster dynamically with numerous parnter domains in membrane microdomains, forming a network of multimolecular complexes, the "tetraspanin web". CD53 is a tetraspanin of the lymphoid-myeloid lineage and has been implicated in apoptosis protection. It associates with integrin alpha4beta1. Some of the cellular responses modulated by CD53 may be mediated by JNK activation and/or via the AKT pathway.бА0АкА0АаАCDDбАаАз9вА0А0АаАВ√cd03165, NET-5_like_LEL, Tetraspanin, extracellular domain or large extracellular loop (LEL), NET-5_like family. Tetraspanins are trans-membrane proteins with 4 trans-membrane segments. Both the N- and C-termini lie on the intracellular side of the membrane. This alignment model spans the extracellular domain between the 3rd and 4th trans-membrane segment. Tetraspanins are involved in diverse processes and their various functions may relate to their ability to act as molecular facilitators. Tetraspanins associate laterally with one another and cluster dynamically with numerous parnter domains in membrane microdomains, forming a network of multimolecular complexes, the "tetraspanin web". This sub-family contains proteins similar to human tetraspan NET-5.бА0АкА0АаАCDDбАаАз:вА0А0АаАВ~cd03166, CD63_LEL, Tetraspanin, extracellular domain or large extracellular loop (LEL), CD63 family. Tetraspanins are trans-membrane proteins with 4 trans-membrane segments. Both the N- and C-termini lie on the intracellular side of the membrane. This alignment model spans the extracellular domain between the 3rd and 4th trans-membrane segment. Tetraspanins are involved in diverse processes and their various functions may relate to their ability to act as molecular facilitators. Tetraspanins associate laterally with one another and cluster dynamically with numerous parnter domains in membrane microdomains, forming a network of multimolecular complexes, the "tetraspanin web". CD63 is present in platelets, neutrophils, and endothelial cells, amongst others. In platelets it associates with the integrin alphaIIBbeta3 and may modulate alphaIIbbeta3-dependent cytoskeletal reorganization.бА0АкА0АаАCDDбАаАз;вА0А0АаАВkcd03167, oculospanin_like_LEL, Tetraspanin, extracellular domain or large extracellular loop (LEL), oculospanin_like family. Tetraspanins are trans-membrane proteins with 4 trans-membrane segments. Both the N- and C-termini lie on the intracellular side of the membrane. This alignment model spans the extracellular domain between the 3rd and 4th trans-membrane segment. Tetraspanins are involved in diverse processes and their various functions may relate to their ability to act as molecular facilitators. Tetraspanins associate laterally with one another and cluster dynamically with numerous parnter domains in membrane microdomains, forming a network of multimolecular complexes, the "tetraspanin web". This subfamily contains sequences similar to oculospanin, which is found to be expressed in retinal pigment epithelium, iris, ciliary body, and retinal ganglion cells.бА0АкА0АаАCDDбАаАз<вА0А0АаАВacd03169, GATase1_PfpI_1, Type 1 glutamine amidotransferase (GATase1)-like domain found in a subgroup of proteins similar to PfpI from Pyrococcus furiosus. Type 1 glutamine amidotransferase (GATase1)-like domain found in a subgroup of proteins similar to PfpI from Pyrococcus furiosus. PfpI is an ATP-independent intracellular proteases which may hydrolyze small peptides to provide a nutritional source. Only Cys of the catalytic triad typical of GATase1 domains is conserved in this group. This Cys residue is found in the sharp turn between a beta strand and an alpha helix termed the nucleophile elbow.бА0АкА0АаАCDDбАаАVЫвА0А0АаАВ═cd03171, SORL_Dfx_classI, Superoxide reductase-like (SORL) domain, class I; SORL-domains are present in a family of mononuclear non-heme iron proteins that includes superoxide reductase and desulfoferrodoxin. Superoxide reductase-like proteins scavenge superoxide anion radicals as a defense mechanism against reactive oxygen species and are found in anaerobic bacteria and archeae, and microaerophilic Treponema pallidum. Desulfoferrodoxin (class I) is a homodimeric protein, with each protomer comprised of two domains, the N-terminal desulforedoxin (DSRD) domain and C-terminal SORL domain. Each domain has a distinct iron center: the DSRD iron center I, Fe(S-Cys)4; and the SORL iron center II, Fe[His4Cys(Glu)].бА0АкА0АаАCDDбАаАз=вА0А0АаАВucd03172, SORL_classII, Superoxide reductase-like (SORL) domain, class II; SORL-domains are present in a family of mononuclear non-heme iron proteins that includes superoxide reductase and desulfoferrodoxin. Superoxide reductase-like proteins scavenge superoxide anion radicals as a defense mechanism against reactive oxygen species and are found in anaerobic bacteria and archeae, and microaerophilic Treponema pallidum. The SORL domain contains an active iron site, Fe[His4Cys(Glu)], which in the reduced state loses the glutamate ligand. Superoxide reductase (class II) forms a homotetramer with four Fe[His4Cys(Glu)] centers.бА0АкА0АаАCDDбАаАз>вА0А0АаАВнcd03173, DUF619-like, DUF619 domain of various N-acetylglutamate Kinases and N-acetylglutamate Synthases. DUF619-like: This family includes the DUF619 domain of various N-acetylglutamate synthases (NAGS) of the urea cycle found in humans and fish, the DUF619 domain of the NAGS of the fungal arginine-biosynthetic pathway (FABP), as well as the DUF619 domain present C-terminal of a NAG kinase-like domain in a limited number of predicted NAGSs found in bacteria and Dictyostelium. Ureogenic NAGS is a mitochondrial enzyme catalyzing the formation of NAG from acetylcoenzyme A and L-glutamate. NAGS is an essential allosteric activator of carbamylphosphate synthase I, the first and rate limiting enzyme of the urea cycle. Domain architecture of ureogenic and fungal NAGS consists of an N-terminal NAG kinase-like domain and a C-terminal DUF619 domain. This subgroup also includes the DUF619 domain of the FABP N-acetylglutamate kinase (NAGK), the enzyme that catalyzes the second reaction of arginine biosynthesis; the phosphorylation of the gamma-carboxyl group of NAG to produce N-acetylglutamylphosphate (NAGP) which is subsequently converted to ornithine in two more steps. The nuclear-encoded, mitochondrial polyprotein precursor (ARG5,6) consists of an N-terminal NAGK (ArgB) domain, a central DUF619 domain, and a C-terminal reductase domain (ArgC, N-acetylglutamate phosphate reductase). The DUF619 domain function has yet to be characterized.бА0АкА0АаАCDDбАаА░ИвА0А0АаАВйcd03174, DRE_TIM_metallolyase, DRE-TIM metallolyase superfamily. The DRE-TIM metallolyase superfamily includes 2-isopropylmalate synthase (IPMS), alpha-isopropylmalate synthase (LeuA), 3-hydroxy-3-methylglutaryl-CoA lyase, homocitrate synthase, citramalate synthase, 4-hydroxy-2-oxovalerate aldolase, re-citrate synthase, transcarboxylase 5S, pyruvate carboxylase, AksA, and FrbC. These members all share a conserved triose-phosphate isomerase (TIM) barrel domain consisting of a core beta(8)-alpha(8) motif with the eight parallel beta strands forming an enclosed barrel surrounded by eight alpha helices. The domain has a catalytic center containing a divalent cation-binding site formed by a cluster of invariant residues that cap the core of the barrel. In addition, the catalytic site includes three invariant residues - an aspartate (D), an arginine (R), and a glutamate (E) - which is the basis for the domain name "DRE-TIM".бА0АкА0АаАCDDбАаАZвА0А0АаАВ┌cd03177, GST_C_Delta_Epsilon, C-terminal, alpha helical domain of Class Delta and Epsilon Glutathione S-transferases. Glutathione S-transferase (GST) C-terminal domain family, Class Delta and Epsilon subfamily; GSTs are cytosolic dimeric proteins involved in cellular detoxification by catalyzing the conjugation of glutathione (GSH) with a wide range of endogenous and xenobiotic alkylating agents, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress. GSTs also show GSH peroxidase activity and are involved in the synthesis of prostaglandins and leukotrienes. The GST fold contains an N-terminal thioredoxin-fold domain and a C-terminal alpha helical domain, with an active site located in a cleft between the two domains. GSH binds to the N-terminal domain while the hydrophobic substrate occupies a pocket in the C-terminal domain. The class Delta and Epsilon subfamily is made up primarily of insect GSTs, which play major roles in insecticide resistance by facilitating reductive dehydrochlorination of insecticides or conjugating them with GSH to produce water-soluble metabolites that are easily excreted. They are also implicated in protection against cellular damage by oxidative stress.бА0АкА0АаАCDDбАаАПвА0А0АаАВ\cd03178, GST_C_Ure2p_like, C-terminal, alpha helical domain of Ure2p and related Glutathione S-transferase-like proteins. Glutathione S-transferase (GST) C-terminal domain family, Ure2p-like subfamily; composed of the Saccharomyces cerevisiae Ure2p, YfcG and YghU from Escherichia coli, and related GST-like proteins. Ure2p is a regulator for nitrogen catabolism in yeast. It represses the expression of several gene products involved in the use of poor nitrogen sources when rich sources are available. A transmissible conformational change of Ure2p results in a prion called [Ure3], an inactive, self-propagating and infectious amyloid. Ure2p displays a GST fold containing an N-terminal thioredoxin-fold domain and a C-terminal alpha helical domain. The N-terminal thioredoxin-fold domain is sufficient to induce the [Ure3] phenotype and is also called the prion domain of Ure2p. In addition to its role in nitrogen regulation, Ure2p confers protection to cells against heavy metal ion and oxidant toxicity, and shows glutathione (GSH) peroxidase activity. YfcG and YghU are two of the nine GST homologs in the genome of Escherichia coli. They display very low or no GSH transferase, but show very good disulfide bond oxidoreductase activity. YghU also shows modest organic hydroperoxide reductase activity. GSTs are cytosolic dimeric proteins involved in cellular detoxification by catalyzing the conjugation of GSH with a wide range of endogenous and xenobiotic alkylating agents, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress. GSTs also show GSH peroxidase activity and are involved in the synthesis of prostaglandins and leukotrienes. The GST active site is located in a cleft between the N- and C-terminal domains. GSH binds to the N-terminal domain while the hydrophobic substrate occupies a pocket in the C-terminal domain.бА0АкА0АаАCDDбАаАРвА0А0АаАВбcd03180, GST_C_2, C-terminal, alpha helical domain of an unknown subfamily 2 of Glutathione S-transferases. Glutathione S-transferase (GST) C-terminal domain family, unknown subfamily 2; composed of uncharacterized bacterial proteins, with similarity to GSTs. GSTs are cytosolic dimeric proteins involved in cellular detoxification by catalyzing the conjugation of glutathione (GSH) with a wide range of endogenous and xenobiotic alkylating agents, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress. GSTs also show GSH peroxidase activity and are involved in the synthesis of prostaglandins and leukotrienes. The GST fold contains an N-terminal thioredoxin-fold domain and a C-terminal alpha helical domain, with an active site located in a cleft between the two domains. GSH binds to the N-terminal domain while the hydrophobic substrate occupies a pocket in the C-terminal domain.бА0АкА0АаАCDDбАаАСвА0А0АаАВYcd03181, GST_C_EF1Bgamma_like, Glutathione S-transferase C-terminal-like, alpha helical domain of the Gamma subunit of Elongation Factor 1B and similar proteins. Glutathione S-transferase (GST) C-terminal domain family, Gamma subunit of Elongation Factor 1B (EF1Bgamma) subfamily; EF1Bgamma is part of the eukaryotic translation elongation factor-1 (EF1) complex which plays a central role in the elongation cycle during protein biosynthesis. EF1 consists of two functionally distinct units, EF1A and EF1B. EF1A catalyzes the GTP-dependent binding of aminoacyl-tRNA to the ribosomal A site concomitant with the hydrolysis of GTP. The resulting inactive EF1A:GDP complex is recycled to the active GTP form by the guanine-nucleotide exchange factor EF1B, a complex composed of at least two subunits, alpha and gamma. Metazoan EFB1 contain a third subunit, beta. The EF1B gamma subunit contains a GST fold consisting of an N-terminal thioredoxin-fold domain and a C-terminal alpha helical domain. The GST-like domain of EF1Bgamma is believed to mediate the dimerization of the EF1 complex, which in yeast is a dimer of the heterotrimer EF1A:EF1Balpha:EF1Bgamma. In addition to its role in protein biosynthesis, EF1Bgamma may also display other functions. The recombinant rice protein has been shown to possess GSH conjugating activity. The yeast EF1Bgamma binds to membranes in a calcium dependent manner and is also part of a complex that binds to the msrA (methionine sulfoxide reductase) promoter suggesting a function in the regulation of its gene expression. Also included in this subfamily is the GST_C-like domain at the N-terminus of human valyl-tRNA synthetase (ValRS) and its homologs. Metazoan ValRS forms a stable complex with Elongation Factor-1H (EF-1H), and together, they catalyze consecutive steps in protein biosynthesis, tRNA aminoacylation and its transfer to EF.бА0АкА0АаАCDDбАаАТвА0А0АаАВcd03182, GST_C_GTT2_like, C-terminal, alpha helical domain of GTT2-like Glutathione S-transferases. Glutathione S-transferase (GST) C-terminal domain family, Saccharomyces cerevisiae GTT2-like subfamily; composed of predominantly uncharacterized proteins with similarity to the Saccharomyces cerevisiae GST protein, GTT2. GSTs are cytosolic dimeric proteins involved in cellular detoxification by catalyzing the conjugation of glutathione (GSH) with a wide range of endogenous and xenobiotic alkylating agents, including carcinogens, therapeutic drugs, environmental toxins, and products of oxidative stress. GSTs also show GSH peroxidase activity and are involved in the synthesis of prostaglandins and leukotrienes. The GST fold contains an N-terminal thioredoxin-fold domain and a C-terminal alpha helical domain, with an active site located in a cleft between the two domains. GSH binds to the N-terminal domain while the hydrophobic substrate occupies a pocket in the C-terminal domain. GTT2, a homodimer, exhibits GST activity with standard substrates. Strains with deleted GTT2 genes are viable but exhibit increased sensitivity to heat shock.бА0АкА0АаАCDDбАаАУвА0А0АаАВcd03382, PAP2_dolichyldiphosphatase, PAP2_like proteins, dolichyldiphosphatase subfamily. Dolichyldiphosphatase is a membrane-associated protein located in the endoplasmic reticulum and hydrolyzes dolichyl pyrophosphate, as well as dolichylmonophosphate at a low rate. The enzyme is necessary for maintaining proper levels of dolichol-linked oligosaccharides and protein N-glycosylation, and might play a role in re-utilization of the glycosyl carrier lipid for additional rounds of lipid intermediate biosynthesis after its release during protein N-glycosylation reactions.бА0АкА0АаАCDDбАаАзuвА0А0АаАВ(cd03383, PAP2_diacylglycerolkinase, PAP2_like proteins, diacylglycerol_kinase like sub-family. In some prokaryotes, PAP2_like phosphatase domains appear fused to E. coli DAGK-like trans-membrane diacylglycerol kinase domains. The cellular function of these architectures remains to be determined.бА0АкА0АаАCDDбАаАзvвА0А0АаАВЕcd03384, PAP2_wunen, PAP2, wunen subfamily. Most likely a family of membrane associated phosphatidic acid phosphatases. Wunen is a drosophila protein expressed in the central nervous system, which provides repellent activity towards primordial germ cells (PGCs), controls the survival of PGCs and is essential in the migration process of these cells towards the somatic gonadal precursors.бА0АкА0АаАCDDбАаАзwвА0А0АаАВ╫cd03385, PAP2_BcrC_like, PAP2_like proteins, BcrC_like subfamily. Several members of this family have been annotated as bacitracin transport permeases, as it was suspected that they form the permease component of an ABC transporter system. It was shown, however, that BcrC from Bacillus subtilis posesses undecaprenyl pyrophosphate (UPP) phospatase activity, and it is hypothesized that it competes with bacitracin for UPP, increasing the cell's resistance to bacitracin.бА0АкА0АаАCDDбАаАзxвА0А0АаАВcd03386, PAP2_Aur1_like, PAP2_like proteins, Aur1_like subfamily. Yeast Aur1p or Ipc1p is necessary for the addition of inositol phosphate to ceramide, an essential step in yeast sphingolipid synthesis, and is the target of several antifungal compounds such as aureobasidin.бА0АкА0АаАCDDбАаАзyвА0А0АаАВУcd03388, PAP2_SPPase1, PAP2_like proteins, sphingosine-1-phosphatase subfamily. Sphingosine-1-phosphatase is an intracellular enzyme located in the endoplasmic reticulum, which regulates the level of sphingosine-1-phosphate (S1P), a bioactive lipid. S1P acts as a second messenger in the cell, and extracellularly by binding to G-protein coupled receptors of the endothelial differentiation gene family.бА0АкА0АаАCDDбАаАзzвА0А0АаАВ^cd03389, PAP2_lipid_A_1_phosphatase, PAP2_like proteins, Lipid A 1-phosphatase subfamily. Lipid A 1-phosphatase, or LpxE from Francisella novicida selectively dephosphorylates lipid A at the 1-position. Lipid A is the membrane-anchor component of lipopolysaccharides (LPS), the major constituents of the outer membrane in many gram-negative bacteria.бА0АкА0АаАCDDбАаАз{вА0А0АаАВ┐cd03390, PAP2_containing_1_like, PAP2, subfamily similar to human phosphatidic_acid_phosphatase_type_2_domain_containing_1. Most likely membrane-associated phosphatidic acid phosphatases. Plant members of this group are constitutively expressed in many tissues and exhibit both diacylglycerol pyrophosphate phosphatase activity as well as phosphatidate (PA) phosphatase activity, they may have a more generic housekeeping role in lipid metabolism.бА0АкА0АаАCDDбАаАз|вА0А0АаАВLcd03391, PAP2_containing_2_like, PAP2, subfamily similar to human phosphatidic_acid_phosphatase_type_2_domain_containing_2. PAP2 is a super-family of phosphatases and haloperoxidases. This subgroup, which is specific to eukaryota, lacks functional characterization and may act as a membrane-associated phosphatidic acid phosphatase.бА0АкА0АаАCDDбАаАз}вА0А0АаАБяcd03392, PAP2_like_2, PAP2_like_2 proteins. PAP2 is a super-family of phosphatases and haloperoxidases. This subgroup, which is specific to bacteria, lacks functional characterization and may act as a membrane-associated lipid phosphatase.бА0АкА0АаАCDDбАаАз~вА0А0АаАБ√cd03393, PAP2_like_3, PAP2_like_3 proteins. PAP2 is a super-family of phosphatases and haloperoxidases. This subgroup, which is specific to bacteria and archaea, lacks functional characterization and may act as a membrane-associated lipid phosphatase.бА0АкА0АаАCDDбАаАзвА0А0АаАБяcd03394, PAP2_like_5, PAP2_like_5 proteins. PAP2 is a super-family of phosphatases and haloperoxidases. This subgroup, which is specific to bacteria, lacks functional characterization and may act as a membrane-associated lipid phosphatase.бА0АкА0АаАCDDбАаАзАвА0А0АаАБяcd03395, PAP2_like_4, PAP2_like_4 proteins. PAP2 is a super-family of phosphatases and haloperoxidases. This subgroup, which is specific to bacteria, lacks functional characterization and may act as a membrane-associated lipid phosphatase.бА0АкА0АаАCDDбАаАзБвА0А0АаАБ·cd03396, PAP2_like_6, PAP2_like_6 proteins. PAP2 is a super-family of phosphatases and haloperoxidases. This subgroup, which mainly contains bacterial proteins, lacks functional characterization and may act as a membrane-associated lipid phosphatase.бА0АкА0АаАCDDбАаАзВвА0А0АаАВ0cd03397, PAP2_acid_phosphatase, PAP2, bacterial acid phosphatase or class A non-specific acid phosphatases. These enzymes catalyze phosphomonoester hydrolysis, with optimal activity in low pH conditions. They are secreted into the periplasmic space, and their physiological role remains to be determined.бА0АкА0АаАCDDбАаАзГвА0А0АаАВшcd03398, PAP2_haloperoxidase, PAP2, haloperoxidase_like subfamily. Haloperoxidases catalyze the oxidation of halides such as bromide or chloride by hydrogen peroxide, which results in subsequent halogenation of organic substrates, or halide-assisted disproportionation of hydrogen peroxide forming dioxygen. They are likely to participate in the biosynthesis of halogenated natural products, such as volatile halogenated hydrocarbons, chiral halogenated terpenes, acetogenins and indoles.бА0АкА0АаАCDDбАаАзДвА0А0АаАВ¤cd03399, SPFH_flotillin, Flotillin or reggie family; SPFH (stomatin, prohibitin, flotillin, and HflK/C) superfamily. The flotillin (reggie) like proteins are lipid raft-associated. Individual proteins of this SPFH family may cluster to form membrane microdomains which may in turn recruit multiprotein complexes. In addition, microdomains formed from flotillin proteins may be dynamic units with their own regulatory functions. Flotillins have been implicated in signal transduction, vesicle trafficking, cytoskeleton rearrangement and interact with a variety of proteins. They may play a role in the progression of prion disease, in the pathogenesis of neurodegenerative diseases such as Parkinson's and Alzheimer's disease and in cancer invasion, and metastasis.бА0АкА0АаАCDDбАаАЎ╓вА0А0АаАВ─cd03401, SPFH_prohibitin, Prohibitin family; SPFH (stomatin, prohibitin, flotillin, and HflK/C) superfamily. This model characterizes proteins similar to prohibitin (a lipid raft-associated integral membrane protein). Individual proteins of the SPFH (band 7) domain superfamily may cluster to form membrane microdomains which may in turn recruit multiprotein complexes. These microdomains, in addition to being stable scaffolds, may also be dynamic units with their own regulatory functions. Prohibitin is a mitochondrial inner-membrane protein which may act as a chaperone for the stabilization of mitochondrial proteins. Human prohibitin forms a hetero-oligomeric complex with Bap-37 (prohibitin 2, an SPFH domain carrying homolog). This complex may protect non-assembled membrane proteins against proteolysis by the m-AAA protease. Prohibitin and Bap-37 yeast homologs have been implicated in yeast longevity and in the maintenance of mitochondrial morphology.бА0АкА0АаАCDDбАаАЎ╫вА0А0АаАВcd03402, SPFH_like_u2, Uncharacterized family; SPFH (stomatin, prohibitin, flotillin, and HflK/C) superfamily. This model summarizes an uncharacterized family of proteins similar to stomatin, prohibitin, flotillin, HflK/C (SPFH) and podocin. The conserved domain common to the SPFH superfamily has also been referred to as the Band 7 domain. Many superfamily members are associated with lipid rafts. Individual proteins of the SPFH superfamily may cluster to form membrane microdomains which may in turn recruit multiprotein complexes. Microdomains formed from flotillin proteins may in addition be dynamic units with their own regulatory functions. Flotillins have been implicated in signal transduction, vesicle trafficking, cytoskeleton rearrangement and are known to interact with a variety of proteins. Stomatin interacts with and regulates members of the degenerin/epithelia Na+ channel family in mechanosensory cells of Caenorhabditis elegans and vertebrate neurons and participates in trafficking of Glut1 glucose transporters. Prohibitin may act as a chaperone for the stabilization of mitochondrial proteins. Prokaryotic HflK/C plays a role in the decision between lysogenic and lytic cycle growth during lambda phage infection. Flotillins have been implicated in the progression of prion disease, in the pathogenesis of neurodegenerative diseases such as Parkinson's and Alzheimer's disease, and in cancer invasion and metastasis. Mutations in the podocin gene give rise to autosomal recessive steroid resistant nephritic syndrome.бА0АкА0АаАCDDбАаАЎ╪вА0А0АаАВЖcd03403, SPFH_stomatin, Stomatin, a subgroup of the stomatin-like proteins (slipins) family; belonging to the SPFH (stomatin, prohibitin, flotillin, and HflK/C) superfamily. Stomatin (or band 7) is widely expressed and, highly expressed in red blood cells. It localizes predominantly to the plasma membrane and to intracellular vesicles of the endocytic pathway, where it is present in higher order homo-oligomeric complexes (of between 9 and 12 monomers). Stomatin interacts with and regulates members of the degenerin/epithelia Na+ channel family in mechanosensory cells of Caenorhabditis elegans and vertebrate neurons and, is implicated in trafficking of Glut1 glucose transporters. This subgroup found in animals, also contains proteins similar to Caenorhabditis elegans MEC-2. MEC-2 interacts with MEC-4, which is part of the degenerin channel complex required for response to gentle body touch.бА0АкА0АаАCDDбАаАЎ┘вА0А0АаАВCcd03404, SPFH_HflK, High frequency of lysogenization K (HflK) family; SPFH (stomatin, prohibitin, flotillin, and HflK/C) superfamily. This model characterizes proteins similar to prokaryotic HflK (High frequency of lysogenization K). Although many members of the SPFH (or band 7) superfamily are lipid raft associated, prokaryote plasma membranes lack cholesterol and are unlikely to have lipid raft domains. Individual proteins of this SPFH domain superfamily may cluster to form membrane microdomains which may in turn recruit multiprotein complexes. Escherichia coli HflK is an integral membrane protein which may localize to the plasma membrane. HflK associates with another SPFH superfamily member (HflC) to form an HflKC complex. HflKC interacts with FtsH in a large complex termed the FtsH holo-enzyme. FtsH is an AAA ATP-dependent protease which exerts progressive proteolysis against membrane-embedded and soluble substrate proteins. HflKC can modulate the activity of FtsH. HflKC plays a role in the decision between lysogenic and lytic cycle growth during lambda phage infection.бА0АкА0АаАCDDбАаАЎ┌вА0А0АаАВCcd03405, SPFH_HflC, High frequency of lysogenization C (HflC) family; SPFH (stomatin, prohibitin, flotillin, and HflK/C) superfamily. This model characterizes proteins similar to prokaryotic HflC (High frequency of lysogenization C). Although many members of the SPFH (or band 7) superfamily are lipid raft associated, prokaryote plasma membranes lack cholesterol and are unlikely to have lipid raft domains. Individual proteins of this SPFH domain superfamily may cluster to form membrane microdomains which may in turn recruit multiprotein complexes. Escherichia coli HflC is an integral membrane protein which may localize to the plasma membrane. HflC associates with another SPFH superfamily member (HflK) to form an HflKC complex. HflKC interacts with FtsH in a large complex termed the FtsH holo-enzyme. FtsH is an AAA ATP-dependent protease which exerts progressive proteolysis against membrane-embedded and soluble substrate proteins. HflKC can modulate the activity of FtsH. HflKC plays a role in the decision between lysogenic and lytic cycle growth during lambda phage infection.бА0АкА0АаАCDDбАаАЎ█вА0А0АаАВcd03406, SPFH_like_u3, Uncharacterized family; SPFH (stomatin, prohibitin, flotillin, and HflK/C) superfamily. This model summarizes an uncharacterized family of proteins similar to stomatin, prohibitin, flotillin, HflK/C (SPFH) and podocin. The conserved domain common to the SPFH superfamily has also been referred to as the Band 7 domain. Many superfamily members are associated with lipid rafts. Individual proteins of the SPFH superfamily may cluster to form membrane microdomains which may in turn recruit multiprotein complexes. Microdomains formed from flotillin proteins may in addition be dynamic units with their own regulatory functions. Flotillins have been implicated in signal transduction, vesicle trafficking, cytoskeleton rearrangement and are known to interact with a variety of proteins. Stomatin interacts with and regulates members of the degenerin/epithelia Na+ channel family in mechanosensory cells of Caenorhabditis elegans and vertebrate neurons and participates in trafficking of Glut1 glucose transporters. Prohibitin may act as a chaperone for the stabilization of mitochondrial proteins. Prokaryotic HflK/C plays a role in the decision between lysogenic and lytic cycle growth during lambda phage infection. Flotillins have been implicated in the progression of prion disease, in the pathogenesis of neurodegenerative diseases such as Parkinson's and Alzheimer's disease and, in cancer invasion and metastasis. Mutations in the podocin gene give rise to autosomal recessive steroid resistant nephritic syndrome.бА0АкА0АаАCDDбАаАЎ▄вА0А0АаАВcd03407, SPFH_like_u4, Uncharacterized family; SPFH (stomatin, prohibitin, flotillin, and HflK/C) superfamily. This model summarizes an uncharacterized family of proteins similar to stomatin, prohibitin, flotillin, HflK/C (SPFH) and podocin. The conserved domain common to the SPFH superfamily has also been referred to as the Band 7 domain. Many superfamily members are associated with lipid rafts. Individual proteins of the SPFH superfamily may cluster to form membrane microdomains which may in turn recruit multiprotein complexes. Microdomains formed from flotillin proteins may in addition be dynamic units with their own regulatory functions. Flotillins have been implicated in signal transduction, vesicle trafficking, cytoskeleton rearrangement and are known to interact with a variety of proteins. Stomatin interacts with and regulates members of the degenerin/epithelia Na+ channel family in mechanosensory cells of Caenorhabditis elegans and vertebrate neurons and participates in trafficking of Glut1 glucose transporters. Prohibitin may act as a chaperone for the stabilization of mitochondrial proteins. Prokaryotic HflK/C plays a role in the decision between lysogenic and lytic cycle growth during lambda phage infection. Flotillins have been implicated in the progression of prion disease, in the pathogenesis of neurodegenerative diseases such as Parkinson's and Alzheimer's disease and, in cancer invasion and metastasis. Mutations in the podocin gene give rise to autosomal recessive steroid resistant nephritic syndrome.бА0АкА0АаАCDDбАаАЎ▌вА0А0АаАВcd03408, SPFH_like_u1, Uncharacterized family; SPFH (stomatin, prohibitin, flotillin, and HflK/C) superfamily. This model summarizes an uncharacterized family of proteins similar to stomatin, prohibitin, flotillin, HflK/C (SPFH) and podocin. The conserved domain common to the SPFH superfamily has also been referred to as the Band 7 domain. Many superfamily members are associated with lipid rafts. Individual proteins of the SPFH superfamily may cluster to form membrane microdomains which may in turn recruit multiprotein complexes. Microdomains formed from flotillin proteins may in addition be dynamic units with their own regulatory functions. Flotillins have been implicated in signal transduction, vesicle trafficking, cytoskeleton rearrangement and are known to interact with a variety of proteins. Stomatin interacts with and regulates members of the degenerin/epithelia Na+ channel family in mechanosensory cells of Caenorhabditis elegans and vertebrate neurons and participates in trafficking of Glut1 glucose transporters. Prohibitin may act as a chaperone for the stabilization of mitochondrial proteins. Prokaryotic HflK/C plays a role in the decision between lysogenic and lytic cycle growth during lambda phage infection. Flotillins have been implicated in the progression of prion disease, in the pathogenesis of neurodegenerative diseases such as Parkinson's and Alzheimer's disease and, in cancer invasion and metastasis. Mutations in the podocin gene give rise to autosomal recessive steroid resistant nephritic syndrome.бА0АкА0АаАCDDбАаАЎ▐вА0А0АаАВЙcd03409, Chelatase_Class_II, Class II Chelatase: a family of ATP-independent monomeric or homodimeric enzymes that catalyze the insertion of metal into protoporphyrin rings. This family includes protoporphyrin IX ferrochelatase (HemH), sirohydrochlorin ferrochelatase (SirB) and the cobaltochelatases, CbiK and CbiX. HemH and SirB are involved in heme and siroheme biosynthesis, respectively, while the cobaltochelatases are associated with cobalamin biosynthesis. Excluded from this family are the ATP-dependent heterotrimeric chelatases (class I) and the multifunctional homodimeric enzymes with dehydrogenase and chelatase activities (class III).бА0АкА0АаАCDDбАаАзПвА0А0АаАВcd03411, Ferrochelatase_N, Ferrochelatase, N-terminal domain: Ferrochelatase (protoheme ferrolyase or HemH) is the terminal enzyme of the heme biosynthetic pathway. It catalyzes the insertion of ferrous iron into the protoporphyrin IX ring yielding protoheme. This enzyme is ubiquitous in nature and widely distributed in bacteria and eukaryotes. Recently, some archaeal members have been identified. The oligomeric state of these enzymes varies depending on the presence of a dimerization motif at the C-terminus.бА0АкА0АаАCDDбАаАзРвА0А0АаАВ╨cd03412, CbiK_N, Anaerobic cobalamin biosynthetic cobalt chelatase (CbiK), N-terminal domain. CbiK is part of the cobalt-early path for cobalamin biosynthesis. It catalyzes the insertion of cobalt into the oxidized form of precorrin-2, factor II (sirohydrochlorin), the second step of the anaerobic branch of vitamin B12 biosynthesis. CbiK belongs to the class II family of chelatases and is a homomeric enzyme that does not require ATP for its enzymatic activity.бА0АкА0АаАCDDбАаАзСвА0А0АаАВ╤cd03413, CbiK_C, Anaerobic cobalamin biosynthetic cobalt chelatase (CbiK), C-terminal domain. CbiK is part of the cobalt-early path for cobalamin biosynthesis. It catalyzes the insertion of cobalt into the oxidized form of precorrin-2, factor II (sirohydrochlorin), the second step of the anaerobic branch of vitamin B12 biosynthesis. CbiK belongs to the class II family of chelatases, and is a homomeric enzyme that does not require ATP for its enzymatic activity.бА0АкА0АаАCDDбАаАзТвА0А0АаАВccd03414, CbiX_SirB_C, Sirohydrochlorin cobalt chelatase (CbiX) and sirohydrochlorin iron chelatase (SirB), C-terminal domain. SirB catalyzes the ferro-chelation of sirohydrochlorin to siroheme, the prosthetic group of sulfite and nitrite reductases. CbiX is a cobaltochelatase, responsible for the chelation of Co2+ into sirohydrochlorin, an important step in the vitamin B12 biosynthetic pathway. CbiX often contains a C-terminal histidine-rich region that may be important for metal delivery and/or storage, and may also contain an iron-sulfur center. Both CbiX and SirB are found in a wide range of bacteria.бА0АкА0АаАCDDбАаАзУвА0А0АаАВ┐cd03415, CbiX_CbiC, Archaeal sirohydrochlorin cobalt chelatase (CbiX) single domain. Proteins in this subgroup contain a single CbiX domain N-terminal to a precorrin-8X methylmutase (CbiC) domain. CbiX is a cobaltochelatase, responsible for the chelation of Co2+ into sirohydrochlorin, while CbiC catalyzes the conversion of cobalt-precorrin 8 to cobyrinic acid by methyl rearrangement. Both CbiX and CbiC are involved in vitamin B12 biosynthesis.бА0АкА0АаАCDDбАаАзФвА0А0АаАВcd03416, CbiX_SirB_N, Sirohydrochlorin cobalt chelatase (CbiX) and sirohydrochlorin iron chelatase (SirB), N-terminal domain. SirB catalyzes the ferro-chelation of sirohydrochlorin to siroheme, the prosthetic group of sulfite and nitrite reductases. CbiX is a cobaltochelatase, responsible for the chelation of Co2+ into sirohydrochlorin, an important step in the vitamin B12 biosynthetic pathway. CbiX often contains a C-terminal histidine-rich region that may be important for metal delivery and/or storage, and may also contain an iron-sulfur center. Both are found in a wide range of bacteria. This subgroup also contains single domain proteins from archaea and bacteria which may represent the ancestral form of class II chelatases before domain duplication occurred.бА0АкА0АаАCDDбАаАзХвА0А0АаАВ3cd03418, GRX_GRXb_1_3_like, Glutaredoxin (GRX) family, GRX bacterial class 1 and 3 (b_1_3)-like subfamily; composed of bacterial GRXs, approximately 10 kDa in size, and proteins containing a GRX or GRX-like domain. GRX is a glutathione (GSH) dependent reductase, catalyzing the disulfide reduction of target proteins such as ribonucleotide reductase. It contains a redox active CXXC motif in a TRX fold and uses a similar dithiol mechanism employed by TRXs for intramolecular disulfide bond reduction of protein substrates. Unlike TRX, GRX has preference for mixed GSH disulfide substrates, in which it uses a monothiol mechanism where only the N-terminal cysteine is required. The flow of reducing equivalents in the GRX system goes from NADPH -> GSH reductase -> GSH -> GRX -> protein substrates. By altering the redox state of target proteins, GRX is involved in many cellular functions including DNA synthesis, signal transduction and the defense against oxidative stress. Different classes are known including E. coli GRX1 and GRX3, which are members of this subfamily.бА0АкА0АаАCDDбАаАзЦвА0А0АаАВ╖cd03419, GRX_GRXh_1_2_like, Glutaredoxin (GRX) family, GRX human class 1 and 2 (h_1_2)-like subfamily; composed of proteins similar to human GRXs, approximately 10 kDa in size, and proteins containing a GRX or GRX-like domain. GRX is a glutathione (GSH) dependent reductase, catalyzing the disulfide reduction of target proteins such as ribonucleotide reductase. It contains a redox active CXXC motif in a TRX fold and uses a similar dithiol mechanism employed by TRXs for intramolecular disulfide bond reduction of protein substrates. Unlike TRX, GRX has preference for mixed GSH disulfide substrates, in which it uses a monothiol mechanism where only the N-terminal cysteine is required. The flow of reducing equivalents in the GRX system goes from NADPH -> GSH reductase -> GSH -> GRX -> protein substrates. By altering the redox state of target proteins, GRX is involved in many cellular functions including DNA synthesis, signal transduction and the defense against oxidative stress. Different classes are known including human GRX1 and GRX2, which are members of this subfamily. Also included in this subfamily are the N-terminal GRX domains of proteins similar to human thioredoxin reductase 1 and 3.бА0АкА0АаАCDDбАаАзЧвА0А0АаАВ│cd03420, SirA_RHOD_Pry_redox, SirA_RHOD_Pry_redox. SirA-like domain located within a multidomain protein of unknown function. Other domains include RHOD (rhodanese homology domain), and Pry_redox (pyridine nucleotide-disulphide oxidoreductase) as well as a C-terminal domain that corresponds to COG2210. This fold is referred to as a two-layered alpha/beta sandwich, structurally similar to that of translation initiation factor 3.бА0АкА0АаАCDDбАаАзШвА0А0АаАВ╤cd03421, SirA_like_N, SirA_like_N, a protein of unknown function with an N-terminal SirA-like domain. The SirA, YedF, YeeD protein family is present in bacteria as well as archaea. SirA (also known as UvrY, and YhhP) belongs to a family of a two-component response regulators that controls secondary metabolism and virulence. The other member of this two-component system is a sensor kinase called BarA which phosphorylates SirA. A variety of microorganisms have similar proteins, all of which contain a common CPxP sequence motif in the N-terminal region. YhhP is suggested to be important for normal cell division and growth in rich nutrient medium. Moreover, despite a low primary sequence similarity, the YccP structure closely resembles the non-homologous C-terminal RNA-binding domain of E. coli translation initiation factor IF3. The signature CPxP motif serves to stabilize the N-terminal helix as part of the N-capping box and might be important in mRNA-binding.бА0АкА0АаАCDDбАаАзЩвА0А0АаАВecd03422, YedF, YedF is a bacterial SirA-like protein of unknown function. SirA (also known as UvrY, and YhhP) belongs to a family of a two-component response regulators that controls secondary metabolism and virulence. The other member of this two-component system is a sensor kinase called BarA which phosphorylates SirA. A variety of microorganisms have similar proteins, all of which contain a common CPxP sequence motif in the N-terminal region. YhhP is suggested to be important for normal cell division and growth in rich nutrient medium. Moreover, despite a low primary sequence similarity, the YccP structure closely resembles the non-homologous C-terminal RNA-binding domain of E. coli translation initiation factor IF3. The signature CPxP motif serves to stabilize the N-terminal helix as part of the N-capping box and might be important in mRNA-binding.бА0АкА0АаАCDDбАаАзЪвА0А0АаАВ%cd03423, SirA, SirA (also known as UvrY, and YhhP) belongs to a family of two-component response regulators that controls secondary metabolism and virulence. The other member of this two-component system is a sensor kinase called BarA which phosphorylates SirA. A variety of microorganisms have similar proteins, all of which contain a common CPxP sequence motif in the N-terminal region. YhhP is thought to be important for normal cell division and growth in rich nutrient medium. Moreover, despite a low primary sequence similarity, the YccP structure closely resembles the non-homologous C-terminal RNA-binding domain of E. coli translation initiation factor IF3. The signature CPxP motif serves to stabilize the N-terminal helix as part of the N-capping box and might be important in mRNA-binding.бА0АкА0АаАCDDбАаАзЫвА0А0АаАВcd03424, ADPRase_NUDT5, ADP-ribose pyrophosphatase (ADPRase) catalyzes the hydrolysis of ADP-ribose and a variety of additional ADP-sugar conjugates to AMP and ribose-5-phosphate. Like other members of the Nudix hydrolase superfamily, it requires a divalent cation, such as Mg2+, for its activity. It also contains a highly conserved 23-residue Nudix motif (GX5EX7REUXEEXGU, where U = I, L or V) which functions as a metal binding site/catalytic site. In addition to the Nudix motif, there are additional conserved amino acid residues, distal from the signature sequence, that correlate with substrate specificity. In humans, there are four distinct ADPRase activities, three putative cytosolic enzymes (ADPRase-I, -II, and -Mn) and a single mitochondrial enzyme (ADPRase-m). Human ADPRase-II is also referred to as NUDT5. It lacks the N-terminal target sequence unique to mitochondrial ADPRase. The different cytosolic types are distinguished by their specificities for substrate and specific requirement for metal ions. NUDT5 forms a homodimer.бА0АкА0АаАCDDбАаАзЬвА0А0АаАВxcd03425, MutT_pyrophosphohydrolase, The MutT pyrophosphohydrolase is a prototypical Nudix hydrolase that catalyzes the hydrolysis of nucleoside and deoxynucleoside triphosphates (NTPs and dNTPs) by substitution at a beta-phosphorus to yield a nucleotide monophosphate (NMP) and inorganic pyrophosphate (PPi). This enzyme requires two divalent cations for activity; one coordinates the phosphoryl groups of the NTP/dNTP substrate, and the other coordinates to the enzyme. It also contains the Nudix motif, a highly conserved 23-residue block (GX5EX7REUXEEXGU, where U = I, L or V), that functions as metal binding and catalytic site. MutT pyrophosphohydrolase is important in preventing errors in DNA replication by hydrolyzing mutagenic nucleotides such as 8-oxo-dGTP (a product of oxidative damage), which can mispair with template adenine during DNA replication, to guanine nucleotides.бА0АкА0АаАCDDбАаАзЭвА0А0АаАВ╤cd03426, CoAse, Coenzyme A pyrophosphatase (CoAse), a member of the Nudix hydrolase superfamily, functions to catalyze the elimination of oxidized inactive CoA, which can inhibit CoA-utilizing enzymes. The need of CoAses mainly arises under conditions of oxidative stress. CoAse has a conserved Nudix fold and requires a single divalent cation for catalysis. In addition to a signature Nudix motif G[X5]E[X7]REUXEEXGU, where U is Ile, Leu, or Val, CoAse contains an additional motif upstream called the NuCoA motif (LLTXT(SA)X3RX3GX3FPGG) which is postulated to be involved in CoA recognition. CoA plays a central role in lipid metabolism. It is involved in the initial steps of fatty acid sythesis in the cytosol, in the oxidation of fatty acids and the citric acid cycle in the mitochondria, and in the oxidation of long-chain fatty acids in peroxisomes. CoA has the important role of activating fatty acids for further modification into key biological signalling molecules.бА0АкА0АаАCDDбАаАзЮвА0А0АаАВзcd03427, MTH1, MutT homolog-1 (MTH1) is a member of the Nudix hydrolase superfamily. MTH1, the mammalian counterpart of MutT, hydrolyzes oxidized purine nucleoside triphosphates, such as 8-oxo-dGTP and 2-hydroxy-ATP, to monophosphates, thereby preventing the incorporation of such oxygen radicals during replication. This is an important step in the repair mechanism in genomic and mitochondrial DNA. Like other members of the Nudix family, it requires a divalent cation, such as Mg2+ or Mn2+, for activity, and contain the Nudix motif, a highly conserved 23-residue block (GX5EX7REUXEEXGU, where U = I, L or V), that functions as a metal binding and catalytic site. MTH1 is predominantly localized in the cytoplasm and mitochondria. Structurally, this enzyme adopts a similar fold to MutT despite low sequence similarity outside the conserved nudix motif. The most distinctive structural difference between MutT and MTH1 is the presence of a beta-hairpin, which is absent in MutT. This results in a much deeper and narrower substrate binding pocket. Mechanistically, MTH1 contains dual specificity for nucleotides that contain 2-OH-adenine bases and those that contain 8-oxo-guanine bases.бА0АкА0АаАCDDбАаАзЯвА0А0АаАВcd03428, Ap4A_hydrolase_human_like, Diadenosine tetraphosphate (Ap4A) hydrolase is a member of the Nudix hydrolase superfamily. Ap4A hydrolases are well represented in a variety of prokaryotic and eukaryotic organisms. Phylogenetic analysis reveals two distinct subgroups where plant enzymes fall into one subfamily and fungi/animals/archaea enzymes, represented by this subfamily, fall into another. Bacterial enzymes are found in both subfamilies. Ap4A is a potential by-product of aminoacyl tRNA synthesis, and accumulation of Ap4A has been implicated in a range of biological events, such as DNA replication, cellular differentiation, heat shock, metabolic stress, and apoptosis. Ap4A hydrolase cleaves Ap4A asymmetrically into ATP and AMP. It is important in the invasive properties of bacteria and thus presents a potential target for inhibition of such invasive bacteria. Besides the signature nudix motif (G[X5]E[X7]REUXEEXGU, where U is Ile, Leu, or Val) that functions as a metal binding and catalytic site, and a required divalent cation, Ap4A hydrolase is structurally similar to the other members of the nudix superfamily with some degree of variation. Several regions in the sequences are poorly defined and substrate and metal binding sites are only predicted based on kinetic studies.бА0АкА0АаАCDDбАаАзавА0А0АаАВМcd03429, NADH_pyrophosphatase, NADH pyrophosphatase, a member of the Nudix hydrolase superfamily, catalyzes the cleavage of NADH into reduced nicotinamide mononucleotide (NMNH) and AMP. Like other members of the Nudix family, it requires a divalent cation, such as Mg2+ or Mn2+, for activity. Members of this family are also recognized by the Nudix motif, a highly conserved 23-residue block (GX5EX7REUXEEXGU, where U = I, L or V), that functions as a metal binding and catalytic site. A block of 8 conserved amino acids downstream of the nudix motif is thought to give NADH pyrophosphatase its specificity for NADH. NADH pyrophosphatase forms a dimer.бА0АкА0АаАCDDбАаАзбвА0А0АаАВЮcd03430, GDPMH, GDP-mannose glycosyl hydrolase (AKA GDP-mannose mannosyl hydrolase (GDPMH)) is a member of the Nudix hydrolase superfamily. This class of enzymes is unique from other members of the superfamily in two aspects. First, it contains a modified Nudix signature sequence. The slight changes to the conserved sequence motif, GX5EX7REUXEEXGU, where U = I, L or V), are believed to contribute to the removal of all magnesium binding sites but one, retaining only the metal site that coordinates the pyrophosphate of the substrate. Secondly, it is not a pyrophosphatase that substitutes at a phosphorus; instead, it hydrolyzes nucleotide sugars such as GDP-mannose to GDP and mannose, cleaving the phosphoglycosyl bond by substituting at a carbon position. GDP-mannose provides mannosyl components for cell wall synthesis and is required for the synthesis of other glycosyl donors (such as GDP-fucose and colitose) for the cell wall. The importance of GDP-sugar hydrolase activities is thus closely related to the regulation of cell wall biosynthesis. Enzymes in this family are believed to regulate the concentration of GDP-mannose and GDP-glucose in the bacterial cell wall.бА0АкА0АаАCDDбАаАзввА0А0АаАВjcd03431, DNA_Glycosylase_C, DNA glycosylase (MutY in bacteria and hMYH in humans) is responsible for repairing misread A*oxoG residues to C*G by removing the inappropriately paired adenine base from the DNA backbone. It belongs to the Nudix hydrolase superfamily and is important for the repair of various genotoxic lesions. Enzymes belonging to this superfamily requires a divalent cation, such as Mg2+ or Mn2+ for their activity. They are also recognized by a highly conserved 23-residue nudix motif (GX5EX7REUXEEXGU, where U = I, L or V). However, DNA glycosylase does not seem to contain this signature motif. DNA glycosylase consists of 2 domains: the N-terminal domain contains the catalytic properties of the enzyme and the C-terminal domain affects substrate (oxoG) binding and enzymatic turnover. The C-terminal domain is highly similar to MutT, based on secondary structure and topology, despite low sequence identity. MutT sanitizes the nucleotide precursor pool by hydrolyzing oxo-dGTP to oxo-dGMO and inorganic pyrophosphate. The similarity strongly suggests that the two proteins share a common evolutionary origin.бА0АкА0АаАCDDбАаАзгвА0А0АаАВ╜cd03440, hot_dog, The hotdog fold was initially identified in the E. coli FabA (beta-hydroxydecanoyl-acyl carrier protein (ACP)-dehydratase) structure and subsequently in 4HBT (4-hydroxybenzoyl-CoA thioesterase) from Pseudomonas. A number of other seemingly unrelated proteins also share the hotdog fold. These proteins have related, but distinct, catalytic activities that include metabolic roles such as thioester hydrolysis in fatty acid metabolism, and degradation of phenylacetic acid and the environmental pollutant 4-chlorobenzoate. This superfamily also includes the PaaI-like protein FapR, a non-catalytic bacterial homolog involved in transcriptional regulation of fatty acid biosynthesis.бА0АкА0АаАCDDбАаАздвА0А0АаАВJcd03441, R_hydratase_like, (R)-hydratase [(R)-specific enoyl-CoA hydratase]. Catalyzes the hydration of trans-2-enoyl CoA to (R)-3-hydroxyacyl-CoA as part of the PHA (polyhydroxyalkanoate) biosynthetic pathway. The structure of the monomer includes a five-strand antiparallel beta-sheet wrapped around a central alpha helix, referred to as a hot dog fold. The active site lies within a substrate-binding tunnel formed by the homodimer. Other enzymes with this fold include MaoC dehydratase, Hydratase-Dehydrogenase-Epimerase protein (HDE), and the fatty acid synthase beta subunit.бА0АкА0АаАCDDбАаАзевА0А0АаАВ╟cd03442, BFIT_BACH, Brown fat-inducible thioesterase (BFIT). Brain acyl-CoA hydrolase (BACH). These enzymes deacylate long-chain fatty acids by hydrolyzing acyl-CoA thioesters to free fatty acids and CoA-SH. Eukaryotic members of this family are expressed in brain, testis, and brown adipose tissues. The archeal and eukaryotic members of this family have two tandem copies of the conserved hot dog fold, while most bacterial members have only one copy.бА0АкА0АаАCDDбАаАзжвА0А0АаАВлcd03443, PaaI_thioesterase, PaaI_thioesterase is a tetrameric acyl-CoA thioesterase with a hot dog fold and one of several proteins responsible for phenylacetic acid (PA) degradation in bacteria. Although orthologs of PaaI exist in archaea and eukaryotes, their function has not been determined. Sequence similarity between PaaI, E. coli medium chain acyl-CoA thioesterase II, and human thioesterase III suggests they all belong to the same thioesterase superfamily. The conserved fold present in these thioesterases is referred to as an asymmetric hot dog fold, similar to those of 4-hydroxybenzoyl-CoA thioesterase (4HBT) and the beta-hydroxydecanoyl-ACP dehydratases (FabA/FabZ).бА0АкА0АаАCDDбАаАззвА0А0АаАВ▒cd03444, Thioesterase_II_repeat1, Thioesterase II (TEII) is thought to regenerate misprimed nonribosomal peptide synthetases (NRPSs) as well as modular polyketide synthases (PKSs) by hydrolyzing acetyl groups bound to the peptidyl carrier protein (PCP) and acyl carrier protein (ACP) domains, respectively. TEII has two tandem asymmetric hot dog folds that are structurally similar to one found in PaaI thioesterase, 4-hydroxybenzoyl-CoA thioesterase (4HBT) and beta-hydroxydecanoyl-ACP dehydratase and thus, the TEII monomer is equivalent to the homodimeric form of the latter three enzymes. Human TEII is expressed in T cells and has been shown to bind the product of the HIV-1 Nef gene.бА0АкА0АаАCDDбАаАзивА0А0АаАВ▒cd03445, Thioesterase_II_repeat2, Thioesterase II (TEII) is thought to regenerate misprimed nonribosomal peptide synthetases (NRPSs) as well as modular polyketide synthases (PKSs) by hydrolyzing acetyl groups bound to the peptidyl carrier protein (PCP) and acyl carrier protein (ACP) domains, respectively. TEII has two tandem asymmetric hot dog folds that are structurally similar to one found in PaaI thioesterase, 4-hydroxybenzoyl-CoA thioesterase (4HBT) and beta-hydroxydecanoyl-ACP dehydratase and thus, the TEII monomer is equivalent to the homodimeric form of the latter three enzymes. Human TEII is expressed in T cells and has been shown to bind the product of the HIV-1 Nef gene.бА0АкА0АаАCDDбАаАзйвА0А0АаАВXcd03446, MaoC_like, MoaC_like Similar to the MaoC (monoamine oxidase C) dehydratase regulatory protein but without the N-terminal PutA domain. This protein family has a hot-dog fold similar to that of (R)-specific enoyl-CoA hydratase, the peroxisomal Hydratase-Dehydrogenase-Epimerase (HDE) protein, and the fatty acid synthase beta subunit.бА0АкА0АаАCDDбАаАзквА0А0АаАБ·cd03447, FAS_MaoC, FAS_MaoC, the MaoC-like hot dog fold of the fatty acid synthase, beta subunit. Other enzymes with this fold include MaoC dehydratase, Hydratase-Dehydrogenase-Epimerase protein (HDE), and 17-beta-hydroxysteriod dehydrogenase (HSD).бА0АкА0АаАCDDбАаАзлвА0А0АаАВcd03448, HDE_HSD, HDE_HSD The R-hydratase-like hot dog fold of the 17-beta-hydroxysteriod dehydrogenase (HSD), and Hydratase-Dehydrogenase-Epimerase (HDE) proteins. Other enzymes with this fold include MaoC dehydratase, and the fatty acid synthase beta subunit.бА0АкА0АаАCDDбАаАзмвА0А0АаАВqcd03449, R_hydratase, (R)-hydratase [(R)-specific enoyl-CoA hydratase] catalyzes the hydration of trans-2-enoyl CoA to (R)-3-hydroxyacyl-CoA as part of the PHA (polyhydroxyalkanoate) biosynthetic pathway. (R)-hydratase contains a hot-dog fold similar to those of thioesterase II, and beta-hydroxydecanoyl-ACP dehydratase, MaoC dehydratase, Hydratase-Dehydrogenase-Epimerase protein (HDE), and the fatty acid synthase beta subunit. The active site lies within a substrate-binding tunnel formed by the (R)-hydratase homodimer. A subset of the bacterial (R)-hydratases contain a C-terminal phosphotransacetylase (PTA) domain.бА0АкА0АаАCDDбАаАзнвА0А0АаАВ7cd03450, NodN, NodN (nodulation factor N) contains a single hot dog fold similar to those of the peroxisomal Hydratase-Dehydrogenase-Epimerase (HDE) protein, and the fatty acid synthase beta subunit. Rhizobium and related species form nodules on the roots of their legume hosts, a symbiotic process that requires production of Nod factors, which are signal molecules involved in root hair deformation and meristematic cell division. The nodulation gene products, including NodN, are involved in producing the Nod factors, however the role played by NodN is unclear.бА0АкА0АаАCDDбАаАзовА0А0АаАВКcd03451, FkbR2, FkbR2 is a Streptomyces hygroscopicus protein with a hot dog fold that belongs to a conserved family of proteins found in prokaryotes and archaea but not in eukaryotes. FkbR2 has sequence similarity to (R)-specific enoyl-CoA hydratase, the peroxisomal Hydratase-Dehydrogenase-Epimerase (HDE) protein, and the fatty acid synthase beta subunit. The function of FkbR2 is unknown.бА0АкА0АаАCDDбАаАзпвА0А0АаАВjcd03452, MaoC_C, MaoC_C The C-terminal hot dog fold of the MaoC (monoamine oxidase C) dehydratase regulatory protein. Orthologs of MaoC include PaaZ [Escherichia coli] and PaaN [Pseudomonas putida], which are putative ring-opening enzymes involved in phenylacetic acid degradation. The C-terminal domain of MaoC has sequence similarity to (R)-specific enoyl-CoA hydratase,Hydratase-Dehydrogenase-Epimerase (HDE) protein, and the fatty acid synthase beta subunit. MaoC also has an N-terminal PutA domain like that found in the E. coli PutA proline dehydrogenase and other members of the aldehyde dehydrogenase family.бА0АкА0АаАCDDбАаАз░вА0А0АаАВ'cd03453, SAV4209_like, SAV4209_like. Similar in sequence to the Streptomyces avermitilis SAV4209 protein, with a hot dog fold that is similar to those of (R)-specific enoyl-CoA hydratase, the peroxisomal Hydratase-Dehydrogenase-Epimerase (HDE) protein, and the fatty acid synthase beta subunit.бА0АкА0АаАCDDбАаАз▒вА0А0АаАВ`cd03454, YdeM, YdeM is a Bacillus subtilis protein that belongs to a family of prokaryotic proteins of unkown function. YdeM has sequence similarity to the hot-dog fold of (R)-specific enoyl-CoA hydratase. Other enzymes with this fold include the peroxisomal Hydratase-Dehydrogenase-Epimerase (HDE) protein, and the fatty acid synthase beta subunit.бА0АкА0АаАCDDбАаАз▓вА0А0АаАВscd03455, SAV4209, SAV4209 is a Streptomyces avermitilis protein with a hot dog fold that is similar to those of (R)-specific enoyl-CoA hydratase, the peroxisomal Hydratase-Dehydrogenase-Epimerase (HDE) protein, and the fatty acid synthase beta subunit. The alpha- and gamma-proteobacterial members of this CD have, in addition to a hot dog fold, an N-terminal extension.бА0АкА0АаАCDDбАаАз│вА0А0АаАВ¤cd03457, intradiol_dioxygenase_like, Intradiol dioxygenase supgroup. Intradiol dioxygenases catalyze the critical ring-cleavage step in the conversion of catecholate derivatives to citric acid cycle intermediates. They break the catechol C1-C2 bond and utilize Fe3+, as opposed to the extradiol-cleaving enzymes which break the C2-C3 or C1-C6 bond and utilize Fe2+ and Mn+. The family contains catechol 1,2-dioxygenases and protocatechuate 3,4-dioxygenases. The specific function of this subgroup is unknown.бА0АкА0АаАCDDбАаАз┤вА0А0АаАВcd03458, Catechol_intradiol_dioxygenases, Catechol intradiol dioxygenases can be divided into several subgroups according to their substrate specificity for catechol, chlorocatechols and hydroxyquinols. Almost all members of this family are homodimers containing one ferric ion (Fe3+) per monomer. They belong to the intradiol dioxygenase family, a family of mononuclear non-heme iron intradiol-cleaving enzymes that catalyze the oxygenation of catecholates to aliphatic acids via the cleavage of aromatic rings.бА0АкА0АаАCDDбАаАз╡вА0А0АаАВ▐cd03459, 3,4-PCD, Protocatechuate 3,4-dioxygenase (3,4-PCD) catalyzes the oxidative ring cleavage of 3,4-dihydroxybenzoate to produce beta-carboxy-cis,cis-muconate. 3,4-PCDs are large aggregates of 12 protomers, each composed of an alpha- and beta-subunit and an Fe3+ ion bound in the beta-subunit at the alpha-beta-subunit interface. 3,4-PCD is a member of the aromatic dioxygenases which are non-heme iron intradiol-cleaving enzymes that break the C1-C2 bond and utilize Fe3+.бА0АкА0АаАCDDбАаАз╢вА0А0АаАВдcd03460, 1,2-CTD, Catechol 1,2 dioxygenase (1,2-CTD) catalyzes an intradiol cleavage reaction of catechol to form cis,cis-muconate. 1,2-CTDs is homodimers with one catalytic non-heme ferric ion per monomer. They belong to the aromatic dioxygenase family, a family of mononuclear non-heme iron intradiol-cleaving enzymes that catalyze the oxygenation of catecholates to aliphatic acids via the cleavage of aromatic rings.бА0АкА0АаАCDDбАаАз╖вА0А0АаАВЪcd03461, 1,2-HQD, Hydroxyquinol 1,2-dioxygenase (1,2-HQD) catalyzes the ring cleavage of hydroxyquinol (1,2,4-trihydroxybenzene), a intermediate in the degradation of a large variety of aromatic compounds including some polychloro- and nitroaromatic pollutants, to form 3-hydroxy-cis,cis-muconates. 1,2-HQD blongs to the aromatic dioxygenase family, a family of mononuclear non-heme intradiol-cleaving enzymes.бА0АкА0АаАCDDбАаАз╕вА0А0АаАВ2cd03462, 1,2-CCD, chlorocatechol 1,2-dioxygenases (1,2-CCDs) (type II enzymes) are homodimeric intradiol dioxygenases that degrade chlorocatechols via the addition of molecular oxygen and the subsequent cleavage between two adjacent hydroxyl groups. This reaction is part of the modified ortho-cleavage pathway which is a central oxidative bacterial pathway that channels chlorocatechols, derived from the degradation of chlorinated benzoic acids, phenoxyacetic acids, phenols, benzenes, and other aromatics into the energy-generating tricarboxylic acid pathway.бА0АкА0АаАCDDбАаАз╣вА0А0АаАВcd03463, 3,4-PCD_alpha, Protocatechuate 3,4-dioxygenase (3,4-PCD) , alpha subunit. 3,4-PCD catalyzes the oxidative ring cleavage of 3,4-dihydroxybenzoate to produce beta-carboxy-cis,cis-muconate. 3,4-PCDs are large aggregates of 12 protomers, each composed of an alpha- and beta-subunit and an Fe3+ ion bound in the beta-subunit at the alpha-subunit-beta-subunit interface. 3,4-PCD is a member of the aromatic dioxygenases which are non-heme iron intradiol-cleaving enzymes that break the C1-C2 bond and utilize Fe3+.бА0АкА0АаАCDDбАаАз║вА0А0АаАВcd03464, 3,4-PCD_beta, Protocatechuate 3,4-dioxygenase (3,4-PCD) , beta subunit. 3,4-PCD catalyzes the oxidative ring cleavage of 3,4-dihydroxybenzoate to produce beta-carboxy-cis,cis-muconate. 3,4-PCDs are large aggregates of 12 protomers, each composed of an alpha- and beta-subunit and an Fe3+ ion bound in the beta-subunit at the alpha-subunit-beta-subunit interface. 3,4-PCD is a member of the aromatic dioxygenases which are non-heme iron intradiol-cleaving enzymes that break the C1-C2 bond and utilize Fe3+.бА0АкА0АаАCDDбАаАз╗вА0А0АаАВQcd03465, URO-D_like, The URO-D _like protein superfamily includes bacterial and eukaryotic uroporphyrinogen decarboxylases (URO-D), coenzyme M methyltransferases and other putative bacterial methyltransferases. Uroporphyrinogen decarboxylase (URO-D) decarboxylates the four acetate side chains of uroporphyrinogen III (uro-III) to create coproporphyrinogen III, an important branching point of the tetrapyrrole biosynthetic pathway. The methyltransferases represented here are important for ability of methanogenic organisms to use other compounds than carbon dioxide for reduction to methane.бА0АкА0АаАCDDбАаАз╝вА0А0АаАВШcd03466, Nitrogenase_NifN_2, Nitrogenase_nifN_2: A subgroup of the NifN subunit of the NifEN complex: NifN forms an alpha2beta2 tetramer with NifE. NifN and nifE are structurally homologous to nitrogenase MoFe protein beta and alpha subunits respectively. NifEN participates in the synthesis of the iron-molybdenum cofactor (FeMoco) of the MoFe protein. NifB-co (an iron and sulfur containing precursor of the FeMoco) from NifB is transferred to the NifEN complex where it is further processed to FeMoco. The nifEN bound precursor of FeMoco has been identified as a molybdenum-free, iron- and sulfur- containing analog of FeMoco. It has been suggested that this nifEN bound precursor also acts as a cofactor precursor in nitrogenase systems which require a cofactor other than FeMoco: i.e. iron-vanadium cofactor (FeVco) or iron only cofactor (FeFeco). This group also contains the Clostidium fused NifN-NifB protein.бА0АкА0АаАCDDбАаАз╜вА0А0АаАВвcd03467, Rieske, Rieske domain; a [2Fe-2S] cluster binding domain commonly found in Rieske non-heme iron oxygenase (RO) systems such as naphthalene and biphenyl dioxygenases, as well as in plant/cyanobacterial chloroplast b6f and mitochondrial cytochrome bc(1) complexes. The Rieske domain can be divided into two subdomains, with an incomplete six-stranded, antiparallel beta-barrel at one end, and an iron-sulfur cluster binding subdomain at the other. The Rieske iron-sulfur center contains a [2Fe-2S] cluster, which is involved in electron transfer, and is liganded to two histidine and two cysteine residues present in conserved sequences called Rieske motifs. In RO systems, the N-terminal Rieske domain of the alpha subunit acts as an electron shuttle that accepts electrons from a reductase or ferredoxin component and transfers them to the mononuclear iron in the alpha subunit C-terminal domain to be used for catalysis.бА0АкА0АаАCDDбАаАз╛вА0А0АаАВИcd03468, PolY_like, DNA Polymerase Y-family. Y-family DNA polymerases are a specialized subset of polymerases that facilitate translesion synthesis (TLS), a process that allows the bypass of a variety of DNA lesions. Unlike replicative polymerases, TLS polymerases lack proofreading activity and have low fidelity and low processivity. They use damaged DNA as templates and insert nucleotides opposite the lesions. The active sites of TLS polymerases are large and flexible to allow the accomodation of distorted bases. Expression of Y-family polymerases is often induced by DNA damage and is believed to be highly regulated. TLS is likely induced by the monoubiquitination of the replication clamp PCNA, which provides a scaffold for TLS polymerases to bind in order to access the lesion. Because of their high error rates, TLS polymerases are potential targets for cancer treatment and prevention.бА0АкА0АаАCDDбАаА▒JвА0А0АаАВ!cd03469, Rieske_RO_Alpha_N, Rieske non-heme iron oxygenase (RO) family, N-terminal Rieske domain of the oxygenase alpha subunit; The RO family comprise a large class of aromatic ring-hydroxylating dioxygenases found predominantly in microorganisms. These enzymes enable microorganisms to tolerate and even exclusively utilize aromatic compounds for growth. ROs consist of two or three components: reductase, oxygenase, and ferredoxin (in some cases) components. The oxygenase component may contain alpha and beta subunits, with the beta subunit having a purely structural function. Some oxygenase components contain only an alpha subunit. The oxygenase alpha subunit has two domains, an N-terminal Rieske domain with an [2Fe-2S] cluster and a C-terminal catalytic domain with a mononuclear Fe(II) binding site. The Rieske [2Fe-2S] cluster accepts electrons from the reductase or ferredoxin component and transfers them to the mononuclear iron for catalysis. Reduced pyridine nucleotide is used as the initial source of two electrons for dioxygen activation.бА0АкА0АаАCDDбАаАз┐вА0А0АаАВцcd03470, Rieske_cytochrome_bc1, Iron-sulfur protein (ISP) component of the bc(1) complex family, Rieske domain; The Rieske domain is a [2Fe-2S] cluster binding domain involved in electron transfer. The bc(1) complex is a multisubunit enzyme found in many different organisms including uni- and multi-cellular eukaryotes, plants (in their mitochondria) and bacteria. The cytochrome bc(1) and b6f complexes are central components of the respiratory and photosynthetic electron transport chains, respectively, which carry out similar core electron and proton transfer steps. The bc(1) and b6f complexes share a common core structure of three catalytic subunits: cyt b, the Rieske ISP, and either a cyt c1 in the bc(1) complex or cyt f in the b6f complex, which are arranged in an integral membrane-bound dimeric complex. While the core of the b6f complex is similar to that of the bc(1) complex, the domain arrangement outside the core and the complement of prosthetic groups are strikingly different.бА0АкА0АаАCDDбАаАз└вА0А0АаАВ,cd03471, Rieske_cytochrome_b6f, Iron-sulfur protein (ISP) component of the b6f complex family, Rieske domain; The Rieske domain is a [2Fe-2S] cluster binding domain involved in electron transfer. The cytochrome b6f complex from Mastigocladus laminosus, a thermophilic cyanobacterium, contains four large subunits, including cytochrome f, cytochrome b6, the Rieske ISP, and subunit IV; as well as four small hydrophobic subunits, PetG, PetL, PetM, and PetN. Rieske ISP, one of the large subunits of the cytochrome bc-type complexes, is involved in respiratory and photosynthetic electron transfer. The core of the chloroplast b6f complex is similar to the analogous respiratory cytochrome bc(1) complex, but the domain arrangement outside the core and the complement of prosthetic groups are strikingly different.бА0АкА0АаАCDDбАаАз┴вА0А0АаАВЯcd03472, Rieske_RO_Alpha_BPDO_like, Rieske non-heme iron oxygenase (RO) family, Biphenyl dioxygenase (BPDO)-like subfamily, N-terminal Rieske domain of the oxygenase alpha subunit; composed of the oxygenase alpha subunits of BPDO and similar proteins including cumene dioxygenase (CumDO), nitrobenzene dioxygenase (NBDO), alkylbenzene dioxygenase (AkbDO) and dibenzofuran 4,4a-dioxygenase (DFDO). ROs comprise a large class of aromatic ring-hydroxylating dioxygenases that enable microorganisms to tolerate and utilize aromatic compounds for growth. The oxygenase alpha subunit contains an N-terminal Rieske domain with an [2Fe-2S] cluster and a C-terminal catalytic domain with a mononuclear Fe(II) binding site. The Rieske [2Fe-2S] cluster accepts electrons from a reductase or ferredoxin component and transfers them to the mononuclear iron for catalysis. BPDO degrades biphenyls and polychlorinated biphenyls (PCB's) while CumDO degrades cumene (isopropylbenzene), an aromatic hydrocarbon that is intermediate in size between ethylbenzene and biphenyl. NBDO catalyzes the initial reaction in nitrobenzene degradation, oxidizing the aromatic rings of mono- and dinitrotoluenes to form catechol and nitrite. NBDO belongs to the naphthalene subfamily of ROs. AkbDO is involved in alkylbenzene catabolism, converting o-xylene to 2,3- and 3,4-dimethylphenol and ethylbenzene to cis-dihydrodiol. DFDO is involved in dibenzofuran degradation.бА0АкА0АаАCDDбАаАз┬вА0А0АаАВЛcd03473, Rieske_CMP_Neu5Ac_hydrolase_N, Cytidine monophosphate-N-acetylneuraminic acid (CMP Neu5Ac) hydroxylase family, N-terminal Rieske domain; The Rieske domain is a [2Fe-2S] cluster binding domain involved in electron transfer. CMP Neu5Ac hydroxylase is the key enzyme for the synthesis of N-glycolylneuraminic acid (NeuGc) from N-acetylneuraminic acid (Neu5Ac), NeuGc and Neu5Ac are members of a family of cell surface sugars called sialic acids. All mammals except humans have both NeuGc variants on their cell surfaces. In humans, the gene encoding CMP Neu5Ac hydroxylase has a mutation within its coding region that abolishes NeuGc production.бА0АкА0АаАCDDбАаАз├вА0А0АаАВ]cd03474, Rieske_T4moC, Toluene-4-monooxygenase effector protein complex (T4mo), Rieske ferredoxin subunit; The Rieske domain is a [2Fe-2S] cluster binding domain involved in electron transfer. T4mo is a four-protein complex that catalyzes the NADH- and O2-dependent hydroxylation of toluene to form p-cresol. T4mo consists of an NADH oxidoreductase (T4moF), a diiron hydroxylase (T4moH), a catalytic effector protein (T4moD), and a Rieske ferredoxin (T4moC). T4moC contains a Rieske domain and functions as an obligate electron carrier between T4moF and T4moH. Rieske ferredoxins are found as subunits of membrane oxidase complexes, cis-dihydrodiol-forming aromatic dioxygenases, bacterial assimilatory nitrite reductases, and arsenite oxidase. Rieske ferredoxins are also found as soluble electron carriers in bacterial dioxygenase and monooxygenase complexes.бА0АкА0АаАCDDбАаАз─вА0А0АаАВШcd03475, Rieske_SoxF_SoxL, SoxF and SoxL family, Rieske domain; The Rieske domain is a [2Fe-2S] cluster binding domain involved in electron transfer. SoxF is a subunit of the terminal oxidase supercomplex SoxM in the plasma membrane of Sulfolobus acidocaldarius that combines features of a cytochrome bc(1) complex and a cytochrome. The Rieske domain of SoxF has a 12 residue insertion which is not found in eukaryotic and bacterial Rieske proteins and is thought to influence the redox properties of the iron-sulfur cluster. SoxL is a Rieske protein which may be part of an archaeal bc-complex homologue whose physiological function is still unknown. SoxL has two features not seen in other Rieske proteins; (i) a significantly greater distance between the two cluster-binding sites and (ii) an unexpected Pro -> Asp substitution at one of the cluster binding sites. SoxF and SoxL are found in archaea and in bacteria.бА0АкА0АаАCDDбАаАз┼вА0А0АаАВ╚cd03476, Rieske_ArOX_small, Small subunit of Arsenite oxidase (ArOX) family, Rieske domain; ArOX is a molybdenum/iron protein involved in the detoxification of arsenic, oxidizing it to arsenate. It consists of two subunits, a large subunit similar to members of the DMSO reductase family of molybdenum enzymes and a small subunit with a Rieske-type [2Fe-2S] cluster. The large subunit of ArOX contains the molybdenum site at which the oxidation of arsenite occurs. The small subunit contains a domain homologous to the Rieske domains of the cytochrome bc(1) and cytochrome b6f complexes as well as naphthalene 1,2-dioxygenase. The Rieske domain is a [2Fe-2S] cluster binding domain involved in electron transfer.бА0АкА0АаАCDDбАаАз╞вА0А0АаАВ/cd03477, Rieske_YhfW_C, YhfW family, C-terminal Rieske domain; YhfW is a protein of unknown function with an N-terminal DadA-like (glycine/D-amino acid dehydrogenase) domain and a C-terminal Rieske domain. The Rieske domain is a [2Fe-2S] cluster binding domain involved in electron transfer. It is commonly found in Rieske non-heme iron oxygenase (RO) systems such as naphthalene and biphenyl dioxygenases, as well as in plant/cyanobacterial chloroplast b6f and mitochondrial cytochrome bc(1) complexes. YhfW is found in bacteria, some eukaryotes and archaea.бА0АкА0АаАCDDбАаАз╟вА0А0АаАВ4cd03478, Rieske_AIFL_N, AIFL (apoptosis-inducing factor like) family, N-terminal Rieske domain; members of this family show similarity to human AIFL, containing an N-terminal Rieske domain and a C-terminal pyridine nucleotide-disulfide oxidoreductase domain (Pyr_redox). The Rieske domain is a [2Fe-2S] cluster binding domain involved in electron transfer. AIFL shares 35% homology with human AIF (apoptosis-inducing factor), mainly in the Pyr_redox domain. AIFL is predominantly localized to the mitochondria. AIFL induces apoptosis in a caspase-dependent manner.бА0АкА0АаАCDDбАаАз╚вА0А0АаАВcd03479, Rieske_RO_Alpha_PhDO_like, Rieske non-heme iron oxygenase (RO) family, Phthalate 4,5-dioxygenase (PhDO)-like subfamily, N-terminal Rieske domain of the oxygenase alpha subunit; composed of the oxygenase alpha subunits of PhDO and similar proteins including 3-chlorobenzoate 3,4-dioxygenase (CBDO), phenoxybenzoate dioxygenase (POB-dioxygenase) and 3-nitrobenzoate oxygenase (MnbA). ROs comprise a large class of aromatic ring-hydroxylating dioxygenases that enable microorganisms to tolerate and utilize aromatic compounds for growth. The oxygenase alpha subunit contains an N-terminal Rieske domain with an [2Fe-2S] cluster and a C-terminal catalytic domain with a mononuclear Fe(II) binding site. The Rieske [2Fe-2S] cluster accepts electrons from a reductase or ferredoxin component and transfers them to the mononuclear iron for catalysis. PhDO and CBDO are two-component RO systems, containing oxygenase and reductase components. PhDO catalyzes the dihydroxylation of phthalate to form the 4,5-dihydro-cis-dihydrodiol of phthalate (DHD). CBDO, together with CbaC dehydrogenase, converts the environmental pollutant 3CBA to protocatechuate (PCA) and 5-Cl-PCA, which are then metabolized by the chromosomal PCA meta (extradiol) ring fission pathway. POB-dioxygenase catalyzes the initial catabolic step in the angular dioxygenation of phenoxybenzoate, converting mono- and dichlorinated phenoxybenzoates to protocatechuate and chlorophenols. These phenoxybenzoates are metabolic products formed during the degradation of pyrethroid insecticides.бА0АкА0АаАCDDбАаАз╔вА0А0АаАВ:cd03480, Rieske_RO_Alpha_PaO, Rieske non-heme iron oxygenase (RO) family, Pheophorbide a oxygenase (PaO) subfamily, N-terminal Rieske domain of the oxygenase alpha subunit; composed of the oxygenase alpha subunits of a small subfamily of enzymes found in plants as well as oxygenic cyanobacterial photosynthesizers including LLS1 (lethal leaf spot 1, also known as PaO) and ACD1 (accelerated cell death 1). ROs comprise a large class of aromatic ring-hydroxylating dioxygenases that enable microorganisms to tolerate and utilize aromatic compounds for growth. The oxygenase alpha subunit contains an N-terminal Rieske domain with an [2Fe-2S] cluster and a C-terminal catalytic domain with a mononuclear Fe(II) binding site. The Rieske [2Fe-2S] cluster accepts electrons from a reductase or ferredoxin component and transfers them to the mononuclear iron for catalysis. PaO expression increases upon physical wounding of plant leaves and is thought to catalyze a key step in chlorophyll degradation. The Arabidopsis-accelerated cell death gene ACD1 is involved in oxygenation of PaO.бА0АкА0АаАCDDбАаАз╩вА0А0АаАВ─cd03481, TopoIIA_Trans_ScTopoIIA, TopoIIA_Trans_ScTopoIIA: Transducer domain, having a ribosomal S5 domain 2-like fold, of the type found in proteins of the type IIA family of DNA topoisomerases similar to Saccharomyces cerevisiae Topo IIA. S. cerevisiae Topo IIA is a homodimer encoded by a single gene. The type IIA enzymes are the predominant form of topoisomerase and are found in some bacteriophages, viruses and archaea, and in all bacteria and eukaryotes. All type IIA topoisomerases are related to each other at amino acid sequence level, though their oligomeric organization sometimes differs. TopoIIA enzymes cut both strands of the duplex DNA to remove (relax) both positive and negative supercoils in DNA. These enzymes covalently attach to the 5' ends of the cut DNA, separate the free ends of the cleaved strands, pass another region of the duplex through this gap, then rejoin the ends. TopoIIA enzymes also catenate/ decatenate duplex rings. This transducer domain is homologous to the second domain of the DNA gyrase B subunit, which is known to be important in nucleotide hydrolysis and the transduction of structural signals from ATP-binding site to the DNA breakage/reunion regions of the enzymes.бА0АкА0АаАCDDбАаАз╦вА0А0АаАВcd03482, MutL_Trans_MutL, MutL_Trans_MutL: transducer domain, having a ribosomal S5 domain 2-like fold, found in proteins similar to Escherichia coli MutL. EcMutL belongs to the DNA mismatch repair (MutL/MLH1/PMS2) family. This transducer domain is homologous to the second domain of the DNA gyrase B subunit, which is known to be important in nucleotide hydrolysis and the transduction of structural signals from the ATP-binding site to the DNA breakage/reunion regions of the enzymes. It has been suggested that during initiation of DNA mismatch repair in E. coli, the mismatch recognition protein MutS recruits MutL in the presence of ATP. The MutS(ATP)-MutL ternary complex formed, then recruits the latent endonuclease MutH. Prokaryotic MutS and MutL are homodimers.бА0АкА0АаАCDDбАаАз╠вА0А0АаАВ═cd03483, MutL_Trans_MLH1, MutL_Trans_MLH1: transducer domain, having a ribosomal S5 domain 2-like fold, found in proteins similar to yeast and human MLH1 (MutL homologue 1). This transducer domain is homologous to the second domain of the DNA gyrase B subunit, which is known to be important in nucleotide hydrolysis and the transduction of structural signals from ATP-binding site to the DNA breakage/reunion regions of the enzymes. MLH1 forms heterodimers with PMS2, PMS1 and MLH3. These three complexes have distinct functions in meiosis. hMLH1-hPMS2 also participates in the repair of all DNA mismatch repair (MMR) substrates. Roles for hMLH1-hPMS1 or hMLH1-hMLH3 in MMR have not been established. Cells lacking hMLH1 have a strong mutator phenotype and display microsatellite instability (MSI). Mutation in hMLH1 causes predisposition to HNPCC, Muir-Torre syndrome and Turcot syndrome (HNPCC variant). Mutation in hMLH1 accounts for a large fraction of HNPCC families.бА0АкА0АаАCDDбАаАз═вА0А0АаАВycd03484, MutL_Trans_hPMS_2_like, MutL_Trans_hPMS2_like: transducer domain, having a ribosomal S5 domain 2-like fold, found in proteins similar to human PSM2 (hPSM2). hPSM2 belongs to the DNA mismatch repair (MutL/MLH1/PMS2) family. This transducer domain is homologous to the second domain of the DNA gyrase B subunit, which is known to be important in nucleotide hydrolysis and the transduction of structural signals from ATP-binding site to the DNA breakage/reunion regions of the enzymes. Included in this group are proteins similar to yeast PMS1. The yeast MLH1-PMS1 and the human MLH1-PMS2 heterodimers play a role in meiosis. hMLH1-hPMS2 also participates in the repair of all DNA mismatch repair (MMR) substrates. Cells lacking hPMS2 have a strong mutator phenotype and display microsatellite instability (MSI). Mutation in hPMS2 causes predisposition to HPNCC and Turcot syndrome.бА0АкА0АаАCDDбАаАз╬вА0А0АаАВ▐cd03485, MutL_Trans_hPMS_1_like, MutL_Trans_hPMS1_like: transducer domain, having a ribosomal S5 domain 2-like fold, found in proteins similar to human PSM1 (hPSM1) and yeast MLH2. hPSM1 and yMLH2 are members of the DNA mismatch repair (MutL/MLH1/PMS2) family. This transducer domain is homologous to the second domain of the DNA gyrase B subunit, which is known to be important in nucleotide hydrolysis and the transduction of structural signals from ATP-binding site to the DNA breakage/reunion regions of the enzymes. PMS1 forms a heterodimer with MLH1. The MLH1-PMS1 complex functions in meiosis. Loss of yMLH2 results in a small but significant decrease in spore viability and a significant increase in gene conversion frequencies. A role for hMLH1-hPMS1 in DNA mismatch repair has not been established. Mutation in hMLH1 accounts for a large fraction of Lynch syndrome (HNPCC) families, however there is no convincing evidence to support hPMS1 having a role in HNPCC predisposition.бА0АкА0АаАCDDбАаАз╧вА0А0АаАВ2cd03486, MutL_Trans_MLH3, MutL_Trans_MLH3: transducer domain, having a ribosomal S5 domain 2-like fold, found in proteins similar to yeast and human MLH3 (MutL homologue 3). MLH3 belongs to the DNA mismatch repair (MutL/MLH1/PMS2) family. This transducer domain is homologous to the second domain of the DNA gyrase B subunit, which is known to be important in nucleotide hydrolysis and the transduction of structural signals from ATP-binding site to the DNA breakage/reunion regions of the enzymes. MLH1 forms heterodimers with MLH3. The MLH1-MLH3 complex plays a role in meiosis. A role for hMLH1-hMLH3 in DNA mismatch repair (MMR) has not been established. It has been suggested that hMLH3 may be a low risk gene for colorectal cancer; however there is little evidence to support it having a role in classical HNPCC.бА0АкА0АаАCDDбАаАз╨вА0А0АаАВ└cd03487, RT_Bac_retron_II, RT_Bac_retron_II: Reverse transcriptases (RTs) in bacterial retrotransposons or retrons. The polymerase reaction of this enzyme leads to the production of a unique RNA-DNA complex called msDNA (multicopy single-stranded (ss)DNA) in which a small ssDNA branches out from a small ssRNA molecule via a 2'-5'phosphodiester linkage. Bacterial retron RTs produce cDNA corresponding to only a small portion of the retron genome.бА0АкА0АаАCDDбАаАз╤вА0А0АаАВЮcd03488, Topoisomer_IB_N_htopoI_like, Topoisomer_IB_N_htopoI_like : N-terminal DNA binding fragment found in eukaryotic DNA topoisomerase (topo) IB proteins similar to the monomeric yeast and human topo I. Topo I enzymes are divided into: topo type IA (bacterial) and type IB (eukaryotic). Topo I relaxes superhelical tension in duplex DNA by creating a single-strand nick, the broken strand can then rotate around the unbroken strand to remove DNA supercoils and, the nick is religated, liberating topo I. These enzymes regulate the topological changes that accompany DNA replication, transcription and other nuclear processes. Human topo I is the target of a diverse set of anticancer drugs including camptothecins (CPTs). CPTs bind to the topo I-DNA complex and inhibit religation of the single-strand nick, resulting in the accumulation of topo I-DNA adducts. This family may represent more than one structural domain.бА0АкА0АаАCDDбАаАз╥вА0А0АаАВрcd03489, Topoisomer_IB_N_LdtopoI_like, Topoisomer_IB_N_LdtopoI_like: N-terminal DNA binding fragment found in eukaryotic DNA topoisomerase (topo) IB proteins similar to the heterodimeric topo I from Leishmania donvanni. Topo I enzymes are divided into: topo type IA (bacterial) and type IB (eukaryotic). Topo I relaxes superhelical tension in duplex DNA by creating a single-strand nick, the broken strand can then rotate around the unbroken strand to remove DNA supercoils and, the nick is religated, liberating topo I. These enzymes regulate the topological changes that accompany DNA replication, transcription and other nuclear processes. Human topo I is the target of a diverse set of anticancer drugs including camptothecins (CPTs). CPTs bind to the topo I-DNA complex and inhibit re-ligation of the single-strand nick, resulting in the accumulation of topo I-DNA adducts. In addition to differences in structure and some biochemical properties, Trypanosomatid parasite topo I differ from human topo I in their sensitivity to CPTs and other classical topo I inhibitors. Trypanosomatid topo I play putative roles in organizing the kinetoplast DNA network unique to these parasites. This family may represent more than one structural domain.бА0АкА0АаАCDDбАаАз╙вА0А0АаАВ cd03490, Topoisomer_IB_N_1, Topoisomer_IB_N_1: A subgroup of the N-terminal DNA binding fragment found in eukaryotic DNA topoisomerase (topo) IB. Topo IB proteins include the monomeric yeast and human topo I and heterodimeric topo I from Leishmania donvanni. Topo I enzymes are divided into: topo type IA (bacterial) and type IB (eukaryotic). Topo I relaxes superhelical tension in duplex DNA by creating a single-strand nick, the broken strand can then rotate around the unbroken strand to remove DNA supercoils and, the nick is religated, liberating topo I. These enzymes regulate the topological changes that accompany DNA replication, transcription and other nuclear processes. Human topo I is the target of a diverse set of anticancer drugs including camptothecins (CPTs). CPTs bind to the topo I-DNA complex and inhibit religation of the single-strand nick, resulting in the accumulation of topo I-DNA adducts. In addition to differences in structure and some biochemical properties, Trypanosomatid parasite topos I differ from human topo I in their sensitivity to CPTs and other classical topo I inhibitors. Trypanosomatid topos I have putative roles in organizing the kinetoplast DNA network unique to these parasites. This family may represent more than one structural domain.бА0АкА0АаАCDDбАаАз╘вА0А0АаАВ╠cd03493, SQR_QFR_TM, Succinate:quinone oxidoreductase (SQR) and Quinol:fumarate reductase (QFR) family, transmembrane subunits; SQR catalyzes the oxidation of succinate to fumarate coupled to the reduction of quinone to quinol, while QFR catalyzes the reverse reaction. SQR, also called succinate dehydrogenase or Complex II, is part of the citric acid cycle and the aerobic respiratory chain, while QFR is involved in anaerobic respiration with fumarate as the terminal electron acceptor. SQRs may reduce either high or low potential quinones while QFRs oxidize only low potential quinols. SQR and QFR share a common subunit arrangement, composed of a flavoprotein catalytic subunit, an iron-sulfur protein and one or two hydrophobic transmembrane subunits. The structural arrangement allows efficient electron transfer between the catalytic subunit, through iron-sulfur centers, and the transmembrane subunit(s) containing the electron donor/acceptor (quinol or quinone). The reversible reduction of quinone is an essential feature of respiration, allowing the transfer of electrons between respiratory complexes. SQRs and QFRs can be classified into five types (A-E) according to the number of their hydrophobic subunits and heme groups. This classification is consistent with the characteristics and phylogeny of the catalytic and iron-sulfur subunits. Type E proteins, e.g. non-classical archael SQRs, contain atypical transmembrane subunits and are not included in this hierarchy. The heme and quinone binding sites reside in the transmembrane subunits. Although succinate oxidation and fumarate reduction are carried out by separate enzymes in most organisms, some bifunctional enzymes that exhibit both SQR and QFR activities exist.бА0АкА0АаАCDDбАаАз╒вА0А0АаАВРcd03494, SQR_TypeC_SdhD, Succinate:quinone oxidoreductase (SQR) Type C subfamily, Succinate dehydrogenase D (SdhD) subunit; SQR catalyzes the oxidation of succinate to fumarate coupled to the reduction of quinone to quinol. E. coli SQR, a member of this subfamily, reduces the high potential quinine, ubiquinone. SQR is also called succinate dehydrogenase or Complex II, and is part of the citric acid cycle and the aerobic respiratory chain. SQR is composed of a flavoprotein catalytic subunit, an iron-sulfur protein and one or two hydrophobic transmembrane subunits. Members of this subfamily are classified as Type C SQRs because they contain two transmembrane subunits and one heme group. SdhD and SdhC are the two transmembrane proteins of bacterial SQRs. They contain heme and quinone binding sites. The two-electron oxidation of succinate in the flavoprotein active site is coupled to the two-electron reduction of quinone in the membrane anchor subunits via electron transport through FAD and three iron-sulfur centers. The reversible reduction of quinone is an essential feature of respiration, allowing transfer of electrons between respiratory complexes.бА0АкА0АаАCDDбАаАз╓вА0А0АаАВcd03495, SQR_TypeC_SdhD_like, Succinate:quinone oxidoreductase (SQR) Type C subfamily, Succinate dehydrogenase D (SdhD) subunit-like; composed of predominantly uncharacterized bacterial proteins with similarity to the E. coli SdhD subunit. One characterized protein is the respiratory Complex II SdhD subunit of the only eukaryotic member, Reclinomonas americana. SQR catalyzes the oxidation of succinate to fumarate coupled to the reduction of quinone to quinol. It is also called succinate dehydrogenase or Complex II, and is part of the citric acid cycle and the aerobic respiratory chain. SQR is composed of a flavoprotein catalytic subunit, an iron-sulfur protein and one or two hydrophobic transmembrane subunits. E. coli SQR is classified as Type C SQRs because it contains two transmembrane subunits and one heme group. The SdhD and SdhC subunits are membrane anchor subunits containing heme and quinone binding sites. The two-electron oxidation of succinate in the flavoprotein active site is coupled to the two-electron reduction of quinone in the membrane anchor subunits via electron transport through FAD and three iron-sulfur centers. The reversible reduction of quinone is an essential feature of respiration, allowing transfer of electrons between respiratory complexes.бА0АкА0АаАCDDбАаАз╫вА0А0АаАВ1cd03496, SQR_TypeC_CybS, SQR catalyzes the oxidation of succinate to fumarate coupled to the reduction of quinone to quinol. Eukaryotic SQRs reduce high potential quinones such as ubiquinone. SQR is also called succinate dehydrogenase or Complex II, and is part of the citric acid cycle and the aerobic respiratory chain. SQR is composed of a flavoprotein catalytic subunit, an iron-sulfur protein and one or two hydrophobic transmembrane subunits. Members of this subfamily are classified as Type C SQRs because they contain two transmembrane subunits and one heme group. CybS and CybL are the two transmembrane proteins of eukaryotic SQRs. They contain heme and quinone binding sites. CybS is the eukaryotic homolog of the bacterial SdhD subunit. The two-electron oxidation of succinate in the flavoprotein active site is coupled to the two-electron reduction of quinone in the transmembrane subunits via electron transport through FAD and three iron-sulfur centers. The reversible reduction of quinone is an essential feature of respiration, allowing transfer of electrons between respiratory complexes. Mutations in human Complex II result in various physiological disorders including hereditary paraganglioma and pheochromocytoma tumors. The gene encoding for the SdhD subunit is classified as a tumor suppressor gene.бА0АкА0АаАCDDбАаАз╪вА0А0АаАВ╜cd03497, SQR_TypeB_1_TM, Succinate:quinone oxidoreductase (SQR) Type B subfamily 1, transmembrane subunit; composed of proteins similar to Bacillus subtilis SQR. SQR catalyzes the oxidation of succinate to fumarate coupled to the reduction of quinone to quinol. Bacillus subtilis SQR reduces low potential quinones such as menaquinone. SQR is also called succinate dehydrogenase (Sdh) or Complex II and is part of the citric acid cycle and the aerobic respiratory chain. SQR is composed of a flavoprotein catalytic subunit, an iron-sulfur protein and one or two hydrophobic transmembrane subunits. Members of this subfamily are classified as Type B as they contain one transmembrane subunit and two heme groups. The heme and quinone binding sites reside on the transmembrane subunit. The transmembrane subunit of Bacillus subtilis SQR is also called Sdh cytochrome b558 subunit. The structural arrangement allows efficient electron transfer between the catalytic subunit, through iron-sulfur centers, and the transmembrane subunit containing the electron acceptor (quinone). The reversible reduction of quinone is an essential feature of respiration, allowing transfer of electrons between respiratory complexes.бА0АкА0АаАCDDбАаАз┘вА0А0АаАВЯcd03498, SQR_TypeB_2_TM, Succinate:quinone oxidoreductase (SQR)-like Type B subfamily 2, transmembrane subunit; composed of proteins with similarity to the SQRs of Geobacter metallireducens and Corynebacterium glutamicum. SQR catalyzes the oxidation of succinate to fumarate coupled to the reduction of quinone to quinol. C. glutamicum SQR reduces low potential quinones such as menaquinone. SQR is also called succinate dehydrogenase (Sdh) or Complex II and is part of the citric acid cycle and the aerobic respiratory chain. SQR is composed of a flavoprotein catalytic subunit, an iron-sulfur protein and one or two hydrophobic transmembrane subunits. Members of this subfamily are classified as Type B as they contain one transmembrane subunit and two heme groups. The heme and quinone binding sites reside in the transmembrane subunit. The transmembrane subunit of members of this subfamily is also called Sdh cytochrome b558 subunit based on the Bacillus subtilis protein. The structural arrangement allows efficient electron transfer between the catalytic subunit, through iron-sulfur centers, and the transmembrane subunit containing the electron acceptor (quinone). The reversible reduction of quinone is an essential feature of respiration, allowing transfer of electrons between respiratory complexes. Proteins in this subfamily from G. metallireducens and G. sulfurreducens are bifunctional enzymes with SQR and QFR activities.бА0АкА0АаАCDDбАаАз┌вА0А0АаАВcd03499, SQR_TypeC_SdhC, Succinate:quinone oxidoreductase (SQR) Type C subfamily, Succinate dehydrogenase C (SdhC) subunit; composed of bacterial SdhC and eukaryotic large cytochrome b binding (CybL) proteins. SQR catalyzes the oxidation of succinate to fumarate coupled to the reduction of quinone to quinol. Members of this family reduce high potential quinones such as ubiquinone. SQR is also called succinate dehydrogenase or Complex II, and is part of the citric acid cycle and the aerobic respiratory chain. SQR is composed of a flavoprotein catalytic subunit, an iron-sulfur protein and one or two hydrophobic transmembrane subunits. Proteins in this subfamily are classified as Type C SQRs because they contain two transmembrane subunits and one heme group. The heme and quinone binding sites reside in the transmembrane subunits. The SdhC or CybL protein is one of the two transmembrane subunits of bacterial and eukaryotic SQRs. The two-electron oxidation of succinate in the flavoprotein active site is coupled to the two-electron reduction of quinone in the membrane anchor subunits via electron transport through FAD and three iron-sulfur centers. The reversible reduction of quinone is an essential feature of respiration, allowing transfer of electrons between respiratory complexes.бА0АкА0АаАCDDбАаАз█вА0А0АаАВЖcd03500, SQR_TypeA_SdhD_like, Succinate:quinone oxidoreductase (SQR) Type A subfamily, Succinate dehydrogenase D (SdhD)-like subunit; SQR catalyzes the oxidation of succinate to fumarate coupled to the reduction of quinone to quinol. Members of this subfamily reduce low potential quinones such as menaquinone and thermoplasmaquinone. SQR is also called succinate dehydrogenase or Complex II, and is part of the citric acid cycle and the aerobic respiratory chain. SQR is composed of a flavoprotein catalytic subunit, an iron-sulfur protein and one or two hydrophobic transmembrane subunits. Members of this subfamily are similar to the Thermoplasma acidophilum SQR and are classified as Type A because they contain two transmembrane subunits as well as two heme groups. Although there are no structures available for this subfamily, the presence of two hemes has been proven spectroscopically for T. acidophilum. The two membrane anchor subunits are similar to the SdhD and SdhC subunits of bacterial SQRs, which contain heme and quinone binding sites. The two-electron oxidation of succinate in the flavoprotein active site is coupled to the two-electron reduction of quinone in the membrane anchor subunits via electron transport through FAD and three iron-sulfur centers. The reversible reduction of quinone is an essential feature of respiration, allowing transfer of electrons between respiratory complexes.бА0АкА0АаАCDDбАаАз▄вА0А0АаАВЗcd03501, SQR_TypeA_SdhC_like, Succinate:quinone oxidoreductase (SQR) Type A subfamily, Succinate dehydrogenase C (SdhC)-like subunit; SQR catalyzes the oxidation of succinate to fumarate coupled to the reduction of quinone to quinol. Members of this subfamily reduce low potential quinones such as menaquinone and thermoplasmaquinone. SQR is also called succinate dehydrogenase or Complex II, and is part of the citric acid cycle and the aerobic respiratory chain. SQR is composed of a flavoprotein catalytic subunit, an iron-sulfur protein and one or two hydrophobic transmembrane subunits. Members of this subfamily are similar to the Thermoplasma acidophilum SQR and are classified as Type A because they contain two transmembrane subunits as well as two heme groups. Although there are no structures available for this subfamily, the presence of two hemes has been proven spectroscopically for T. acidophilum. The two membrane anchor subunits are similar to the SdhD and SdhC subunits of bacterial SQRs, which contain heme and quinone binding sites. The two-electron oxidation of succinate in the flavoprotein active site is coupled to the two-electron reduction of quinone in the membrane anchor subunits via electron transport through FAD and three iron-sulfur centers. The reversible reduction of quinone is an essential feature of respiration, allowing transfer of electrons between respiratory complexes.бА0АкА0АаАCDDбАаАз▌вА0А0АаАВcd03505, Delta9-FADS-like, The Delta9 Fatty Acid Desaturase (Delta9-FADS)-like CD includes the delta-9 and delta-11 acyl CoA desaturases found in various eukaryotes including vertebrates, insects, higher plants, and fungi. The delta-9 acyl-lipid desaturases are found in a wide range of bacteria. These enzymes play essential roles in fatty acid metabolism and the regulation of cell membrane fluidity. Acyl-CoA desaturases are the enzymes involved in the CoA-bound desaturation of fatty acids. Mammalian stearoyl-CoA delta-9 desaturase is a key enzyme in the biosynthesis of monounsaturated fatty acids, and in yeast, the delta-9 acyl-CoA desaturase (OLE1) reaction accounts for all de nova unsaturated fatty acid production in Saccharomyces cerevisiae. These non-heme, iron-containing, ER membrane-bound enzymes are part of a three-component enzyme system involving cytochrome b5, cytochrome b5 reductase, and the delta-9 fatty acid desaturase. This complex catalyzes the NADH- and oxygen-dependent insertion of a cis double bond between carbons 9 and 10 of the saturated fatty acyl substrates, palmitoyl (16:0)-CoA or stearoyl (18:0)-CoA, yielding the monoenoic products palmitoleic (16:l) or oleic (18:l) acids, respectively. In cyanobacteria, the biosynthesis of unsaturated fatty acids is initiated by delta 9 acyl-lipid desaturase (DesC) which introduces the first double bond at the delta-9 position of a saturated fatty acid that has been esterified to a glycerolipid. This domain family has extensive hydrophobic regions that would be capable of spanning the membrane bilayer at least twice. Comparison of sequences also reveals the existence of three regions of conserved histidine cluster motifs that contain the residues: HXXXXH, HXXHH, and H/QXXHH. These histidine residues are reported to be catalytically essential and proposed to be the ligands for the iron atoms contained within the rat stearoyl CoA delta-9 desaturase. Some eukaryotic (Fungi, Euglenozoa, Mycetozoa, Rhodophyta) desaturase domains have an adjacent C-terminal cytochrome b5-like domain.бА0АкА0АаАCDDбАаАз▐вА0А0АаАВ┤cd03506, Delta6-FADS-like, The Delta6 Fatty Acid Desaturase (Delta6-FADS)-like CD includes the integral-membrane enzymes: delta-4, delta-5, delta-6, delta-8, delta-8-sphingolipid, and delta-11 desaturases found in vertebrates, higher plants, fungi, and bacteria. These desaturases are required for the synthesis of highly unsaturated fatty acids (HUFAs), which are mainly esterified into phospholipids and contribute to maintaining membrane fluidity. While HUFAs may be required for cold tolerance in bacteria, plants and fish, the primary role of HUFAs in mammals is cell signaling. These enzymes are described as front-end desaturases because they introduce a double bond between the pre-exiting double bond and the carboxyl (front) end of the fatty acid. Various substrates are involved, with both acyl-coenzyme A (CoA) and acyl-lipid desaturases present in this CD. Acyl-lipid desaturases are localized in the membranes of cyanobacterial thylakoid, plant endoplasmic reticulum (ER), and plastid; and acyl-CoA desaturases are present in ER membrane. ER-bound plant acyl-lipid desaturases and acyl-CoA desaturases require cytochrome b5 as an electron donor. Most of the eukaryotic desaturase domains have an adjacent N-terminal cytochrome b5-like domain. This domain family has extensive hydrophobic regions that would be capable of spanning the membrane bilayer at least twice. Comparison of sequences also reveals the existence of three regions of conserved histidine cluster motifs that contain the residues: HXXXH, HXX(X)HH, and Q/HXXHH. These histidine residues are reported to be catalytically essential and proposed to be the ligands for the iron atoms contained within the homolog, stearoyl CoA desaturase.бА0АкА0АаАCDDбАаАз▀вА0А0АаАВ &cd03507, Delta12-FADS-like, The Delta12 Fatty Acid Desaturase (Delta12-FADS)-like CD includes the integral-membrane enzymes, delta-12 acyl-lipid desaturases, oleate 12-hydroxylases, omega3 and omega6 fatty acid desaturases, and other related proteins, found in a wide range of organisms including higher plants, green algae, diatoms, nematodes, fungi, and bacteria. The expression of these proteins appears to be temperature dependent: decreases in temperature result in increased levels of fatty acid desaturation within membrane lipids subsequently altering cell membrane fluidity. An important enzyme for the production of polyunsaturates in plants is the oleate delta-12 desaturase (Arabidopsis FAD2) of the endoplasmic reticulum. This enzyme accepts l-acyl-2-oleoyl-sn-glycero-3-phosphocholine as substrate and requires NADH:cytochrome b oxidoreductase, cytochrome b, and oxygen for activity. FAD2 converts oleate(18:1) to linoleate (18:2) and is closely related to oleate 12-hydroxylase which catalyzes the hydroxylation of oleate to ricinoleate. Plastid-bound desaturases (Arabidopsis delta-12 desaturase (FAD6), omega-3 desaturase (FAD8), omega-6 desaturase (FAD6)), as well as, the cyanobacterial thylakoid-bound FADSs require oxygen, ferredoxin, and ferredoxin oxidoreductase for activity. As in higher plants, the cyanobacteria delta-12 (DesA) and omega-3 (DesB) FADSs desaturate oleate (18:1) to linoleate (18:2) and linoleate (18:2) to linolenate (18:3), respectively. Omega-3 (DesB/FAD8) and omega-6 (DesD/FAD6) desaturases catalyze reactions that introduce a double bond between carbons three and four, and carbons six and seven, respectively, from the methyl end of fatty acids. As with other members of this superfamily, this domain family has extensive hydrophobic regions that would be capable of spanning the membrane bilayer at least twice. Comparison of sequences also reveals the existence of three regions of conserved histidine cluster motifs that contain eight histidine residues: HXXXH, HXX(X)HH, and HXXHH. These histidine residues are reported to be catalytically essential and proposed to be the ligands for the iron atoms contained within the homologue, stearoyl CoA desaturase. Mutation of any one of four of these histidines in the Synechocystis delta-12 acyl-lipid desaturase resulted in complete inactivity.бА0АкА0АаАCDDбАаАзрвА0А0АаАВ0cd03508, Delta4-sphingolipid-FADS-like, The Delta4-sphingolipid Fatty Acid Desaturase (Delta4-sphingolipid-FADS)-like CD includes the integral-membrane enzymes, dihydroceramide Delta-4 desaturase, involved in the synthesis of sphingosine; and the human membrane fatty acid (lipid) desaturase (MLD), reported to modulate biosynthesis of the epidermal growth factor receptor; and other related proteins. These proteins are found in various eukaryotes including vertebrates, higher plants, and fungi. Studies show that MLD is localized to the endoplasmic reticulum. As with other members of this superfamily, this domain family has extensive hydrophobic regions that would be capable of spanning the membrane bilayer at least twice. Comparison of sequences also reveals the existence of three regions of conserved histidine cluster motifs that contain eight histidine residues: HXXXH, HXXHH, and HXXHH. These histidine residues are reported to be catalytically essential and proposed to be the ligands for the iron atoms contained within the homolog, stearoyl CoA desaturase.бА0АкА0АаАCDDбАаАзсвА0А0АаАВOcd03509, DesA_FADS-like, Fatty acid desaturase protein family subgroup, a delta-12 acyl-lipid desaturase-like, DesA-like, yet uncharacterized subgroup of membrane fatty acid desaturase proteins found in alpha-, beta-, and gamma-proteobacteria. Sequences of this domain family appear to be structurally related to membrane fatty acid desaturases and alkane hydroxylases. They all share in common extensive hydrophobic regions that would be capable of spanning the membrane bilayer at least twice. Comparison of these sequences also reveals three regions of conserved histidine cluster motifs that contain eight histidine residues: HXXXH, HXXHH, and HXXHH. These histidine residues are reported to be catalytically essential and proposed to be the ligands for the iron atoms contained within homologs, stearoyl CoA desaturase and alkane hydroxylase.бА0АкА0АаАCDDбАаАзтвА0А0АаАВЙcd03510, Rhizobitoxine-FADS-like, This CD includes the dihydrorhizobitoxine fatty acid desaturase (RtxC) characterized in Bradyrhizobium japonicum USDA110, and other related proteins. Dihydrorhizobitoxine desaturase is reported to be involved in the final step of rhizobitoxine biosynthesis. This domain family appears to be structurally related to the membrane fatty acid desaturases and the alkane hydroxylases. They all share in common extensive hydrophobic regions that would be capable of spanning the membrane bilayer at least twice. Comparison of sequences also reveals the existence of three regions of conserved histidine cluster motifs that contain eight histidine residues: HXXXH, HXX(X)HH, and HXXHH. These histidine residues are reported to be catalytically essential and proposed to be the ligands for the iron atoms contained within homologs, stearoyl CoA desaturase and alkane hydroxylase.бА0АкА0АаАCDDбАаАзувА0А0АаАВcd03511, Rhizopine-oxygenase-like, This CD includes the putative hydrocarbon oxygenase, MocD, a bacterial rhizopine (3-O-methyl-scyllo-inosamine, 3-O-MSI) oxygenase, and other related proteins. It has been proposed that MocD, MocE (Rieske-like ferredoxin), and MocF (ferredoxin reductase) under the regulation of MocR, act in concert to form a ferredoxin oxygenase system that demethylates 3-O-MSI to form scyllo-inosamine. This domain family appears to be structurally related to the membrane fatty acid desaturases and the alkane hydroxylases. They all share in common extensive hydrophobic regions that would be capable of spanning the membrane bilayer at least twice. Comparison of sequences also reveals the existence of three regions of conserved histidine cluster motifs that contain eight histidine residues: HXXXH, HXXHH, and HXXHH. These histidine residues are reported to be catalytically essential and proposed to be the ligands for the iron atoms contained within homologs, stearoyl CoA desaturase and alkane hydroxylase.бА0АкА0АаАCDDбАаАзфвА0А0АаАВэcd03512, Alkane-hydroxylase, Alkane hydroxylase is a bacterial, integral-membrane di-iron enzyme that shares a requirement for iron and oxygen for activity similar to that of the non-heme integral-membrane acyl coenzyme A (CoA) desaturases and acyl lipid desaturases. The alk genes in Pseudomonas oleovorans encode conversion of alkanes to acyl CoA. The alkane omega-hydroxylase (AlkB) system is responsible for the initial oxidation of inactivated alkanes. It is a three-component system comprising a soluble NADH-rubredoxin reductase (AlkT), a soluble rubredoxin (AlkG), and the integral membrane oxygenase (AlkB). AlkB utilizes the oxygen rebound mechanism to hydroxylate alkanes. This mechanism involves homolytic cleavage of the C-H bond by an electrophilic metal-oxo intermediate to generate a substrate-based radical. As with other members of this superfamily, this domain family has extensive hydrophobic regions that would be capable of spanning the membrane bilayer at least twice. The active site structure of AlkB is not known, however, spectroscopic and genetic evidence points to a nitrogen-rich coordination environment located in the cytoplasm with as many as eight histidines coordinating the two iron ions and a carboxylate residue bridging the two metals. Like all other members of this superfamily, there are eight conserved histidines seen in the histidine cluster motifs: HXXXH, HXXXHH, and HXXHH. These histidine residues are reported to be catalytically essential and proposed to be the ligands for the iron atoms contained within the homolog, stearoyl CoA desaturase. Also included in this CD are terminal alkane hydroxylases (AlkM), xylene monooxygenase hydroxylases (XylM), p-cymene monooxygenase hydroxylases (CymAa), and other related proteins.бА0АкА0АаАCDDбАаАзхвА0А0АаАВ└cd03513, CrtW_beta-carotene-ketolase, Beta-carotene ketolase/oxygenase (CrtW, also known as CrtO), the carotenoid astaxanthin biosynthetic enzyme, initially catalyzes the addition of two keto groups to carbons C4 and C4' of beta-carotene. Carotenoids are important natural pigments produced by many microorganisms and plants. Astaxanthin is reported to be an antioxidant, an anti-cancer agent, and an immune system stimulant. A number of bacteria and green algae can convert beta-carotene into astaxanthin by using several ketocarotenoids as intermediates and CrtW and a beta-carotene hydroxylase (CrtZ). CrtW initially converts beta-carotene to canthaxanthin via echinenone, and CrtZ initially mediates the conversion of beta-carotene to zeaxanthin via beta-cryptoxanthin. After a few more intermediates are formed, CrtW and CrtZ act in combination to produce astaxanthin. Sequences of this domain family appear to be structurally related to membrane fatty acid desaturases and alkane hydroxylases. They all share in common extensive hydrophobic regions that are capable of spanning the membrane bilayer at least twice. Comparison of these sequences also reveals three regions of conserved histidine cluster motifs that contain eight histidine residues: HXXXH, HXXHH, and HXXHH. These histidine residues are reported to be catalytically essential and proposed to be the ligands for the iron atoms contained within homologs, stearoyl CoA desaturase and alkane hydroxylase.бА0АкА0АаАCDDбАаАзцвА0А0АаАВcd03514, CrtR_beta-carotene-hydroxylase, Beta-carotene hydroxylase (CrtR), the carotenoid zeaxanthin biosynthetic enzyme catalyzes the addition of hydroxyl groups to the beta-ionone rings of beta-carotene to form zeaxanthin and is found in bacteria and red algae. Carotenoids are important natural pigments; zeaxanthin and lutein are the only dietary carotenoids that accumulate in the macular region of the retina and lens. It is proposed that these carotenoids protect ocular tissues against photooxidative damage. CrtR does not show overall amino acid sequence similarity to the beta-carotene hydroxylases similar to CrtZ, an astaxanthin biosynthetic beta-carotene hydroxylase. However, CrtR does show sequence similarity to the green alga, Haematococcus pluvialis, beta-carotene ketolase (CrtW), which converts beta-carotene to canthaxanthin. Sequences of the CrtR_beta-carotene-hydroxylase domain family, as well as, the CrtW_beta-carotene-ketolase domain family appear to be structurally related to membrane fatty acid desaturases and alkane hydroxylases. They all share in common extensive hydrophobic regions that would be capable of spanning the membrane bilayer at least twice. Comparison of these sequences also reveals three regions of conserved histidine cluster motifs that contain eight histidine residues: HXXXH, HXXHH, and HXXHH. These histidine residues are reported to be catalytically essential and proposed to be the ligands for the iron atoms contained within homologs, stearoyl CoA desaturase and alkane hydroxylase.бА0АкА0АаАCDDбАаАзчвА0А0АаАВУcd03515, Link_domain_TSG_6_like, This is the extracellular link domain of the type found in human TSG-6. The link domain is a hyaluronan (HA)-binding domain. TSG-6 is the protein product of tumor necrosis factor-stimulated gene-6. TSG-6 is up-regulated in inflammatory lesions and in the ovary during ovulation. It has a strong anti-inflammatory and chondroprotective effect in models of acute inflammation and autoimmune arthritis and plays an essential role in female fertility. Also included in this group are the stabilins: stabilin-1 (FEEL-1, CLEVER-1) and stabilin-2 (FEEL-2). Stabilin-2 functions as the major liver and lymph node-scavenging receptor for HA and related glycosaminoglycans. Stabilin-2 is a scavenger receptor with a broad range of ligands including advanced glycation end (AGE) products, acetylated low density lipoprotein and procollagen peptides. In contrast, stabilin-1 does not bind HA, but binds acetylated low density lipoprotein and AGEs with lower affinity. As AGEs accumulate in vascular tissues during aging and diabetes, these receptors may be implicated in the pathologies of these states. Both stabilins are present in the early endocytic pathway in hepatic sinusoidal epithelium associating with clathrin/AP-2. Stabilin-1 is expressed in macrophages. Stabilin-2 is absent from the latter. In macrophages: stabilin-1 is involved in trafficking between early/sorting endosomes and the trans-Golgi network. Stabilin-1 has also been implicated in angiogenesis and possibly leucocyte trafficking. Both stabilins bind gram-positive and gram-negative bacteria. TSG-6 and stabilins contain a single link module which supports high affinity binding to HA.бА0АкА0АаАCDDбАаАзшвА0А0АаАВ2cd03516, Link_domain_CD44_like, This domain is a hyaluronan (HA)-binding domain. It is found in CD44 receptor and mediates adhesive interactions during inflammatory leukocyte homing and tumor metastasis. It also plays an important role in arteriogenesis. The functional HA-binding domain of CD44 is an extended domain comprised of a single link module flanked with N-and C- extensions. These extensions are essential for folding and for functional activity. This group also contains the cell surface retention sequence (CRS) binding protein-1 (CRSBP-1) and lymph vessel endothelial receptor-1 (LYVE-1). CRSBP-1 is a cell surface binding protein for the CRS motif of PDGF-BB (platelet-derived growth factor-BB) and is responsible for the cell surface retention of PDGF-BB in SSV-transformed cells. CRSBP-1 may play a role in autocrine regulation of cell growth mediated by CRS containing growth regulators. LYVE-1 is preferentially expressed on the lymphatic endothelium and is used as a molecular marker for the detection and characterization of lymphatic vessels in tumors.бА0АкА0АаАCDDбАаАзщвА0А0АаАВtcd03517, Link_domain_CSPGs_modules_1_3, Link_domain_CSPGs_modules_1_3; this extracellular link domain is found in the first and third link modules of the chondroitin sulfate proteoglycan core protein (CSPG) aggrecan. In addition, it is found in the first link module of three other CSPGs: versican, neurocan, and brevican. The link domain is a hyaluronan (HA)-binding domain. CSPGs are characterized by an N-terminal globular domain (G1 domain) containing two contiguous link modules (modules 1 and 2). Both link modules of the G1 domain of aggrecan are involved in interaction with HA. In addition, aggrecan contains a second globular domain (G2) which contains link modules 3 and 4. G2 appears to lack HA-binding activity. In cartilage, aggrecan forms cartilage link protein stabilized aggregates with HA. These aggregates contribute to the tissue's load bearing properties. Aggregates having other CSPGs substituting for aggrecan may contribute to the structural integrity of many different tissues. Members of the vertebrate HPLN (hyaluronan/HA and proteoglycan binding link) protein family are physically linked adjacent to CSPG genes.бА0АкА0АаАCDDбАаАзъвА0А0АаАВMcd03518, Link_domain_HAPLN_module_1, Link_domain_HAPLN_module_1; this link domain is found in the first link module of proteins similar to the vertebrate HAPLN (hyaluronan/HA and proteoglycan binding link) protein family which includes cartilage link protein. The link domain is a HA-binding domain. HAPLNs contain two contiguous link modules. Both link modules of cartilage link protein are involved in interaction with HA. In cartilage, a chondroitin sulfate proteoglycan core protein (CSPG) aggrecan forms cartilage link protein stabilized aggregates with HA. These aggregates contribute to the tissue's load bearing properties. Aggregates with other CSPGs substituting for aggregan may contribute to the structural integrity of many different tissues. Members of the vertebrate HAPLN gene family are physically linked adjacent to CSPG genes.бА0АкА0АаАCDDбАаАзывА0А0АаАВNcd03519, Link_domain_HAPLN_module_2, Link_domain_HAPLN_module_2; this link domain is found in the second link module of proteins similar to the vertebrate HAPLN (hyaluronan/HA and proteoglycan binding link) protein family which includes cartilage link protein. The link domain is a HA-binding domain. HAPLNs contain two contiguous link modules. Both link modules of cartilage link protein are involved in interaction with HA. In cartilage, a chondroitin sulfate proteoglycan core protein (CSPG) aggrecan forms cartilage link protein stabilized aggregates with HA. These aggregates contribute to the tissue's load bearing properties. Aggregates with other CSPGs substituting for aggregan may contribute to the structural integrity of many different tissues. Members of the vertebrate HAPLN gene family are physically linked adjacent to CSPG genes.бА0АкА0АаАCDDбАаАзьвА0А0АаАВBcd03520, Link_domain_CSPGs_modules_2_4, Link_domain_CSPGs_modules_2_4; this link domain is found in the second and fourth link modules of the chondroitin sulfate proteoglycan core protein (CSPG) aggrecan and, in the second link module of three other CSPGs: versican, neurocan, and brevican. The link domain is a hyaluronan (HA)-binding domain. CSPGs are characterized by an N-terminal globular domain (G1 domain) containing two contiguous link modules (modules 1 and 2). Both link modules of the G1 domain of aggrecan are involved in interaction with HA. Aggrecan in addition contains a second globular domain (G2) having link modules 3 and 4 which lack HA-binding activity. In cartilage, aggrecan forms cartilage link protein stabilized aggregates with HA. These aggregates contribute to the tissue's load bearing properties. Aggregates having other CSPGs substituting for aggregan may contribute to the structural integrity of many different tissues. Members of the vertebrate HPLN (hyaluronan/HA and proteoglycan binding link) protein family are physically linked adjacent to CSPG genes.бА0АкА0АаАCDDбАаАзэвА0А0АаАВHcd03521, Link_domain_KIAA0527_like, Link_domain_KIAA0527_like; this domain is found in the human protein KIAA0527. Sequence-wise, it is highly similar to the link domain. The link domain is a hyaluronan-binding (HA) domain. KIAA0527 contains a single link module. The KIAA0527 gene was originally cloned from human brain tissue.бА0АкА0АаАCDDбАаАзювА0А0АаАВcd03522, MoeA_like, MoeA_like. This domain is similar to a domain found in a variety of proteins involved in biosynthesis of molybdopterin cofactor, like MoaB, MogA, and MoeA. There this domain is presumed to bind molybdopterin. The exact function of this subgroup is unknown.бА0АкА0АаАCDDбАаАзявА0А0АаАВХcd03523, NTR_like, NTR_like domain; a beta barrel with an oligosaccharide/oligonucleotide-binding fold found in netrins, complement proteins, tissue inhibitors of metalloproteases (TIMP), and procollagen C-proteinase enhancers (PCOLCE), amongst others. In netrins, the domain plays a role in controlling axon branching in neural development, while the common function of these modules in TIMPs appears to be binding to metzincins. A subset of this family is also known as the C345C domain because it occurs as a C-terminal domain in complement C3, C4 and C5. In C5, the domain interacts with various partners during the formation of the membrane attack complex.бА0АкА0АаАCDDбАаАзЁвА0А0АаАВmcd03524, RPA2_OBF_family, RPA2_OBF_family: A family of oligonucleotide binding (OB) folds with similarity to the OB fold of the single strand (ss) DNA-binding domain (DBD)-D of human RPA2 (also called RPA32). RPA2 is a subunit of Replication protein A (RPA). RPA is a nuclear ssDNA-binding protein (SSB) which appears to be involved in all aspects of DNA metabolism including replication, recombination, and repair. RPA also mediates specific interactions of various nuclear proteins. In animals, plants, and fungi, RPA is a heterotrimer with subunits of 70KDa (RPA1), 32kDa (RPA2), and 14 KDa (RPA3). RPA contains six OB folds, which are involved in ssDNA binding and in trimerization. The ssDNA binding mechanism is believed to be multistep and to involve conformational change. This family also includes OB folds similar to those found in Escherichia coli SSB, the wedge domain of E. coli RecG (a branched-DNA-specific helicase), E. coli ssDNA specific exodeoxyribonuclease VII large subunit, Pyrococcus abyssi DNA polymerase II (Pol II) small subunit, Sulfolobus solfataricus SSB, and Bacillus subtilis YhaM (a 3'-to-5'exoribonuclease). It also includes the OB folds of breast cancer susceptibility gene 2 protein (BRCA2), Oxytricha nova telomere end binding protein (TEBP), Saccharomyces cerevisiae telomere-binding protein (Cdc13), and human protection of telomeres 1 protein (POT1).бА0АкА0АаАCDDбАаАзёвА0А0АаАВТcd03526, SQR_QFR_TypeB_TM, Succinate:quinone oxidoreductase (SQR) and Quinol:fumarate reductase (QFR) Type B subfamily, transmembrane subunit; SQR catalyzes the oxidation of succinate to fumarate coupled to the reduction of quinone to quinol, while QFR catalyzes the reverse reaction. SQR, also called succinate dehydrogenase or Complex II, is part of the citric acid cycle and the aerobic respiratory chain, while QFR is involved in anaerobic respiration with fumarate as the terminal electron acceptor. SQR and QFR share a common subunit arrangement, composed of a flavoprotein catalytic subunit, an iron-sulfur protein and one or two hydrophobic transmembrane subunits. Type B proteins contain one transmembrane subunit and two heme groups. The heme and quinone binding sites reside in the transmembrane subunits. The structural arrangement allows efficient electron transfer between the catalytic subunit, through iron-sulfur centers, and the transmembrane subunit containing the electron donor/acceptor (quinol or quinone). The reversible reduction of quinone is an essential feature of respiration, allowing the transfer of electrons between respiratory complexes.бА0АкА0АаАCDDбАаАзЄвА0А0АаАВ-cd03527, RuBisCO_small, Ribulose bisphosphate carboxylase/oxygenase (Rubisco), small subunit. Rubisco is a bifunctional enzyme catalyzes the initial steps of two opposing metabolic pathways: photosynthetic carbon fixation and the competing process of photorespiration. Rubisco Form I, present in plants and green algae, is composed of eight large and eight small subunits. The nearly identical small subunits are encoded by a family of nuclear genes. After translation, the small subunits are translocated across the chloroplast membrane, where an N-terminal signal peptide is cleaved off. While the large subunits contain the catalytic activities, it has been shown that the small subunits are important for catalysis by enhancing the catalytic rate through inducing conformational changes in the large subunits.бА0АкА0АаАCDDбАаАзєвА0А0АаАВ▒cd03528, Rieske_RO_ferredoxin, Rieske non-heme iron oxygenase (RO) family, Rieske ferredoxin component; composed of the Rieske ferredoxin component of some three-component RO systems including biphenyl dioxygenase (BPDO) and carbazole 1,9a-dioxygenase (CARDO). The RO family comprise a large class of aromatic ring-hydroxylating dioxygenases found predominantly in microorganisms. These enzymes enable microorganisms to tolerate and even exclusively utilize aromatic compounds for growth. ROs consist of two or three components: reductase, oxygenase, and ferredoxin (in some cases) components. The ferredoxin component contains either a plant-type or Rieske-type [2Fe-2S] cluster. The Rieske ferredoxin component in this family carries an electron from the RO reductase component to the terminal RO oxygenase component. BPDO degrades biphenyls and polychlorinated biphenyls. BPDO ferredoxin (BphF) has structural features consistent with a minimal and perhaps archetypical Rieske protein in that the insertions that give other Rieske proteins unique structural features are missing. CARDO catalyzes dihydroxylation at the C1 and C9a positions of carbazole. Rieske ferredoxins are found as subunits of membrane oxidase complexes, cis-dihydrodiol-forming aromatic dioxygenases, bacterial assimilatory nitrite reductases, and arsenite oxidase. Rieske ferredoxins are also found as soluble electron carriers in bacterial dioxygenase and monooxygenase complexes.бА0АкА0АаАCDDбАаАзЇвА0А0АаАВqcd03529, Rieske_NirD, Assimilatory nitrite reductase (NirD) family, Rieske domain; Assimilatory nitrate and nitrite reductases convert nitrate through nitrite to ammonium. Members include bacterial and fungal proteins. The bacterial NirD contains a single Rieske domain while fungal proteins have a C-terminal Rieske domain in addition to several other domains. The fungal NirD is involved in nutrient acquisition, functioning at the soil/fungus interface to control nutrient exchange between the fungus and the host plant. The Rieske domain is a [2Fe-2S] cluster binding domain involved in electron transfer. The Rieske [2Fe-2S] cluster is liganded to two histidine and two cysteine residues present in conserved sequences called Rieske motifs. In this family, only a few members contain these residues. Other members may have lost the ability to bind the Rieske [2Fe-2S] cluster.бА0АкА0АаАCDDбАаАзївА0А0АаАВЦcd03530, Rieske_NirD_small_Bacillus, Small subunit of nitrite reductase (NirD) family, Rieske domain; composed of proteins similar to the Bacillus subtilis small subunit of assimilatory nitrite reductase containing a Rieske domain. The Rieske domain is a [2Fe-2S] cluster binding domain involved in electron transfer. Assimilatory nitrate and nitrite reductases convert nitrate through nitrite to ammonium.бА0АкА0АаАCDDбАаАзЎвА0А0АаАВЩcd03531, Rieske_RO_Alpha_KSH, The alignment model represents the N-terminal rieske iron-sulfur domain of KshA, the oxygenase component of 3-ketosteroid 9-alpha-hydroxylase (KSH). The terminal oxygenase component of KSH is a key enzyme in the microbial steroid degradation pathway, catalyzing the 9 alpha-hydroxylation of 4-androstene-3,17-dione (AD) and 1,4-androstadiene-3,17-dione (ADD). KSH is a two-component class IA monooxygenase, with terminal oxygenase (KshA) and oxygenase reductase (KshB) components. KSH activity has been found in many actino- and proteo- bacterial genera including Rhodococcus, Nocardia, Arthrobacter, Mycobacterium, and Burkholderia.бА0АкА0АаАCDDбАаАзўвА0А0АаАВQcd03532, Rieske_RO_Alpha_VanA_DdmC, Rieske non-heme iron oxygenase (RO) family, Vanillate-O-demethylase oxygenase (VanA) and dicamba O-demethylase oxygenase (DdmC) subfamily, N-terminal Rieske domain of the oxygenase alpha subunit; ROs comprise a large class of aromatic ring-hydroxylating dioxygenases that enable microorganisms to tolerate and utilize aromatic compounds for growth. The oxygenase alpha subunit contains an N-terminal Rieske domain with an [2Fe-2S] cluster and a C-terminal catalytic domain with a mononuclear Fe(II) binding site. The Rieske [2Fe-2S] cluster accepts electrons from a reductase or ferredoxin component and transfers them to the mononuclear iron for catalysis. Vanillate-O-demethylase is a heterodimeric enzyme consisting of a terminal oxygenase (VanA) and reductase (VanB) components. This enzyme reductively catalyzes the conversion of vanillate into protocatechuate and formaldehyde. Protocatechuate and vanillate are important intermediate metabolites in the degradation pathway of lignin-derived compounds such as ferulic acid and vanillin by soil microbes. DDmC is the oxygenase component of a three-component dicamba O-demethylase found in Pseudomonas maltophila, that catalyzes the conversion of a widely used herbicide called herbicide dicamba (2-methoxy-3,6-dichlorobenzoic acid) to DCSA (3,6-dichlorosalicylic acid).бА0АкА0АаАCDDбАаАз°вА0А0АаАВ┌cd03535, Rieske_RO_Alpha_NDO, Rieske non-heme iron oxygenase (RO) family, Nathphalene 1,2-dioxygenase (NDO) subfamily, N-terminal Rieske domain of the oxygenase alpha subunit; ROs comprise a large class of aromatic ring-hydroxylating dioxygenases that enable microorganisms to tolerate and utilize aromatic compounds for growth. The oxygenase alpha subunit contains an N-terminal Rieske domain with an [2Fe-2S] cluster and a C-terminal catalytic domain with a mononuclear Fe(II) binding site. The Rieske [2Fe-2S] cluster accepts electrons from a reductase or ferredoxin component and transfers them to the mononuclear iron for catalysis. NDO is a three-component RO system consisting of a reductase, a ferredoxin, and a hetero-hexameric alpha-beta subunit oxygenase component. NDO catalyzes the oxidation of naphthalene to cis-(1R,2S)-dihydroxy-1,2-dihydronaphthalene (naphthalene cis-dihydrodiol) with the consumption of O2 and NAD(P)H. NDO has a relaxed substrate specificity and can oxidize almost 100 substrates. Included in its varied activities are the enantiospecific cis-dihydroxylation of polycyclic aromatic hydrocarbons and benzocycloalkenes, benzylic hydroxylation, N- and O-dealkylation, sulfoxidation and desaturation reactions.бА0АкА0АаАCDDбАаАз∙вА0А0АаАВГcd03536, Rieske_RO_Alpha_DTDO, This alignment model represents the N-terminal rieske domain of the oxygenase alpha subunit (DitA) of diterpenoid dioxygenase (DTDO). DTDO is a novel aromatic-ring-hydroxylating dioxygenase found in Pseudomonas and other proteobacteria that degrades dehydroabietic acid (DhA). Specifically, DitA hydroxylates 7-oxodehydroabietic acid to 7-oxo-11,12-dihydroxy-8, 13-abietadien acid. The ditA1 and ditA2 genes encode the alpha and beta subunits of the oxygenase component of DTDO while the ditA3 gene encodes the ferredoxin component of DTDO. The organization of the genes encoding the various diterpenoid dioxygenase components, the phylogenetic distinctiveness of both the alpha subunit and the ferredoxin component, and the unusual iron-sulfur cluster of the ferredoxin all suggest that this enzyme belongs to a new class of aromatic ring-hydroxylating dioxygenases.бА0АкА0АаАCDDбАаАз·вА0А0АаАВcd03537, Rieske_RO_Alpha_PrnD, This alignment model represents the N-terminal rieske domain of the oxygenase alpha subunit of aminopyrrolnitrin oxygenase (PrnD). PrnD is a novel Rieske N-oxygenase that catalyzes the final step in the pyrrolnitrin biosynthetic pathway, the oxidation of the amino group in aminopyrrolnitrin to a nitro group, forming the antibiotic pyrrolnitrin. The biosynthesis of pyrrolnitrin is one of the best examples of enzyme-catalyzed arylamine oxidation. Although arylamine oxygenases are widely distributed within the microbial world and used in a variety of metabolic reactions, PrnD represents one of only two known examples of arylamine oxygenases or N-oxygenases involved in arylnitro group formation, the other being AurF involved in aureothin biosynthesis.бА0АкА0АаАCDDбАаАз√вА0А0АаАВ}cd03538, Rieske_RO_Alpha_AntDO, Rieske non-heme iron oxygenase (RO) family, Anthranilate 1,2-dioxygenase (AntDO) subfamily, N-terminal Rieske domain of the oxygenase alpha subunit; ROs comprise a large class of aromatic ring-hydroxylating dioxygenases that enable microorganisms to tolerate and utilize aromatic compounds for growth. The oxygenase alpha subunit contains an N-terminal Rieske domain with an [2Fe-2S] cluster and a C-terminal catalytic domain with a mononuclear Fe(II) binding site. The Rieske [2Fe-2S] cluster accepts electrons from a reductase or ferredoxin component and transfers them to the mononuclear iron for catalysis. AntDO converts anthranilate to catechol, a naturally occurring compound formed through tryptophan degradation and an important intermediate in the metabolism of many N-heterocyclic compounds such as indole, o-nitrobenzoate, carbazole, and quinaldine.бА0АкА0АаАCDDбАаАз№вА0А0АаАВRcd03539, Rieske_RO_Alpha_S5H, This alignment model represents the N-terminal rieske iron-sulfur domain of the oxygenase alpha subunit (NagG) of salicylate 5-hydroxylase (S5H). S5H converts salicylate (2-hydroxybenzoate), a metabolic intermediate of phenanthrene, to gentisate (2,5-dihydroxybenzoate) as part of an alternate pathway for naphthalene catabolism. S5H is a multicomponent enzyme made up of NagGH (the oxygenase components), NagAa (the ferredoxin reductase component), and NagAb (the ferredoxin component). The oxygenase component is made up of alpha (NagG) and beta (NagH) subunits.бА0АкА0АаАCDDбАаАз¤вА0А0АаАВгcd03541, Rieske_RO_Alpha_CMO, Rieske non-heme iron oxygenase (RO) family, Choline monooxygenase (CMO) subfamily, N-terminal Rieske domain of the oxygenase alpha subunit; ROs comprise a large class of aromatic ring-hydroxylating dioxygenases that enable microorganisms to tolerate and utilize aromatic compounds for growth. The oxygenase alpha subunit contains an N-terminal Rieske domain with an [2Fe-2S] cluster and a C-terminal catalytic domain with a mononuclear Fe(II) binding site. The Rieske [2Fe-2S] cluster accepts electrons from a reductase or ferredoxin component and transfers them to the mononuclear iron for catalysis. CMO is a novel RO found in certain plants which catalyzes the first step in betaine synthesis. CMO is not found in animals or bacteria. In these organisms, the first step in betaine synthesis is catalyzed by either the membrane-bound choline dehydrogenase (CDH) or the soluble choline oxidase (COX).бА0АкА0АаАCDDбАаАз■вА0А0АаАВcd03542, Rieske_RO_Alpha_HBDO, Rieske non-heme iron oxygenase (RO) family, 2-Halobenzoate 1,2-dioxygenase (HBDO) subfamily, N-terminal Rieske domain of the oxygenase alpha subunit; ROs comprise a large class of aromatic ring-hydroxylating dioxygenases that enable microorganisms to tolerate and utilize aromatic compounds for growth. The oxygenase alpha subunit contains an N-terminal Rieske domain with an [2Fe-2S] cluster and a C-terminal catalytic domain with a mononuclear Fe(II) binding site. The Rieske [2Fe-2S] cluster accepts electrons from a reductase or ferredoxin component and transfers them to the mononuclear iron for catalysis. HBDO catalyzes the double hydroxylation of 2-halobenzoates with concomitant release of halogenide and carbon dioxide, yielding catechol.бА0АкА0АаАCDDбАаАз вА0А0АаАВacd03545, Rieske_RO_Alpha_OHBDO_like, Rieske non-heme iron oxygenase (RO) family, Ortho-halobenzoate-1,2-dioxygenase (OHBDO)-like subfamily, N-terminal Rieske domain of the oxygenase alpha subunit; composed of the oxygenase alpha subunits of OHBDO, salicylate 5-hydroxylase (S5H), terephthalate 1,2-dioxygenase system (TERDOS) and similar proteins. ROs comprise a large class of aromatic ring-hydroxylating dioxygenases that enable microorganisms to tolerate and utilize aromatic compounds for growth. The oxygenase alpha subunit contains an N-terminal Rieske domain with an [2Fe-2S] cluster and a C-terminal catalytic domain with a mononuclear Fe(II) binding site. The Rieske [2Fe-2S] cluster accepts electrons from a reductase or ferredoxin component and transfers them to the mononuclear iron for catalysis. OHBDO converts 2-chlorobenzoate (2-CBA) to catechol as well as 2,4-dCBA and 2,5-dCBA to 4-chlorocatechol, as part of the chlorobenzoate degradation pathway. Although ortho-substituted chlorobenzoates appear to be particularly recalcitrant to biodegradation, several strains utilize 2-CBA and the dCBA derivatives as a sole carbon and energy source. S5H converts salicylate (2-hydroxybenzoate), a metabolic intermediate of phenanthrene, to gentisate (2,5-dihydroxybenzoate) as part of an alternate pathway for naphthalene catabolism. S5H is a multicomponent enzyme made up of NagGH (the oxygenase components), NagAa (the ferredoxin reductase component), and NagAb (the ferredoxin component). The oxygenase component is made up of alpha (NagG) and beta (NagH) subunits. TERDOS is present in gram-positive bacteria and proteobacteria where it converts terephthalate (1,4-dicarboxybenzene) to protocatechuate as part of the terephthalate degradation pathway. The oxygenase component of TERDOS, called TerZ, is a hetero-hexamer with 3 alpha (TerZalpha) and 3 beta (TerZbeta) subunits.бА0АкА0АаАCDDбАаАивА0А0АаАВ|cd03548, Rieske_RO_Alpha_OMO_CARDO, Rieske non-heme iron oxygenase (RO) family, 2-Oxoquinoline 8-monooxygenase (OMO) and Carbazole 1,9a-dioxygenase (CARDO) subfamily, N-terminal Rieske domain of the oxygenase alpha subunit; ROs comprise a large class of aromatic ring-hydroxylating dioxygenases that enable microorganisms to tolerate and utilize aromatic compounds for growth. The oxygenase alpha subunit contains an N-terminal Rieske domain with an [2Fe-2S] cluster and a C-terminal catalytic domain with a mononuclear Fe(II) binding site. The Rieske [2Fe-2S] cluster accepts electrons from a reductase or ferredoxin component and transfers them to the mononuclear iron for catalysis. OMO catalyzes the NADH-dependent oxidation of the N-heterocyclic aromatic compound 2-oxoquinoline to 8-hydroxy-2-oxoquinoline, the second step in the bacterial degradation of quinoline. OMO consists of a reductase component (OMR) and an oxygenase component (OMO) that together function to shuttle electrons from the reduced pyridine nucleotide to the active site of OMO, where O2 activation and 2-oxoquinoline hydroxylation occurs. CARDO, which contains oxygenase (CARDO-O), ferredoxin (CARDO-F) and ferredoxin reductase (CARDO-R) components, catalyzes the dihydroxylation at the C1 and C9a positions of carbazole. The oxygenase component of OMO and CARDO contain only alpha subunits arranged in a trimeric structure.бА0АкА0АаАCDDбАаАивА0А0АаАВГcd03556, L-fucose_isomerase, L-fucose isomerase (FucIase); FucIase converts L-fucose, an aldohexose, to its ketose form, which prepares it for aldol cleavage (similar to the isomerization of glucose during glycolysis). L-fucose (or 6-deoxy-L-galactose) is found in blood group determinants as well as in various oligo- and polysaccharides, and glycosides in mammals, bacteria and plants.бА0АкА0АаАCDDбАаАивА0А0АаАВЁcd03557, L-arabinose_isomerase, L-Arabinose isomerase (AI) catalyzes the isomerization of L-arabinose to L-ribulose, the first reaction in its conversion into D-xylulose-5-phosphate, an intermediate in the pentose phosphate pathway, which allows L-arabinose to be used as a carbon source. AI can also convert D-galactose to D-tagatose at elevated temperatures in the presence of divalent metal ions. D-tagatose, rarely found in nature, is of commercial interest as a low-calorie sugar substitute.бА0АкА0АаАCDDбАаАивА0А0АаАВ+cd03561, VHS, VHS domain family; The VHS domain is present in Vps27 (Vacuolar Protein Sorting), Hrs (Hepatocyte growth factor-regulated tyrosine kinase substrate) and STAM (Signal Transducing Adaptor Molecule). It has a superhelical structure similar to that of the ARM (Armadillo) repeats and is present at the N-termini of proteins involved in intracellular membrane trafficking. There are four general groups of VHS domain containing proteins based on their association with other domains. The first group consists of proteins of the STAM/EAST/Hbp family which has the domain composition VHS-SH3-ITAM. The second consists of proteins with a FYVE domain C-terminal to VHS. The third consists of GGA proteins with a domain composition VHS-GAT (GGA and TOM)-GAE (gamma-adaptin ear) domain. The fourth consists of proteins with a VHS domain alone or with domains other than those mentioned above. In GGA proteins, VHS domains are involved in cargo recognition in trans-Golgi, thereby having a general membrane targeting/cargo recognition role in vesicular trafficking.бА0АкА0АаАCDDбАаАивА0А0АаАВrcd03562, CID, CID (CTD-Interacting Domain) domain family; CID is present in several RNA-processing factors such as Pcf11 and Nrd1. Pcf11 is a conserved and essential subunit of the yeast cleavage factor IA, which is required for polyadenylation-dependent 3'-RNA processing and transcription termination. Nrd1 is implicated in polyadenylation-independent 3'-RNA processing. CID binds tightly to the carboxy-terminal domain (CTD) of RNA polymerase (Pol) II. During transcription, Pol II synthesizes eukaryotic messenger RNA. Transcription is coupled to RNA processing through the CTD, which consists of up to 52 repeats of the sequence Tyr 1-Ser 2-Pro 3-Thr 4-Ser 5-Pro 6-Ser 7. CID contains eight alpha-helices in a right-handed superhelical arrangement, which closely resembles that of the VHS domains and ARM (Armadillo) repeat proteins, except for its two amino-terminal helices.бА0АкА0АаАCDDбАаАивА0А0АаАВcd03564, ANTH_AP180_CALM, ANTH domain family; composed of adaptor protein 180 (AP180), clathrin assembly lymphoid myeloid leukemia protein (CALM) and similar proteins. A set of proteins previously designated as harboring an ENTH domain in fact contains a highly similar, yet unique module referred to as an AP180 N-terminal homology (ANTH) domain. AP180 and CALM play important roles in clathrin-mediated endocytosis. AP180 is a brain-specific clathrin-binding protein which stimulates clathrin assembly during the recycling of synaptic vesicles. The ANTH domain is structurally similar to the VHS domain and is composed of a superhelix of eight alpha helices. ANTH domains bind both inositol phospholipids and proteins, and contribute to the nucleation and formation of clathrin coats on membranes. ANTH-bearing proteins have recently been shown to function with adaptor protein-1 and GGA adaptors at the trans-Golgi network, which suggests that the ANTH domain is a universal component of the machinery for clathrin-mediated membrane budding.бА0АкА0АаАCDDбАаАивА0А0АаАВjcd03565, VHS_Tom1, VHS domain family, Tom1 subfamily; The VHS domain is an essential part of Tom1 (Target of myb1 - retroviral oncogene) protein. The VHS domain has a superhelical structure similar to the structure of the ARM repeats and is present at the very N-termini of proteins. It is a right-handed superhelix of eight alpha helices. The VHS domain has been found in a number of proteins, some of which have been implicated in intracellular trafficking and sorting. The VHS domain of the Tom1 protein is essential for the negative regulation of Interleukin-1 and Tumor Necrosis Factor-induced signaling pathways.бА0АкА0АаАCDDбАаАивА0А0АаАВ/cd03567, VHS_GGA, VHS domain family, GGA subfamily; GGA (Golgi-localized, Gamma-ear-containing, Arf-binding) comprise a subfamily of ubiquitously expressed, monomeric, motif-binding cargo/clathrin adaptor proteins. The VHS domain has a superhelical structure similar to the structure of the ARM (Armadillo) repeats and is present at the N-termini of proteins. GGA proteins have a multidomain structure consisting of an N-terminal VHS domain linked by a short proline-rich linker to a GAT (GGA and TOM) domain, which is followed by a long flexible linker to the C-terminal appendage, GAE (gamma-adaptin ear) domain. The VHS domain of GGA proteins binds to the acidic-cluster dileucine (DxxLL) motif found on the cytoplasmic tails of cargo proteins trafficked between the trans-Golgi network and the endosomal system.бА0АкА0АаАCDDбАаАивА0А0АаАВcd03568, VHS_STAM, VHS domain family, STAM subfamily; members include STAM (Signal Transducing Adaptor Molecule), EAST (EGFR-associated protein with SH3 and TAM domains) and Hbp (Hrs-binding protein). Collectively, they are referred to as STAM. All STAMs have at their N-termini a VHS domain, which is involved in cytokine-mediated intracellular signal transduction and has a superhelical structure similar to the structure of ARM (Armadillo) repeats, followed by a SH3 (Src homology 3) domain, a well-established protein-protein interaction domain. At the C-termini of most vertebrate STAMS, an ITAM (Immunoreceptor Tyrosine-based Activation) motif is present, which mediates the binding of HRS (hepatocyte growth factor-regulated tyrosine kinase substrate) in endocytic and exocytic machineries.бА0АкА0АаАCDDбАаАи вА0А0АаАВ°cd03569, VHS_Hrs_Vps27p, VHS domain family, Hrs and Vps27p subfamily; composed of Hrs (Hepatocyte growth factor-regulated tyrosine kinase substrate) and its yeast homolog Vps27p (vacuolar protein sorting). The VHS domain, an essential part of Hrs/Vps27p, has a superhelical structure similar to the structure of ARM (Armadillo) repeats and is present at the N-termini of proteins. Hrs also contains a FYVE (Fab1p, YOTB, Vac1p, and EEA1) zinc finger domain C-terminal to VHS, as well as two coiled-coil domains. Hrs has been proposed to play a role in at least three vesicle trafficking events: exocytosis, endocytosis, and endosome to lysosome trafficking. Hrs is involved in promoting rapid recycling of endocytosed signaling receptors to the plasma membrane.бА0АкА0АаАCDDбАаАи вА0А0АаАВ3cd03571, ENTH_epsin, ENTH domain, Epsin family; The epsin (Eps15 interactor) N-terminal homology (ENTH) domain is an evolutionarily conserved protein module found primarily in proteins that participate in clathrin-mediated endocytosis. A set of proteins previously designated as harboring an ENTH domain in fact contains a highly similar, yet unique module referred to as an AP180 N-terminal homology (ANTH) domain. ENTH and ANTH (E/ANTH) domains are structurally similar to the VHS domain and are composed of a superhelix of eight alpha helices. E/ANTH domains bind both inositol phospholipids and proteins and contribute to the nucleation and formation of clathrin coats on membranes. ENTH domains also function in the development of membrane curvature through lipid remodeling during the formation of clathrin-coated vesicles. E/ANTH-bearing proteins have recently been shown to function with adaptor protein-1 and GGA adaptors at the trans-Golgi network, which suggests that E/ANTH domains are universal components of the machinery for clathrin-mediated membrane budding.бА0АкА0АаАCDDбАаАивА0А0АаАВrcd03572, ENTH_epsin_related, ENTH domain, Epsin Related family; composed of hypothetical proteins containing an ENTH-like domain. The epsin N-terminal homology (ENTH) domain is an evolutionarily conserved protein module found primarily in proteins that participate in clathrin-mediated endocytosis. A set of proteins previously designated as harboring an ENTH domain in fact contains a highly similar, yet unique module referred to as an AP180 N-terminal homology (ANTH) domain. ENTH and ANTH (E/ANTH) domains are structurally similar to the VHS domain and are composed of a superhelix of eight alpha helices. E/ANTH domains bind both inositol phospholipids and proteins and contribute to the nucleation and formation of clathrin coats on membranes. ENTH domains also function in the development of membrane curvature through lipid remodeling during the formation of clathrin-coated vesicles. E/ANTH-bearing proteins have recently been shown to function with adaptor protein-1 and GGA adaptors at the trans-Golgi network, which suggests that E/ANTH domains are universal components of the machinery for clathrin-mediated membrane budding.бА0АкА0АаАCDDбАаАивА0А0АаАВ~cd03574, NTR_complement_C345C, NTR/C345C domain; The NTR domains that are found in the C-termini of complement C3, C4 and C5, are also called C345C domains. In C5, the domain interacts with various partners during the formation of the membrane attack complex, a fundamental process in the mammalian defense against infection. It's role in component C3 and C4 is not well understood.бА0АкА0АаАCDDбАаАи вА0А0АаАВXcd03575, NTR_WFIKKN, NTR domain, WFIKKN subfamily; WFIKKN proteins contain a C-terminal NTR domain and are putative secreted proteins which may be multivalent protease inhibitors that act on serine proteases as well as metalloproteases. Human WFIKKN and a related protein sharing the same domain architecture were observed to have distinct tissue expression patterns. WFIKKN is also referred to as growth and differentiation factor-associated serum protein-1 (GASP-1). It inhibits the activity of mature myostatin, a specific regulator of skeletal muscle mass and a member of the TGFbeta superfamily.бА0АкА0АаАCDDбАаАивА0А0АаАВнcd03576, NTR_PCOLCE, NTR domain, PCOLCE subfamily; Procollagen C-endopeptidase enhancers (PCOLCEs) are extracellular matrix proteins that enhance the activity of procollagen C-proteases, by binding to the procollagen I C-peptide. They contain a C-terminal NTR domain, which have been suggested to possess inhibitory functions towards specific serine proteases but not towards metzincins, which are inhibited by the related TIMPs.бА0АкА0АаАCDDбАаАивА0А0АаАВ╒cd03577, NTR_TIMP_like, NTR domain, TIMP-like subfamily; TIMPs, or tissue inibitors of metalloproteases, are essential regulators of extracellular matrix turnover and remodeling. They form complexes with matrix metalloproteases (MMPs) and inactivate them irreversibly by non-covalently binding their active zinc-binding sites. This group contains domains similar to the TIMP NTR domain, which binds MMPs. Members of this group may or may not function as MMP inhibitors.бА0АкА0АаАCDDбАаАивА0А0АаАВ cd03578, NTR_netrin-4_like, NTR domain, Netrin-4-like subfamily; composed of the C-terminal NTR domains of netrin-4 (beta netrin) and similar proteins. Netrins are secreted proteins that function as tropic cues in the direction of axon growth and cell migration during neural development. Netrin-4 is a basement membrane component that is important in neural, kidney and vascular development. It may also be involved in regulating the outgrowth and shape of epithelial cells during lung branching morphogenesis.бА0АкА0АаАCDDбАаАивА0А0АаАВ▀cd03579, NTR_netrin-1_like, NTR domain, Netrin-1-like subfamily; The C-terminal NTR domain of netrins is also called domain C in the context of C. elegans netrin UNC-6. Netrins are secreted proteins that function as tropic cues in the direction of axon growth and cell migration during neural development. These proteins may be chemoattractive to some neurons and chemorepellant for others. In the case of netrin-1, attraction and repulsion responses are mediated by the DCC and UNC-5 receptor families. The biological activities of C. elegans UNC-6, which may either attract or repel migrating cells or axons, are mediated by its different domains. The C-terminal NTR domain of UNC-6 has been shown to inhibit axon branching activity.бА0АкА0АаАCDDбАаАивА0А0АаАВЫcd03580, NTR_Sfrp1_like, NTR domain, Secreted frizzled-related protein (Sfrp) 1-like subfamily; composed of proteins similar to human Sfrp1, Sfrp2 and Sfrp5. Sfrps are soluble proteins containing an NTR domain C-terminal to a cysteine-rich Frizzled domain. They show diverse functions and are thought to work in Wnt signaling indirectly, as modulators or antagonists by binding Wnt ligands, and directly, via the Wnt receptor, Frizzled. They participate in regulating the patterning along the anteroposterior axis in vertebrates. Human Sfrp1 has been found frequently to be downregulated in breast cancer and is associated with disease progression and poor prognosis.бА0АкА0АаАCDDбАаАивА0А0АаАВncd03581, NTR_Sfrp3_like, NTR domain, Secreted frizzled-related protein (Sfrp) 3-like subfamily; composed of proteins similar to human Sfrp3 and Sfrp4. Sfrps are soluble proteins containing an NTR domain C-terminal to a cysteine-rich Frizzled domain. They show diverse functions and are thought to work in Wnt signaling indirectly, as modulators or antagonists by binding Wnt ligands, and directly, via the Wnt receptor, Frizzled. They participate in regulating the patterning along the anteroposterior axis in vertebrates. Human Sfrp3 may suppress the growth and invasiveness of androgen-independent prostate cancer cells.бА0АкА0АаАCDDбАаАивА0А0АаАВуcd03582, NTR_complement_C5, NTR/C345C domain, complement C5 subfamily; The NTR domain found in complement C5 is also known as C345C because it occurs at the C-terminus of complement C3, C4 and C5. Complement C5 is activated by C5 convertase, which itself is a complex between C3b and C3 convertase. The small cleavage fragment, C5a, is the most important small peptide mediator of inflammation, and the larger active fragment, C5b, initiates late events of complement activation. The NTR/C345C domain is important in the function of C5 as it interacts with enzymes that convert C5 to the active form, C5b. The domain has also been found to bind to complement components C6 and C7, and may specifically interact with their factor I modules.бА0АкА0АаАCDDбАаАивА0А0АаАВНcd03583, NTR_complement_C3, NTR/C345C domain, complement C3 subfamily; The NTR domain found in complement C3 is also known as the C345C domain because it occurs at the C-terminus of complement C3, C4 and C5. Complement C3 plays a pivotal role in the activation of the complement systems, as all pathways (classical, alternative, and lectin) result in the processing of C3 by C3 convertase. The larger fragment, activated C3b, contains the NTR/C345C domain and binds covalently, via a reactive thioester, to cell surface carbohydrates including components of bacterial cell walls and immune aggregates. The smaller cleavage product, C3a, acts independently as a diffusible signal to mediate local inflammatory processes. The structure of C3 shows that the NTR/C345C domain is located in an exposed position relative to the rest of the molecule. The function of the domain in complement C3 is poorly understood.бА0АкА0АаАCDDбАаАивА0А0АаАВ?cd03584, NTR_complement_C4, NTR/C345C domain, complement C4 subfamily; The NTR domain found in complement C4 is also known as the C345C domain because it occurs at the C-terminus of complement C3, C4 and C5. Complement C4 is a key player in the activation of the component classical pathway. C4 is cleaved by activated C1 to yield C4a anaphylatoxin, and the larger fragment C4b, an essential component of the C3- and C5-convertase enzymes. C4b binds covalently to the surface of pathogens through a reactive thioester. The role of the NTR/C345C domain in C4 (C4b) is unclear.бА0АкА0АаАCDDбАаАивА0А0АаАВ▀cd03585, NTR_TIMP, NTR domain, TIMP subfamily; TIMPs, or tissue inibitors of metalloproteases, are essential regulators of extracellular matrix turnover and remodeling. They form complexes with matrix metalloproteases (MMPs) and inactivate them irreversibly by non-covalently binding their active zinc-binding sites. The levels of activated membrane-type MMPs, MMPs, and free TIMPs determine the balance between matrix degradation and matrix formation or stabilization. Consequently, TIMPs play roles in processes that require the remodeling and degradation of connective tissue, such as development, morphogenesis, wound healing, as well as in various diseases and pathological states such as tumor cell metastasis, arthritis, and artherosclerosis. Most TIMPs bind to a variety of MMPs. TIMP-1 and TIMP-2 appear to be multifunctional proteins with diverse biological action. They may exhibit growth factor-like activity and can inhibit angiogenesis. TIMP-3 has been implicated in apoptosis.бА0АкА0АаАCDDбАаАивА0А0АаАВcd03586, PolY_Pol_IV_kappa, DNA Polymerase IV/Kappa. Pol IV, also known as Pol kappa, DinB, and Dpo4, is a translesion synthesis (TLS) polymerase. Translesion synthesis is a process that allows the bypass of a variety of DNA lesions. TLS polymerases lack proofreading activity and have low fidelity and low processivity. They use damaged DNA as templates and insert nucleotides opposite the lesions. Known primarily as Pol IV in prokaryotes and Pol kappa in eukaryotes, this polymerase has a propensity for generating frameshift mutations. The eukaryotic Pol kappa differs from Pol IV and Dpo4 by an N-terminal extension of ~75 residues known as the "N-clasp" region. The structure of Pol kappa shows DNA that is almost totally encircled by Pol kappa, with the N-clasp region augmenting the interactions between DNA and the polymerase. Pol kappa is more resistant than Pol eta and Pol iota to bulky guanine adducts and is efficient at catalyzing the incorporation of dCTP. Bacterial pol IV has a higher error rate than other Y-family polymerases.бА0АкА0АаАCDDбАаА▒KвА0А0АаАВ╙cd03587, SOCS, SOCS (suppressors of cytokine signaling) box. The SOCS box is found in the C-terminal region of CIS/SOCS family proteins (in combination with a SH2 domain), ASBs (ankyrin repeat-containing proteins with a SOCS box), SSBs (SPRY domain-containing proteins with a SOCS box), and WSBs (WD40 repeat-containing proteins with a SOCS box), as well as, other miscellaneous proteins. The function of the SOCS box is the recruitment of the ubiquitin-transferase system. The SOCS box interacts with Elongins B and C, Cullin-5 or Cullin-2, Rbx-1, and E2. Therefore, SOCS-box-containing proteins probably function as E3 ubiquitin ligases and mediate the degradation of proteins associated through their N-terminal regions.бА0АкА0АаАCDDбАаАивА0А0АаАВtcd03588, CLECT_CSPGs, C-type lectin-like domain (CTLD) of the type found in chondroitin sulfate proteoglycan core proteins. CLECT_CSPGs: C-type lectin-like domain (CTLD) of the type found in chondroitin sulfate proteoglycan core proteins (CSPGs) in human and chicken aggrecan, frog brevican, and zebra fish dermacan. CTLD refers to a domain homologous to the carbohydrate-recognition domains (CRDs) of the C-type lectins. In cartilage, aggrecan forms cartilage link protein stabilized aggregates with hyaluronan (HA). These aggregates contribute to the tissue's load bearing properties. Aggregates having other CSPGs substituting for aggrecan may contribute to the structural integrity of many different tissues. Xenopus brevican is expressed in the notochord and the brain during early embryogenesis. Zebra fish dermacan is expressed in dermal bones and may play a role in dermal bone development. CSPGs do contain LINK domain(s) which bind HA. These LINK domains are considered by one classification system to be a variety of CTLD, but are omitted from this hierarchical classification based on insignificant sequence similarity.бА0АкА0АаАCDDбАаАUтвА0А0АаАВ┼cd03589, CLECT_CEL-1_like, C-type lectin-like domain (CTLD) of the type found in CEL-1 from Cucumaria echinata and Echinoidin from Anthocidaris crassispina. CLECT_CEL-1_like: C-type lectin-like domain (CTLD) of the type found in CEL-1 from Cucumaria echinata and Echinoidin from Anthocidaris crassispina. CTLD refers to a domain homologous to the carbohydrate-recognition domains (CRDs) of the C-type lectins. The CEL-1 CTLD binds three calcium ions and has a high specificity for N-acteylgalactosamine (GalNAc). CEL-1 exhibits strong cytotoxicity which is inhibited by GalNAc. This protein may play a role as a toxin defending against predation. Echinoidin is found in the coelomic fluid of the sea urchin and is specific for GalBeta1-3GalNAc. Echinoidin has a cell adhesive activity towards human cancer cells which is not mediated through the CTLD. Both CEL-1 and Echinoidin are multimeric proteins comprised of multiple dimers linked by disulfide bonds.бА0АкА0АаАCDDбАаАUувА0А0АаАВ Qcd03590, CLECT_DC-SIGN_like, C-type lectin-like domain (CTLD) of the type found in human dendritic cell (DC)-specific intercellular adhesion molecule 3-grabbing non-integrin (DC-SIGN) and the related receptor, DC-SIGN receptor (DC-SIGNR). CLECT_DC-SIGN_like: C-type lectin-like domain (CTLD) of the type found in human dendritic cell (DC)-specific intercellular adhesion molecule 3-grabbing non-integrin (DC-SIGN) and the related receptor, DC-SIGN receptor (DC-SIGNR). This group also contains proteins similar to hepatic asialoglycoprotein receptor (ASGP-R) and langerin in human. These proteins are type II membrane proteins with a CTLD ectodomain. CTLD refers to a domain homologous to the carbohydrate-recognition domains (CRDs) of the C-type lectins. DC-SIGN is thought to mediate the initial contact between dendritic cells and resting T cells, and may also mediate the rolling of DCs on epithelium. DC-SIGN and DC-SIGNR bind to oligosaccharides present on human tissues, as well as, on pathogens including parasites, bacteria, and viruses. DC-SIGN and DC-SIGNR bind to HIV enhancing viral infection of T cells. DC-SIGN and DC-SIGNR are homotetrameric, and contain four CTLDs stabilized by a coiled coil of alpha helices. The hepatic ASGP-R is an endocytic recycling receptor which binds and internalizes desialylated glycoproteins having a terminal galactose or N-acetylgalactosamine residues on their N-linked carbohydrate chains, via the clathrin-coated pit mediated endocytic pathway, and delivers them to lysosomes for degradation. It has been proposed that glycoproteins bearing terminal Sia (sialic acid) alpha2, 6GalNAc and Sia alpha2, 6Gal are endogenous ligands for ASGP-R and that ASGP-R participates in regulating the relative concentration of serum glycoproteins bearing alpha 2,6-linked Sia. The human ASGP-R is a hetero-oligomer composed of two subunits, both of which are found within this group. Langerin is expressed in a subset of dendritic leukocytes, the Langerhans cells (LC). Langerin induces the formation of Birbeck Granules (BGs) and associates with these BGs following internalization. Langerin binds, in a calcium-dependent manner, to glyco-conjugates containing mannose and related sugars mediating their uptake and degradation. Langerin molecules oligomerize as trimers with three CTLDs held together by a coiled-coil of alpha helices.бА0АкА0АаАCDDбАаАUфвА0А0АаАВ╕cd03591, CLECT_collectin_like, C-type lectin-like domain (CTLD) of the type found in human collectins including lung surfactant proteins A and D, mannose- or mannan binding lectin (MBL), and CL-L1 (collectin liver 1). CLECT_collectin_like: C-type lectin-like domain (CTLD) of the type found in human collectins including lung surfactant proteins A and D, mannose- or mannan binding lectin (MBL), and CL-L1 (collectin liver 1). CTLD refers to a domain homologous to the carbohydrate-recognition domains (CRDs) of the C-type lectins. The CTLDs of these collectins bind carbohydrates on surfaces (e.g. pathogens, allergens, necrotic, or apoptotic cells) and mediate functions associated with killing and phagocytosis. MBPs recognize high mannose oligosaccharides in a calcium dependent manner, bind to a broad range of pathogens, and trigger cell killing by activating the complement pathway. MBP also acts directly as an opsonin. SP-A and SP-D in addition to functioning as host defense components, are components of pulmonary surfactant which play a role in surfactant homeostasis. Pulmonary surfactant is a phospholipid-protein complex which reduces the surface tension within the lungs. SP-A binds the major surfactant lipid: dipalmitoylphosphatidylcholine (DPPC). SP-D binds two minor components of surfactant that contain sugar moieties: glucosylceramide and phosphatidylinositol (PI). MBP and SP-A, -D monomers are homotrimers with an N-terminal collagen region and three CTLDs. Multiple homotrimeric units associate to form supramolecular complexes. MBL deficiency results in an increased susceptibility to a large number of different infections and to inflammatory disease, such as rheumatoid arthritis.бА0АкА0АаАCDDбАаАUхвА0А0АаАВ█cd03592, CLECT_selectins_like, C-type lectin-like domain (CTLD) of the type found in the type 1 transmembrane proteins: P(platlet)-, E(endothelial)-, and L(leukocyte)- selectins (sels). CLECT_selectins_like: C-type lectin-like domain (CTLD) of the type found in the type 1 transmembrane proteins: P(platlet)-, E(endothelial)-, and L(leukocyte)- selectins (sels). CTLD refers to a domain homologous to the carbohydrate-recognition domains (CRDs) of the C-type lectins. P- E- and L-sels are cell adhesion receptors that mediate the initial attachment, tethering, and rolling of lymphocytes on inflamed vascular walls enabling subsequent lymphocyte adhesion and transmigration. L- sel is expressed constitutively on most leukocytes. P-sel is stored in the Weibel-Palade bodies of endothelial cells and in the alpha granules of platlets. E- sels are present on endothelial cells. Following platelet and/or endothelial cell activation P- sel is rapidly translocated to the cell surface and E-sel expression is induced. The initial step in leukocyte migration involves interactions of selectins with fucosylated, sialylated, and sulfated carbohydrate moieties on target ligands displayed on glycoprotein scaffolds on endothelial cells and leucocytes. A major ligand of P- E- and L-sels is PSGL-1 (P-sel glycoprotein ligand). Interactions of E- and P- sels with tumor cells may promote extravasation of cancer cells. Regulation of L-sel and P-sel function includes proteolytic shedding of the most extracellular portion (containing the CTLD) from the cell surface. Increased levels of the soluble form of P-sel in the plasma have been found in a number of diseases including coronary disease and diabetes. E- and P- sel also play roles in the development of synovial inflammation in inflammatory arthritis. Platelet P-sel, but not endothelial P-sel, plays a role in the inflammatory response and neointimal formation after arterial injury. Selectins may also function as signal-transducing receptors.бА0АкА0АаАCDDбАаАUцвА0А0АаАВ 2cd03593, CLECT_NK_receptors_like, C-type lectin-like domain (CTLD) of the type found in natural killer cell receptors (NKRs). CLECT_NK_receptors_like: C-type lectin-like domain (CTLD) of the type found in natural killer cell receptors (NKRs), including proteins similar to oxidized low density lipoprotein (OxLDL) receptor (LOX-1), CD94, CD69, NKG2-A and -D, osteoclast inhibitory lectin (OCIL), dendritic cell-associated C-type lectin-1 (dectin-1), human myeloid inhibitory C-type lectin-like receptor (MICL), mast cell-associated functional antigen (MAFA), killer cell lectin-like receptors: subfamily F, member 1 (KLRF1) and subfamily B, member 1 (KLRB1), and lys49 receptors. CTLD refers to a domain homologous to the carbohydrate-recognition domains (CRDs) of the C-type lectins. NKRs are variously associated with activation or inhibition of natural killer (NK) cells. Activating NKRs stimulate cytolysis by NK cells of virally infected or transformed cells; inhibitory NKRs block cytolysis upon recognition of markers of healthy self cells. Most Lys49 receptors are inhibitory; some are stimulatory. OCIL inhibits NK cell function via binding to the receptor NKRP1D. Murine OCIL in addition to inhibiting NK cell function inhibits osteoclast differentiation. MAFA clusters with the type I Fc epsilon receptor (FcepsilonRI) and inhibits the mast cells secretory response to FcepsilonRI stimulus. CD72 is a negative regulator of B cell receptor signaling. NKG2D is an activating receptor for stress-induced antigens; human NKG2D ligands include the stress induced MHC-I homologs, MICA, MICB, and ULBP family of glycoproteins Several NKRs have a carbohydrate-binding capacity which is not mediated through calcium ions (e.g. OCIL binds a range of high molecular weight sulfated glycosaminoglycans including dextran sulfate, fucoidan, and gamma-carrageenan sugars). Dectin-1 binds fungal beta-glucans and in involved in the innate immune responses to fungal pathogens. MAFA binds saccharides having terminal alpha-D mannose residues in a calcium-dependent manner. LOX-1 is the major receptor for OxLDL in endothelial cells and thought to play a role in the pathology of atherosclerosis. Some NKRs exist as homodimers (e.g.Lys49, NKG2D, CD69, LOX-1) and some as heterodimers (e.g. CD94/NKG2A). Dectin-1 can function as a monomer in vitro.бА0АкА0АаАCDDбАаАUчвА0А0АаАВ[cd03594, CLECT_REG-1_like, C-type lectin-like domain (CTLD) of the type found in Human REG-1 (lithostathine), REG-4, and avian eggshell-specific proteins: ansocalcin, structhiocalcin-1(SCA-1), and -2(SCA-2). CLECT_REG-1_like: C-type lectin-like domain (CTLD) of the type found in Human REG-1 (lithostathine), REG-4, and avian eggshell-specific proteins: ansocalcin, structhiocalcin-1(SCA-1), and -2(SCA-2). CTLD refers to a domain homologous to the carbohydrate-recognition domains (CRDs) of the C-type lectins. REG-1 is a proliferating factor which participates in various kinds of tissue regeneration including pancreatic beta-cell regeneration, regeneration of intestinal mucosa, regeneration of motor neurons, and perhaps in tissue regeneration of damaged heart. REG-1 may play a role on the pathophysiology of Alzheimer's disease and in the development of gastric cancers. Its expression is correlated with reduced survival from early-stage colorectal cancer. REG-1 also binds and aggregates several bacterial strains from the intestinal flora and it has been suggested that it is involved in the control of the intestinal bacterial ecosystem. Rat lithostathine has calcium carbonate crystal inhibitor activity in vitro. REG-IV is unregulated in pancreatic, gastric, hepatocellular, and prostrate adenocarcinomas. REG-IV activates the EGF receptor/Akt/AP-1 signaling pathway in colorectal carcinoma. Ansocalcin, SCA-1 and -2 are found at high concentration in the calcified egg shell layer of goose and ostrich, respectively and tend to form aggregates. Ansocalcin nucleates calcite crystal aggregates in vitro.бА0АкА0АаАCDDбАаАUшвА0А0АаАВзcd03595, CLECT_chondrolectin_like, C-type lectin-like domain (CTLD) of the type found in the human type-1A transmembrane proteins chondrolectin (CHODL) and layilin. CLECT_chondrolectin_like: C-type lectin-like domain (CTLD) of the type found in the human type-1A transmembrane proteins chondrolectin (CHODL) and layilin. CTLD refers to a domain homologous to the carbohydrate-recognition domains (CRDs) of the C-type lectins. CHODL is predominantly expressed in muscle cells and is associated with T-cell maturation. Various alternatively spliced isoforms have been of CHODL have been identified. The transmembrane form of CHODL is localized in the ER-Golgi apparatus. Layilin is widely expressed in different cell types. The extracellular CTLD of layilin binds hyaluronan (HA), a major constituent of the extracellular matrix (ECM). The cytoplasmic tail of layilin binds various members of the band 4.1/ERM superfamily (talin, radixin, and merlin). The ERM proteins are cytoskeleton-membrane linker molecules which link actin to receptors in the plasma membrane. Layilin co-localizes in with talin in membrane ruffles and may mediate signals from the ECM to the cell cytoskeleton.бА0АкА0АаАCDDбАаАUщвА0А0АаАВcd03596, CLECT_tetranectin_like, C-type lectin-like domain (CTLD) of the type found in the tetranectin (TN), cartilage derived C-type lectin (CLECSF1), and stem cell growth factor (SCGF). CLECT_tetranectin_like: C-type lectin-like domain (CTLD) of the type found in the tetranectin (TN), cartilage derived C-type lectin (CLECSF1), and stem cell growth factor (SCGF). CTLD refers to a domain homologous to the carbohydrate-recognition domains (CRDs) of the C-type lectins. TN binds to plasminogen and stimulates activation of plasminogen, playing a key role in the regulation of proteolytic processes. The TN CTLD binds two calcium ions. Its calcium free form binds to various kringle-like protein ligands. Two residues involved in the coordination of calcium are critical for the binding of TN to the fourth kringle (K4) domain of plasminogen (Plg K4). TN binds the kringle 1-4 form of angiostatin (AST K1-4). AST K1-4 is a fragment of Plg, commonly found in cancer tissues. TN inhibits the binding of Plg and AST K1-4 to the extracellular matrix (EMC) of endothelial cells and counteracts the antiproliferative effects of AST K1-4 on these cells. TN also binds the tenth kringle domain of apolipoprotein (a). In addition, TN binds fibrin and complex polysaccharides in a Ca2+ dependent manner. The binding site for complex sulfated polysaccharides is N-terminal to the CTLD. TN is homotrimeric; N-terminal to the CTLD is an alpha helical domain responsible for trimerization of monomeric units. TN may modulate angiogenesis through interactions with angiostatin and coagulation through interaction with fibrin. TN may play a role in myogenesis and in bone development. Mice having a deletion in the TN gene exhibit a kyphotic spine abnormality. TN is a useful prognostic marker of certain cancer types. CLECSF1 is expressed in cartilage tissue, which is primarily intracellular matrix (ECM), and is a candidate for organizing ECM. SCGF is strongly expressed in bone marrow and is a cytokine for primitive hematopoietic progenitor cells.бА0АкА0АаАCDDбАаАUъвА0А0АаАВocd03597, CLECT_attractin_like, C-type lectin-like domain (CTLD) of the type found in human and mouse attractin (AtrN) and attractin-like protein (ALP). CLECT_attractin_like: C-type lectin-like domain (CTLD) of the type found in human and mouse attractin (AtrN) and attractin-like protein (ALP). CTLD refers to a domain homologous to the carbohydrate-recognition domains (CRDs) of the C-type lectins. Mouse AtrN (the product of the mahogany gene) has been shown to bind Agouti protein and to function in agouti-induced pigmentation and obesity. Mutations in AtrN have also been shown to cause spongiform encephalopathy and hypomyelination in rats and hamsters. The cytoplasmic region of mouse ALP has been shown to binds to melanocortin receptor (MCR4). Signaling through MCR4 plays a role in appetite suppression. Attractin may have therapeutic potential in the treatment of obesity. Human attractin (hAtrN) has been shown to be expressed on activated T cells and released extracellularly. The circulating serum attractin induces the spreading of monocytes that become the focus of the clustering of non-proliferating T cells.бА0АкА0АаАCDDбАаАUывА0А0АаАВюcd03598, CLECT_EMBP_like, C-type lectin-like domain (CTLD) of the type found in the human proteins, eosinophil major basic protein (EMBP) and prepro major basic protein homolog (MBPH). CLECT_EMBP_like: C-type lectin-like domain (CTLD) of the type found in the human proteins, eosinophil major basic protein (EMBP) and prepro major basic protein homolog (MBPH). CTLD refers to a domain homologous to the carbohydrate-recognition domains (CRDs) of the C-type lectins. Eosinophils and basophils carry out various functions in allergic, parasitic, and inflammatory diseases. EMBP is stored in eosinophil crystalloid granules and is released upon degranulation. EMBP is also expressed in basophils. The proform of EMBP is expressed in placental X cells and breast tissue and increases significantly during human pregnancy. EMBP has cytotoxic properties and damages bacteria and mammalian cells, in vitro, as well as, helminth parasites. EMBP deposition has been observed in the inflamed tissue of allergy patients in a variety of diseases including asthma, atopic dermatitis, and rhinitis. In addition to its cytotoxic functions, EMBP activates cells and stimulates cytokine production. EMBP has been shown to bind the proteoglycan heparin. The binding site is similar to the carbohydrate binding site of other classical CTLD, such as mannose-binding protein (MBP1), however, heparin binding to EMBP is calcium ion independent. MBPH has reduced potency in cytotoxic and cytostimulatory assays compared with EMBP.бА0АкА0АаАCDDбАаАUьвА0А0АаАВбcd03599, CLECT_DGCR2_like, C-type lectin-like domain (CTLD) of the type found in DGCR2, an integral membrane protein deleted in DiGeorge Syndrome (DGS). CLECT_DGCR2_like: C-type lectin-like domain (CTLD) of the type found in DGCR2, an integral membrane protein deleted in DiGeorge Syndrome (DGS). CTLD refers to a domain homologous to the carbohydrate-recognition domains (CRDs) of the C-type lectins. DGS is also known velo-cardio-facial syndrome (VCFS). DGS is a genetic abnormality that results in malformations of the heart, face, and limbs and is associated with schizophrenia and depressive disorders. DGCR2 is a candidate for involvement in the pathogenesis of DGS since the DGCR2 gene lies within the minimal DGS critical region (MDGRC) of 22q11, which when deleted gives rise to DGS, and the DGCR2 gene is in close proximity to the balanced translocation breakpoint in a DGS patient having a balanced translocation.бА0АкА0АаАCDDбАаАUэвА0А0АаАВ╜cd03600, CLECT_thrombomodulin_like, C-type lectin-like domain (CTLD) of the type found in human thrombomodulin(TM), Endosialin, C14orf27, and C1qR. CLECT_thrombomodulin_like: C-type lectin-like domain (CTLD) of the type found in human thrombomodulin(TM), Endosialin, C14orf27, and C1qR. CTLD refers to a domain homologous to the carbohydrate-recognition domains (CRDs) of the C-type lectins. In these thrombomodulin-like proteins the residues involved in coordinating Ca2+ in the classical MBP-A CTLD are not conserved. TM exerts anti-fibrinolytic and anti-inflammatory activity. TM also regulates blood coagulation in the anticoagulant protein C pathway. In this pathway, the procoagulant properties of thrombin (T) are lost when it binds TM. TM also plays a key role in tumor biology. It is expressed on endothelial cells and on several type of tumor cell including squamous cell carcinoma. Loss of TM expression correlates with advanced stage and poor prognosis. Loss of function of TM function may be associated with arterial or venous thrombosis and with late fetal loss. Soluble molecules of TM retaining the CTLD are detected in human plasma and urine where higher levels indicate injury and/or enhanced turnover of the endothelium. C1qR is expressed on endothelial cells and stem cells. It is also expressed on monocots and neutrophils, where it is subject to ectodomain shedding. Soluble forms of C1qR retaining the CTLD is detected in human plasma. C1qR modulates the phagocytosis of apoptotic cells in vivo. C1qR-deficient mice are defective in clearance of apoptotic cells in vivo. The cytoplasmic tail of C1qR, C-terminal to the CTLD of CD93, contains a PDZ binding domain which interacts with the PDZ domain-containing adaptor protein, GIPC. The juxtamembrane region of this tail interacts with the ezrin/radixin/moesin family. Endosialin functions in the growth and progression of abdominal tumors and is expressed in the stroma of several tumors.бА0АкА0АаАCDDбАаАUювА0А0АаАВмcd03601, CLECT_TC14_like, C-type lectin-like domain (CTLD) of the type found in lectins TC14, TC14-2, TC14-3, and TC14-4 from the budding tunicate Polyandrocarpa misakiensis and PfG6 from the Acorn worm. CLECT_TC14_like: C-type lectin-like domain (CTLD) of the type found in lectins TC14, TC14-2, TC14-3, and TC14-4 from the budding tunicate Polyandrocarpa misakiensis and PfG6 from the Acorn worm. CTLD refers to a domain homologous to the carbohydrate-recognition domains (CRDs) of the C-type lectins. TC14 is homodimeric. The CTLD of TC14 binds D-galactose and D-fucose. TC14 is expressed constitutively by multipotent epithelial and mesenchymal cells and plays in role during budding, in inducing the aggregation of undifferentiated mesenchymal cells to give rise to epithelial forming tissue. TC14-2 and TC14-3 shows calcium-dependent galactose binding activity. TC14-3 is a cytostatic factor which blocks cell growth and dedifferentiation of the atrial epithelium during asexual reproduction. It may also act as a differentiation inducing factor. Galactose inhibits the cytostatic activity of TC14-3. The gene for Acorn worm PfG6 is gill-specific; PfG6 may be a secreted protein.бА0АкА0АаАCDDбАаАUявА0А0АаАВOcd03602, CLECT_1, C-type lectin (CTL)/C-type lectin-like (CTLD) domain subgroup 1; a subgroup of protein domains homologous to the carbohydrate-recognition domains (CRDs) of the C-type lectins. CLECT_1: C-type lectin (CTL)/C-type lectin-like (CTLD) domain subgroup 1; a subgroup of protein domains homologous to the carbohydrate-recognition domains (CRDs) of the C-type lectins. Many CTLDs are calcium-dependent carbohydrate binding modules; other CTLDs bind protein ligands, lipids, and inorganic surfaces including CaCO3 and ice. Animal C-type lectins are involved in such functions as extracellular matrix organization, endocytosis, complement activation, pathogen recognition, and cell-cell interactions. CTLDs may bind a variety of carbohydrate ligands including mannose, N-acetylglucosamine, galactose, N-acetylgalactosamine, and fucose. CTLDs associate with each other through several different surfaces to form dimers, trimers, or tetramers from which ligand-binding sites project in different orientations. In some CTLDs a loop extends to the adjoining domain to form a loop-swapped dimer.бА0АкА0АаАCDDбАаАUЁвА0А0АаАВйcd03603, CLECT_VCBS, A bacterial subgroup of the C-type lectin-like (CTLD) domain; a subgroup of bacterial protein domains homologous to the carbohydrate-recognition domains (CRDs) of the C-type lectins. CLECT_VCBS: A bacterial subgroup of the C-type lectin-like (CTLD) domain; a subgroup of bacterial protein domains homologous to the carbohydrate-recognition domains (CRDs) of the C-type lectins. Many CTLDs are calcium-dependent carbohydrate binding modules; other CTLDs bind protein ligands, lipids, and inorganic surfaces including CaCO3 and ice. Bacterial CTLDs within this group are functionally uncharacterized. Animal C-type lectins are involved in such functions as extracellular matrix organization, endocytosis, complement activation, pathogen recognition, and cell-cell interactions. CTLDs may bind a variety of carbohydrate ligands including mannose, N-acetylglucosamine, galactose, N-acetylgalactosamine, and fucose. CTLDs associate with each other through several different surfaces to form dimers, trimers, or tetramers from which ligand-binding sites project in different orientations. In some CTLDs a loop extends to the adjoining domain to form a loop-swapped dimer.бА0АкА0АаАCDDбАаАUёвА0А0АаАВВcd03670, ADPRase_NUDT9, ADP-ribose pyrophosphatase (ADPRase) catalyzes the hydrolysis of ADP-ribose to AMP and ribose-5-P. Like other members of the Nudix hydrolase superfamily of enzymes, it is thought to require a divalent cation, such as Mg2+, for its activity. It also contains a 23-residue Nudix motif (GX5EX7REUXEEXGU, where U = I, L or V) which functions as a metal binding site/catalytic site. In addition to the Nudix motif, there are additional conserved amino acid residues, distal from the signature sequence, that correlate with substrate specificity. In humans, there are four distinct ADPRase activities, three putative cytosolic (ADPRase-I, -II, and -Mn) and a single mitochondrial enzyme (ADPRase-m). ADPRase-m is also known as NUDT9. It can be distinugished from the cytosolic ADPRase by a N-terminal target sequence unique to mitochondrial ADPRase. NUDT9 functions as a monomer.бА0АкА0АаАCDDбАаАивА0А0АаАВ╞cd03671, Ap4A_hydrolase_plant_like, Diadenosine tetraphosphate (Ap4A) hydrolase is a member of the Nudix hydrolase superfamily. Members of this family are well represented in a variety of prokaryotic and eukaryotic organisms. Phylogenetic analysis reveals two distinct subgroups where plant enzymes fall into one group (represented by this subfamily) and fungi/animals/archaea enzymes fall into another. Bacterial enzymes are found in both subfamilies. Ap4A is a potential by-product of aminoacyl tRNA synthesis, and accumulation of Ap4A has been implicated in a range of biological events, such as DNA replication, cellular differentiation, heat shock, metabolic stress, and apoptosis. Ap4A hydrolase cleaves Ap4A asymmetrically into ATP and AMP. It is important in the invasive properties of bacteria and thus presents a potential target for the inhibition of such invasive bacteria. Besides the signature nudix motif (G[X5]E[X7]REUXEEXGU where U is Ile, Leu, or Val), Ap4A hydrolase is structurally similar to the other members of the nudix superfamily with some degree of variations. Several regions in the sequences are poorly defined and substrate and metal binding sites are only predicted based on kinetic studies.бА0АкА0АаАCDDбАаАивА0А0АаАВ╧cd03672, Dcp2p, mRNA decapping enzyme 2 (Dcp2p), the catalytic subunit, and Dcp1p are the two components of the decapping enzyme complex. Decapping is a key step in both general and nonsense-mediated 5'->3' mRNA-decay pathways. Dcp2p contains an all-alpha helical N-terminal domain and a C-terminal domain which has the Nudix fold. While decapping is not dependent on the N-terminus of Dcp2p, it does affect its efficiency. Dcp1p binds the N-terminal domain of Dcp2p stimulating the decapping activity of Dcp2p. Decapping permits the degradation of the transcript and is a site of numerous control inputs. It is responsible for nonsense-mediated decay as well as AU-rich element (ARE)-mediated decay. In addition, it may also play a role in the levels of mRNA. Enzymes belonging to the Nudix superfamily require a divalent cation, such as Mg2+ or Mn2+, for their activity and are recognized by a highly conserved 23-residue nudix motif (GX5EX7REUXEEXGU, where U = I, L or V).бА0АкА0АаАCDDбАаАивА0А0АаАВ cd03673, Ap6A_hydrolase, Diadenosine hexaphosphate (Ap6A) hydrolase is a member of the Nudix hydrolase superfamily. Ap6A hydrolase specifically hydrolyzes diadenosine polyphosphates, but not ATP or diadenosine triphosphate, and it generates ATP as the product. Ap6A, the most preferred substrate, hydrolyzes to produce two ATP molecules, which is a novel hydrolysis mode for Ap6A. These results indicate that Ap6A hydrolase is a diadenosine polyphosphate hydrolase. It requires the presence of a divalent cation, such as Mn2+, Mg2+, Zn2+, and Co2+, for activity. Members of the Nudix superfamily are recognized by a highly conserved 23-residue nudix motif (GX5EX7REUXEEXGU, where U = I, L or V), which forms a structural motif that functions as a metal binding and catalytic site.бА0АкА0АаАCDDбАаАивА0А0АаАВcd03674, Nudix_Hydrolase_1, Members of the Nudix hydrolase superfamily catalyze the hydrolysis of NUcleoside DIphosphates linked to other moieties, X. Enzymes belonging to this superfamily require a divalent cation, such as Mg2+ or Mn2+, for their activity. They also contain a highly conserved 23-residue nudix motif (GX5EX7REUXEEXGU, U=I, L or V), which forms a structural motif that functions as a metal binding and catalytic site. Substrates of nudix hydrolases include intact and oxidatively damaged nucleoside triphosphates, dinucleoside polyphosphates, nucleotide-sugars and dinucleotide enzymes. These substrates are metabolites or cell signaling molecules that require regulation during different stages of the cell cycle or during periods of stress. In general, the role of the nudix hydrolase is to sanitize the nucleotide pools and to maintain cell viability, thereby serving as surveillance & "house-cleaning" enzymes. Substrate specificity is used to define families within the superfamily. Differences in substrate specificity are determined by the N-terminal extension or by residues in variable loop regions. Mechanistically, substrate hydrolysis occurs by a nucleophilic substitution reaction, with variation in the numbers and roles of divalent cations required.бА0АкА0АаАCDDбАаАивА0А0АаАВДcd03675, Nudix_Hydrolase_2, Contains a crystal structure of the Nudix hydrolase from Nitrosomonas europaea, which has an unknown function. In general, members of the Nudix hydrolase superfamily catalyze the hydrolysis of NUcleoside DIphosphates linked to other moieties, X. Enzymes belonging to this superfamily require a divalent cation, such as Mg2+ or Mn2+, for their activity. They also contain a highly conserved 23-residue nudix motif (GX5EX7REUXEEXGU, where U = I, L or V), which forms a structural motif that functions as a metal binding and catalytic site. Substrates of nudix hydrolases include intact and oxidatively damaged nucleoside triphosphates, dinucleoside polyphosphates, nucleotide-sugars and dinucleotide enzymes. These substrates are metabolites or cell signaling molecules that require regulation during different stages of the cell cycle or during periods of stress. In general, the role of the nudix hydrolase is to sanitize the nucleotide pools and to maintain cell viability, thereby serving as surveillance & "house-cleaning" enzymes. Substrate specificity is used to define families within the superfamily. Differences in substrate specificity are determined by the N-terminal extension or by residues in variable loop regions. Mechanistically, substrate hydrolysis occurs by a nucleophilic substitution reaction, with variation in the numbers and roles of divalent cations required.бА0АкА0АаАCDDбАаАивА0А0АаАВтcd03676, Nudix_hydrolase_3, Members of the Nudix hydrolase superfamily catalyze the hydrolysis of NUcleoside DIphosphates linked to other moieties, X. Enzymes belong to this superfamily requires a divalent cation, such as Mg2+ or Mn2+, for their activity and contain a highly conserved 23-residue nudix motif (GX5EX7REUXEEXGU, where U = I, L or V), which functions as a metal binding and catalytic site. Substrates of nudix hydrolases include intact and oxidatively damaged nucleoside triphosphates, dinucleoside polyphosphates, nucleotide-sugars and dinucleotide enzymes. These substrates are metabolites or cell signaling molecules that require regulation during different stages of the cell cycle or during periods of stress. In general, the role of the nudix hydrolase is to sanitize the nucleotide pools and to maintain cell viability, thereby serving as surveillance & "house-cleaning" enzymes. Substrate specificity is used to define families within the superfamily. Differences in substrate specificity are determined by the N-terminal extension or by residues in variable loop regions. Mechanistically, substrate hydrolysis occurs by a nucleophilic substitution reaction, with variation in the numbers and roles of divalent cations required.бА0АкА0АаАCDDбАаАи вА0А0АаАВэcd03677, MM_CoA_mutase_beta, Coenzyme B12-dependent-methylmalonyl coenzyme A (CoA) mutase (MCM) family, Beta subunit-like subfamily; contains bacterial proteins similar to the beta subunit of MCMs from Propionbacterium shermanni and Streptomyces cinnamonensis, which are alpha/beta heterodimers. For P. shermanni MCM, it is known that only the alpha subunit binds coenzyme B12 and substrates. The role of the beta subunit is unclear. MCM catalyzes the isomerization of methylmalonyl-CoA to succinyl-CoA. The reaction proceeds via radical intermediates beginning with a substrate-induced homolytic cleavage of the Co-C bond of coenzyme B12 to produce cob(II)alamin and the deoxyadenosyl radical. MCM plays an important role in the conversion of propionyl-CoA to succinyl-CoA during the degradation of propionate for the Krebs cycle. Methylobacterium extorquens MCM participates in the glyoxylate regeneration pathway. In M. extorquens, MCM forms a complex with MeaB; MeaB may protect MCM from irreversible inactivation. In some bacteria, MCM is involved in the reverse metabolic reaction, the rearrangement of succinyl-CoA to methylmalonyl-CoA. Examples include P. shermanni MCM during propionic acid fermentation and Streptomyces MCM in polyketide biosynthesis.бА0АкА0АаАCDDбАаАи!вА0А0АаАВjcd03678, MM_CoA_mutase_1, Coenzyme B12-dependent-methylmalonyl coenzyme A (CoA) mutase (MCM) family, unknown subfamily 1; composed of uncharacterized bacterial proteins containing a C-terminal MCM domain. MCM catalyzes the isomerization of methylmalonyl-CoA to succinyl-CoA. The reaction proceeds via radical intermediates beginning with a substrate-induced homolytic cleavage of the Co-C bond of coenzyme B12 to produce cob(II)alamin and the deoxyadenosyl radical. MCM plays an important role in the conversion of propionyl-CoA to succinyl-CoA during the degradation of propionate for the Krebs cycle. In some bacteria, MCM is involved in the reverse metabolic reaction, the rearrangement of succinyl-CoA to methylmalonyl-CoA. Members of this subfamily also contain an N-terminal coenzyme B12 binding domain followed by a domain similar to the E. coli ArgK membrane ATPase.бА0АкА0АаАCDDбАаАи"вА0А0АаАВCcd03679, MM_CoA_mutase_alpha_like, Coenzyme B12-dependent-methylmalonyl coenzyme A (CoA) mutase (MCM) family, Alpha subunit-like subfamily; contains proteins similar to the alpha subunit of Propionbacterium shermanni MCM, as well as human and E. coli MCM. Members of this subfamily contain an N-terminal MCM domain and a C-terminal coenzyme B12 binding domain. MCM catalyzes the isomerization of methylmalonyl-CoA to succinyl-CoA. The reaction proceeds via radical intermediates beginning with a substrate-induced homolytic cleavage of the Co-C bond of coenzyme B12 to produce cob(II)alamin and the deoxyadenosyl radical. MCM plays an important role in the conversion of propionyl-CoA to succinyl-CoA during the degradation of propionate for the Krebs cycle. In higher animals, MCM is involved in the breakdown of odd-chain fatty acids, several amino acids, and cholesterol. Methylobacterium extorquens MCM participates in the glyoxylate regeneration pathway. In M. extorquens, MCM forms a complex with MeaB; MeaB may protect MCM from irreversible inactivation. In some bacteria, MCM is involved in the reverse metabolic reaction, the rearrangement of succinyl-CoA to methylmalonyl-CoA. Examples include P. shermanni MCM during propionic acid fermentation, E.coli MCM in a pathway for the conversion of succinate to propionate and Streptomyces MCM in polyketide biosynthesis. Sinorhizobium meliloti strain SU47 MCM plays a role in the polyhydroxyalkanoate degradation pathway. P. shermanni and Streptomyces cinnamonensis MCMs are alpha/beta heterodimers. It has been shown for P. shermanni MCM that only the alpha subunit binds coenzyme B12 and substrates. Human MCM is a homodimer with two active sites. Mouse and E.coli MCMs are also homodimers. In humans, impaired activity of MCM results in methylmalonic aciduria, a disorder of propionic acid metabolism.бА0АкА0АаАCDDбАаАи#вА0А0АаАВ╤cd03680, MM_CoA_mutase_ICM_like, Coenzyme B12-dependent-methylmalonyl coenzyme A (CoA) mutase (MCM) family, isobutyryl-CoA mutase (ICM)-like subfamily; contains archaeal and bacterial proteins similar to the large subunit of Streptomyces cinnamonensis coenzyme B12-dependent ICM. ICM from S. cinnamonensis is comprised of a large and a small subunit. The holoenzyme appears to be an alpha2beta2 heterotetramer with up to 2 molecules of coenzyme B12 bound. The small subunit binds coenzyme B12. ICM catalyzes the reversible rearrangement of n-butyryl-CoA to isobutyryl-CoA, intermediates in fatty acid and valine catabolism, which in S. cinnamonensis can be converted to methylmalonyl-CoA and used in polyketide synthesis.бА0АкА0АаАCDDбАаАи$вА0А0АаАВ╢cd03681, MM_CoA_mutase_MeaA, Coenzyme B12-dependent-methylmalonyl coenzyme A (CoA) mutase (MCM) family, MeaA-like subfamily; contains various methylmalonyl coenzyme A (CoA) mutase (MCM)-like proteins similar to the Streptomyces cinnamonensis MeaA, Methylobacterium extorquens MeaA and Streptomyces collinus B12-dependent mutase. Members of this subfamily contain an N-terminal MCM domain and a C-terminal coenzyme B12 binding domain. S. cinnamonensis MeaA is a putative B12-dependent mutase which provides methylmalonyl-CoA precursors for the biosynthesis of the monensin polyketide via an unknown pathway. S. collinus B12-dependent mutase may be involved in a pathway for acetate assimilation.бА0АкА0АаАCDDбАаАи%вА0А0АаАВDcd03682, ClC_sycA_like, ClC sycA-like chloride channel proteins. This ClC family presents in bacteria, where it facilitates acid resistance in acidic soil. Mutation of this gene (sycA) in Rhizobium tropici CIAT899 causes serious deficiencies in nodule development, nodulation competitiveness, and N2 fixation on Phaseolus vulgaris plants, due to its reduced ability for acid resistance. This family is part of the ClC chloride channel superfamiy. These proteins catalyse the selective flow of Cl- ions across cell membranes and Cl-/H+ exchange transport. These proteins share two characteristics that are apparently inherent to the entire ClC chloride channel superfamily: a unique double-barreled architecture and voltage-dependent gating mechanism. The gating is conferred by the permeating anion itself, acting as the gating charge.бА0АкА0АаАCDDбАаАи&вА0А0АаАВ cd03683, ClC_1_like, ClC-1-like chloride channel proteins. This CD includes isoforms ClC-0, ClC-1, ClC-2 and ClC_K. ClC-1 is expressed in skeletal muscle and its mutation leads to both recessively and dominantly-inherited forms of muscle stiffness or myotonia. ClC-K is exclusively expressed in kidney. Similarly, mutation of ClC-K leads to nephrogenic diabetes insipidus in mice and Bartter's syndrome in human. These proteins belong to the ClC superfamily of chloride ion channels, which share the unique double-barreled architecture and voltage-dependent gating mechanism. The gating is conferred by the permeating anion itself, acting as the gating charge. This domain is found in the eukaryotic halogen ion (Cl-, Br- and I-) channel proteins, that perform a variety of functions including cell volume regulation, regulation of intracelluar chloride concentration, membrane potential stabilization, charge compensation necessary for the acidification of intracellular organelles and transepithelial chloride transport.бА0АкА0АаАCDDбАаАи'вА0А0АаАВ\cd03684, ClC_3_like, ClC-3-like chloride channel proteins. This CD includes ClC-3, ClC-4, ClC-5 and ClC-Y1. ClC-3 was initially cloned from rat kidney. Expression of ClC-3 produces outwardly-rectifying Cl currents that are inhibited by protein kinase C activation. It has been suggested that ClC-3 may be a ubiquitous swelling-activated Cl channel that has very similar characteristics to those of native volume-regulated Cl currents. The function of ClC-4 is unclear. Studies of human ClC-4 have revealed that it gives rise to Cl currents that rapidly activate at positive voltages, and are sensitive to extracellular pH, with currents decreasing when pH falls below 6.5. ClC-4 is broadly distributed, especially in brain and heart. ClC-5 is predominantly expressed in the kidney, but can be found in the brain and liver. Mutations in the ClC-5 gene cause certain hereditary diseases, including Dent's disease, an X-chromosome linked syndrome characterised by proteinuria, hypercalciuria, and kidney stones (nephrolithiasis), leading to progressive renal failure. These proteins belong to the ClC superfamily of chloride ion channels, which share the unique double-barreled architecture and voltage-dependent gating mechanism. The gating is conferred by the permeating anion itself, acting as the gating charge. This domain is found in the eukaryotic halogen ion (Cl- and I-) channel proteins, that perform a variety of functions including cell volume regulation, the membrane potential stabilization, transepithelial chloride transport and charge compensation necessary for the acidification of intracellular organelles.бА0АкА0АаАCDDбАаАи(вА0А0АаАВ cd03685, ClC_6_like, ClC-6-like chloride channel proteins. This CD includes ClC-6, ClC-7 and ClC-B, C, D in plants. Proteins in this family are ubiquitous in eukarotes and their functions are unclear. They are expressed in intracellular organelles membranes. This family belongs to the ClC superfamily of chloride ion channels, which share the unique double-barreled architecture and voltage-dependent gating mechanism. The gating is conferred by the permeating anion itself, acting as the gating charge. ClC chloride ion channel superfamily perform a variety of functions including cellular excitability regulation, cell volume regulation, membrane potential stabilization, acidification of intracellular organelles, signal transduction, and transepithelial transport in animals.бА0АкА0АаАCDDбАаАи)вА0А0АаАВ:cd03687, Dehydratase_LU, Dehydratase large subunit. This family contains the large (alpha) subunit of B12-dependent glycerol dehydratases (GDHs) and B12-dependent diol dehydratases (DDHs). GDH is isofunctional with DDH. These enzymes can each catalyze the conversion of 1,2-propanediol, glycerol, and 1,2-ethanediol to the corresponding aldehydes via a coenzyme B12 (adenosylcobalamin)-dependent radical mechanism. Both enzymes exhibit a subunit composition of alpha2beta2gamma2. The enzymes differ in substrate specificity; glycerol is the preferred substrate for GDH and 1,2-propanediol for DDH. GDH shows almost equal affinity for both (R) and (S)-isomers while DDH prefers the (S) isomer. GDH plays a key role in the dihydroxyacetone (DHA) pathway and DDH in the anaerobic degradation of 1,2-diols. The radical mechanism has been well studied for Klebsiella oxytoca DDH and involves binding of 1,2-propanediol to the enzyme to induce hemolytic cleavage of the Co-C5' bond of the coenzyme to form cob(II)alamin and the adenosyl radical. Hydrogen abstraction from the substrate follows producing a substrate generated radical and 5'-deoxyadenosine. Rearrangement to the product radical is then followed by abstraction of a hydrogen atom from 5'-deoxyadenosine to produce the hydrated propionaldehyde and regenerate the adenosyl radical. After the Co-C5' bond is reformed and the hydrated aldehyde dehydrated, the process is complete. GDH has a higher affinity for coenzyme B12 than DDH. Both GDH and DDH are activated by various monovalent cations with K+, NH4+, and Rb+ being the most effective. However, DDH differs from GDH in that it is partially active with Cs+ and Na+. In general, the alpha and beta subunits for both enzymes are on different chains. However, for a subset of the GDHs, alpha and beta subunits appear to be on a single chain.бА0АкА0АаАCDDбАаАи*вА0А0АаАВHcd03688, eIF2_gamma_II, Domain II of the gamma subunit of eukaryotic translation initiation factor 2. This subfamily represents domain II of the gamma subunit of eukaryotic translation initiation factor 2 (eIF2-gamma) found in eukaryota and archaea. eIF2 is a G protein that delivers the methionyl initiator tRNA to the small ribosomal subunit and releases it upon GTP hydrolysis after the recognition of the initiation codon. eIF2 is composed of three subunits, alpha, beta and gamma. Subunit gamma shows strongest conservation, and it confers both tRNA binding and GTP/GDP binding.бА0АкА0АаАCDDбАаА|вА0А0АаАВ┴cd03689, RF3_II, Domain II of bacterial Release Factor 3. This subfamily represents domain II of bacterial Release Factor 3 (RF3). Termination of protein synthesis by the ribosome requires two release factor (RF) classes. The class II RF3 is a GTPase that removes class I RFs (RF1 or RF2) from the ribosome after release of the nascent polypeptide. RF3 in the GDP state binds to the ribosomal class I RF complex, followed by an exchange of GDP for GTP and release of the class I RF. Sequence comparison of class II release factors with elongation factors shows that prokaryotic RF3 is more similar to EF-G whereas eukaryotic eRF3 is more similar to eEF1A, implying that their precise function may differ.бА0АкА0АаАCDDбАаА|вА0А0АаАВ6cd03690, Tet_II, Domain II of ribosomal protection proteins Tet(M) and Tet(O). This subfamily represents domain II of ribosomal protection proteins Tet(M) and Tet(O). This domain has homology to domain II of the elongation factors EF-G and EF-2. Tet(M) and Tet(O) catalyze the release of tetracycline (Tc) from the ribosome in a GTP-dependent manner thereby mediating Tc resistance. Tcs are broad-spectrum antibiotics. Typical Tcs bind to the ribosome and inhibit the elongation phase of protein synthesis, by inhibiting the occupation of site A by aminoacyl-tRNA.бА0АкА0АаАCDDбАаА|вА0А0АаАВОcd03691, BipA_TypA_II, Domain II of BipA. BipA (also called TypA) is a highly conserved protein with global regulatory properties in Escherichia coli. BipA is phosphorylated on a tyrosine residue under some cellular conditions. Mutants show altered regulation of some pathways. BipA functions as a translation factor that is required specifically for the expression of the transcriptional modulator Fis. BipA binds to ribosomes at a site that coincides with that of EF-G and has a GTPase activity that is sensitive to high GDP:GTP ratios and is stimulated by 70S ribosomes programmed with mRNA and aminoacylated tRNAs. The growth rate-dependent induction of BipA allows the efficient expression of Fis, thereby modulating a range of downstream processes, including DNA metabolism and type III secretion. The domain II of BipA shows similarity to the domain II of the elongation factors (EFs) EF-G and EF-Tu.бА0АкА0АаАCDDбАаА|вА0А0АаАВ;cd03692, mtIF2_IVc, C2 subdomain of domain IV in mitochondrial translation initiation factor 2. This model represents the C2 subdomain of domain IV of mitochondrial translation initiation factor 2 (mtIF2) which adopts a beta-barrel fold displaying a high degree of structural similarity with domain II of the translation elongation factor EF-Tu. The C-terminal part of mtIF2 contains the entire fMet-tRNAfmet binding site of IF-2 and is resistant to proteolysis. This C-terminal portion consists of two domains, IF2 C1 and IF2 C2. IF2 C2 has been shown to contain all molecular determinants necessary and sufficient for the recognition and binding of fMet-tRNAfMet. Like IF2 from certain prokaryotes such as Thermus thermophilus, mtIF2lacks domain II which is thought to be involved in binding of E.coli IF-2 to 30S subunits.бА0АкА0АаАCDDбАаА|вА0А0АаАВcd03693, EF1_alpha_II, Domain II of elongation factor 1-alpha. This family represents domain II of elongation factor 1-alpha (EF-1A) that is found in archaea and all eukaryotic lineages. EF-1A is very abundant in the cytosol, where it is involved in the GTP-dependent binding of aminoacyl-tRNAs to the A site of the ribosomes in the second step of translation from mRNAs to proteins. Both domain II of EF-1A and domain IV of IF2/eIF5B have been implicated in recognition of the 3'-ends of tRNA. More than 61% of eukaryotic elongation factor 1A (eEF-1A) in cells is estimated to be associated with actin cytoskeleton. The binding of eEF-1A to actin is a noncanonical function that may link two distinct cellular processes, cytoskeleton organization and gene expression.бА0АкА0АаАCDDбАаА|вА0А0АаАВ∙cd03694, GTPBP_II, Domain II of the GTPBP family of GTP binding proteins. This group includes proteins similar to GTPBP1 and GTPBP2. GTPBP1 is structurally related to elongation factor 1 alpha, a key component of the protein biosynthesis machinery. Immunohistochemical analyses on mouse tissues revealed that GTPBP1 is expressed in some neurons and smooth muscle cells of various organs as well as macrophages. Immunofluorescence analyses revealed that GTPBP1 is localized exclusively in cytoplasm and shows a diffuse granular network forming a gradient from the nucleus to the periphery of the cells in smooth muscle cell lines and macrophages. No significant difference was observed in the immune response to protein antigen between mutant mice and wild-type mice, suggesting normal function of antigen-presenting cells of the mutant mice. The absence of an eminent phenotype in GTPBP1-deficient mice may be due to functional compensation by GTPBP2, which is similar to GTPBP1 in structure and tissue distribution.бА0АкА0АаАCDDбАаА|вА0А0АаАВ╢cd03695, CysN_NodQ_II, Domain II of the large subunit of ATP sulfurylase. This subfamily represents domain II of the large subunit of ATP sulfurylase (ATPS): CysN or the N-terminal portion of NodQ, found mainly in proteobacteria and homologous to the domain II of EF-Tu. Escherichia coli ATPS consists of CysN and a smaller subunit CysD. ATPS produces adenosine-5'-phosphosulfate (APS) from ATP and sulfate, coupled with GTP hydrolysis. In the subsequent reaction, APS is phosphorylated by an APS kinase (CysC), to produce 3'-phosphoadenosine-5'-phosphosulfate (PAPS) for use in amino acid (aa) biosynthesis. The Rhizobiaceae group (alpha-proteobacteria) appears to carry out the same chemistry for the sulfation of a nodulation factor. In Rhizobium meliloti, the heterodimeric complex comprised of NodP and NodQ appears to possess both ATPS and APS kinase activities. The N and C termini of NodQ correspond to CysN and CysC, respectively. Other eubacteria, archaea, and eukaryotes use a different ATP sulfurylase, which shows no amino acid sequence similarity to CysN or NodQ. CysN and the N-terminal portion of NodQ show similarity to GTPases involved in translation, in particular, EF-Tu and EF-1alpha.бА0АкА0АаАCDDбАаА|вА0А0АаАВycd03696, SelB_II, Domain II of elongation factor SelB. This subfamily represents the domain of elongation factor SelB that is homologous to domain II of EF-Tu. SelB may function by replacing EF-Tu. In prokaryotes, the incorporation of selenocysteine as the 21st amino acid, encoded by TGA, requires several elements: SelC is the tRNA itself, SelD acts as a donor of reduced selenium, SelA modifies a serine residue on SelC into selenocysteine, and SelB is a selenocysteine-specific translation elongation factor. 3' or 5' non-coding elements of mRNA have been found as probable structures for directing selenocysteine incorporation.бА0АкА0АаАCDDбАаА| вА0А0АаАВcd03697, EFTU_II, Domain II of elongation factor Tu. Elongation factors Tu (EF-Tu) are three-domain GTPases with an essential function in the elongation phase of mRNA translation. The GTPase center of EF-Tu is in the N-terminal domain (domain I), also known as the catalytic or G-domain. The G-domain is composed of about 200 amino acid residues, arranged into a predominantly parallel six-stranded beta-sheet core surrounded by seven alpha helices. Non-catalytic domains II and III are beta-barrels of seven and six, respectively, antiparallel beta-strands that share an extended interface. Both non-catalytic domains are composed of about 100 amino acid residues. EF-Tu proteins exist in two principal conformations: a compact one, EF-Tu*GTP, with tight interfaces between all three domains and a high affinity for aminoacyl-tRNA; and an open one, EF-Tu*GDP, with essentially no G-domain-domain II interactions and a low affinity for aminoacyl-tRNA. EF-Tu has approximately a 100-fold higher affinity for GDP than for GTP.бА0АкА0АаАCDDбАаА| вА0А0АаАВёcd03698, eRF3_II_like, Domain II of the eukaryotic class II release factor-like proteins. This model represents the domain similar to domain II of the eukaryotic class II release factor (eRF3). In eukaryotes, translation termination is mediated by two interacting release factors, eRF1 and eRF3, which act as class I and II factors, respectively. eRF1 functions as an omnipotent release factor, decoding all three stop codons and triggering the release of the nascent peptide catalyzed by the ribosome. eRF3 is a GTPase, which enhances termination efficiency by stimulating eRF1 activity in a GTP-dependent manner. Sequence comparison of class II release factors with elongation factors shows that eRF3 is more similar to eEF-1alpha whereas prokaryote RF3 is more similar to EF-G, implying that their precise function may differ. Only eukaryote RF3s are found in this group. Saccharomyces cerevisiae eRF3 (Sup35p) is a translation termination factor which is divided into three regions N, M and a C-terminal eEF1a-like region essential for translation termination. Sup35NM is a non-pathogenic prion-like protein with the property of aggregating into polymer-like fibrils. This group also contains proteins similar to S. cerevisiae Hbs1, a G protein known to be important for efficient growth and protein synthesis under conditions of limiting translation initiation and to associate with Dom34. It has been speculated that yeast Hbs1 and Dom34 proteins may function as part of a complex with a role in gene expression.бА0АкА0АаАCDDбАаА|вА0А0АаАВ╒cd03699, EF4_II, Domain II of Elongation Factor 4 (EF4). Elongation factor 4 (EF4 or LepA) is a highly conserved guanosine triphosphatase found in bacteria and eukaryotic mitochondria and chloroplasts. EF4 functions as a translation factor, which promotes back-translocation of tRNAs on posttranslocational ribosome complexes and competes with elongation factor G for interaction with pretranslocational ribosomes, inhibiting the elongation phase of protein synthesis.бА0АкА0АаАCDDбАаА|вА0А0АаАВcd03700, EF2_snRNP_like_II, Domain II of elongation factor 2 and C-terminal domain of the spliceosomal human 116kD U5 small nuclear ribonucleoprotein (snRNP) protein. This subfamily represents domain II of elongation factor (EF) EF-2 found in eukaryotes and archaea, and the C-terminal portion of the spliceosomal human 116kD U5 small nuclear ribonucleoprotein (snRNP) protein (U5-116 kD) and its yeast counterpart Snu114p. During the process of peptide synthesis and tRNA site changes, the ribosome is moved along the mRNA a distance equal to one codon with the addition of each amino acid. This translocation step is catalyzed by EF-2_GTP, which is hydrolyzed to provide the required energy. Thus, this action releases the uncharged tRNA from the P site and transfers the newly formed peptidyl-tRNA from the A site to the P site. Yeast Snu114p is essential for cell viability and for splicing in vivo. U5-116 kD binds GTP. Experiments suggest that GTP binding and probably GTP hydrolysis is important for the function of U5-116 kD/Snu114p.бА0АкА0АаАCDDбАаА| вА0А0АаАВфcd03701, IF2_IF5B_II, Domain II of prokaryotic Initiation Factor 2 and archaeal and eukaryotic Initiation Factor 5. This family represents domain II of prokaryotic Initiation Factor 2 (IF2) and its archaeal and eukaryotic homologue aeIF5B. IF2, the largest initiation factor, is an essential GTP binding protein. In E. coli, three natural forms of IF2 exist in the cell, IF2alpha, IF2beta1, and IF2beta2. Disruption of the eIF5B gene (FUN12) in yeast causes a severe slow-growth phenotype, associated with a defect in translation. eIF5B has a function analogous to prokaryotic IF2 in mediating the joining of the 60S ribosomal subunit. The eIF5B consists of three N-terminal domains (I, II, II) connected by a long helix to domain IV. Domain I is a G domain, domain II and IV are beta-barrels and domain III has a novel alpha-beta-alpha sandwich fold. The G domain and the beta-barrel domain II display a similar structure and arrangement to the homologous domains in EF1A, eEF1A and aeIF2gamma.бА0АкА0АаАCDDбАаА|вА0А0АаАВ╧cd03702, IF2_mtIF2_II, Domain II of bacterial and mitochondrial Initiation Factor 2. This family represents domain II of bacterial Initiation Factor 2 (IF2) and its eukaryotic mitochondrial homolog mtIF2. IF2, the largest initiation factor, is an essential GTP binding protein. In E. coli, three natural forms of IF2 exist in the cell, IF2alpha, IF2beta1, and IF2beta2. Bacterial IF-2 is structurally and functionally related to eukaryotic mitochondrial mtIF-2.бА0АкА0АаАCDDбАаА|вА0А0АаАВ&cd03703, aeIF5B_II, Domain II of archaeal and eukaryotic Initiation Factor 5. This family represents domain II of archaeal and eukaryotic IF5B. aIF5B and eIF5B are homologs of prokaryotic Initiation Factor 2 (IF2). Disruption of the eIF5B gene (FUN12) in yeast causes a severe slow-growth phenotype, associated with a defect in translation. eIF5B has a function analogous to prokaryotic IF2 in mediating the joining of joining of 60S subunits. The eIF5B consists of three N-terminal domains (I, II, II) connected by a long helix to domain IV. Domain I is a G domain, domain II and IV are beta-barrels and domain III has a novel alpha-beta-alpha sandwich fold. The G domain and the beta-barrel domain II display a similar structure and arrangement to the homologous domains of EF1A, eEF1A and aeIF2gamma.бА0АкА0АаАCDDбАаА|вА0А0АаАВзcd03704, eRF3_C_III, C-terminal domain of eRF3. This model represents the eEF1alpha-like C-terminal region of eRF3, which is homologous to the domain III of EF-Tu. eRF3 is a GTPase which enhances termination efficiency by stimulating eRF1 activity in a GTP-dependent manner. The C-terminal region is responsible for translation termination activity and is essential for viability. Saccharomyces cerevisiae eRF3 (Sup35p) is a translation termination factor which is divided into three regions: N, M and a C-terminal eEF1a-like region essential for translation termination. Sup35NM is a non-pathogenic prion-like protein with the property of aggregating into polymer-like fibrils.бА0АкА0АаАCDDбАаА|sвА0А0АаАВ!cd03705, EF1_alpha_III, Domain III of Elongation Factor 1. Eukaryotic elongation factor 1 (EF-1) is responsible for the GTP-dependent binding of aminoacyl-tRNAs to ribosomes. EF-1 is composed of four subunits: the alpha chain, which binds GTP and aminoacyl-tRNAs; the gamma chain that probably plays a role in anchoring the complex to other cellular components; and the beta and delta (or beta') chains. This model represents the alpha subunit, which is the counterpart of bacterial EF-Tu for archaea (aEF-1 alpha) and eukaryotes (eEF-1 alpha).бА0АкА0АаАCDDбАаА|tвА0А0АаАВЗcd03706, mtEFTU_III, Domain III of mitochondrial EF-TU (mtEF-TU). mtEF-TU is highly conserved and is 55-60% identical to bacterial EF-TU. The overall structure is similar to that observed in the Escherichia coli and Thermus aquaticus EF-TU. However, compared with that observed in prokaryotic EF-TU, the nucleotide-binding domain (domain I) of mtEF-TU is in a different orientation relative to the rest of the structure. Furthermore, domain III is followed by a short 11-amino acid extension that forms one helical turn. This extension seems to be specific to the mitochondrial factors and has not been observed in any of the prokaryotic factors.бА0АкА0АаАCDDбАаА|uвА0А0АаАВcd03707, EFTU_III, Domain III of Elongation Factor (EF) Tu. EF-Tu consists of three structural domains, designated I, II, and III. Domain III adopts a beta barrel structure. Domain III is involved in binding to both charged tRNA and to elongation factor Ts (EF-Ts). EF-Ts is the guanine-nucleotide-exchange factor for EF-Tu. EF-Tu and EF-G participate in the elongation phase during protein biosynthesis on the ribosome. Their functional cycles depend on GTP binding and its hydrolysis. The EF-Tu complexed with GTP and aminoacyl-tRNA delivers tRNA to the ribosome, whereas EF-G stimulates translocation, a process in which tRNA and mRNA movements occur in the ribosome. Crystallographic studies revealed structural similarities ("molecular mimicry") between tertiary structures of EF-G and the EF-Tu-aminoacyl-tRNA ternary complex. Domains III, IV, and V of EF-G mimic the tRNA structure in the EF-Tu ternary complex; domains III, IV and V can be related to the acceptor stem, anticodon helix and T stem of tRNA respectively.бА0АкА0АаАCDDбАаА|vвА0А0АаАВЄcd03708, GTPBP_III, Domain III of the GP-1 family of GTPases. This family includes proteins similar to GTPBP1 and GTPBP2. GTPBP1 is structurally related to elongation factor 1 alpha, a key component of the protein biosynthesis machinery. Immunohistochemical analyses on mouse tissues revealed that GTPBP1 is expressed in some neurons and smooth muscle cells of various organs as well as macrophages. Immunofluorescence analyses revealed that GTPBP1 is localized exclusively in the cytoplasm and shows a diffuse granular network forming a gradient from the nucleus to the periphery of the cells in smooth muscle cell lines and macrophages. No significant difference was observed in the immune response to protein antigen between mutant mice and wild-type mice, suggesting normal function of antigen-presenting cells of the mutant mice. The absence of an eminent phenotype in GTPBP1-deficient mice may be due to functional compensation by GTPBP2, which is similar to GTPBP1 in structure and tissue distribution.бА0АкА0АаАCDDбАаА|wвА0А0АаАВЙcd03709, lepA_C, lepA_C: This family represents the C-terminal region of LepA, a GTP-binding protein localized in the cytoplasmic membrane. LepA is ubiquitous in Bacteria and Eukaryota (e.g. Saccharomyces cerevisiae GUF1p), but is missing from Archaea. LepA exhibits significant homology to elongation factors (EFs) Tu and G. The function(s) of the proteins in this family are unknown. The N-terminal domain of LepA is homologous to a domain of similar size found in initiation factor 2 (IF2), and in EF-Tu and EF-G (factors required for translation in Escherichia coli). Two types of phylogenetic tree, rooted by other GTP-binding proteins, suggest that eukaryotic homologs (including S. cerevisiae GUF1) originated within the bacterial LepA family. LepA has never been observed in archaea, and eukaryl LepA is organellar. LepA is therefore a true bacterial GTPase, found only in the bacterial lineage.бА0АкА0АаАCDDбАаАи@вА0А0АаАВэcd03710, BipA_TypA_C, BipA_TypA_C: a C-terminal portion of BipA or TypA having homology to the C terminal domains of the elongation factors EF-G and EF-2. A member of the ribosome binding GTPase superfamily, BipA is widely distributed in bacteria and plants. BipA is a highly conserved protein with global regulatory properties in Escherichia coli. BipA is phosphorylated on a tyrosine residue under some cellular conditions. Mutants show altered regulation of some pathways. BipA functions as a translation factor that is required specifically for the expression of the transcriptional modulator Fis. BipA binds to ribosomes at a site that coincides with that of EF-G and has a GTPase activity that is sensitive to high GDP:GTP ratios and, is stimulated by 70S ribosomes programmed with mRNA and aminoacylated tRNAs. The growth rate-dependent induction of BipA allows the efficient expression of Fis, thereby modulating a range of downstream processes, including DNA metabolism and type III secretion.бА0АкА0АаАCDDбАаАиAвА0А0АаАВєcd03711, Tet_C, Tet_C: C-terminus of ribosomal protection proteins Tet(M) and Tet(O). This domain has homology to the C terminal domains of the elongation factors EF-G and EF-2. Tet(M) and Tet(O) catalyze the release of tetracycline (Tc) from the ribosome in a GTP-dependent manner thereby mediating Tc resistance. Tcs are broad-spectrum antibiotics. Typical Tcs bind to the ribosome and inhibit the elongation phase of protein synthesis, by inhibiting the occupation of site A by aminoacyl-tRNA.бА0АкА0АаАCDDбАаАиBвА0А0АаАВоcd03713, EFG_mtEFG_C, EFG_mtEFG_C: domains similar to the C-terminal domain of the bacterial translational elongation factor (EF) EF-G. Included in this group is the C-terminus of mitochondrial Elongation factor G1 (mtEFG1) and G2 (mtEFG2) proteins. Eukaryotic cells harbor 2 protein synthesis systems: one localized in the cytoplasm, the other in the mitochondria. Most factors regulating mitochondrial protein synthesis are encoded by nuclear genes, translated in the cytoplasm, and then transported to the mitochondria. The eukaryotic system of elongation factor (EF) components is more complex than that in prokaryotes, with both cytoplasmic and mitochondrial elongation factors and multiple isoforms being expressed in certain species. During the process of peptide synthesis and tRNA site changes, the ribosome is moved along the mRNA a distance equal to one codon with the addition of each amino acid. In bacteria this translocation step is catalyzed by EF-G_GTP, which is hydrolyzed to provide the required energy. Thus, this action releases the uncharged tRNA from the P site and transfers the newly formed peptidyl-tRNA from the A site to the P site. Eukaryotic mtEFG1 proteins show significant homology to bacterial EF-Gs. Mutants in yeast mtEFG1 have impaired mitochondrial protein synthesis, respiratory defects and a tendency to lose mitochondrial DNA. No clear phenotype has been found for mutants in the yeast homologue of mtEFG2, MEF2.бА0АкА0АаАCDDбАаАиCвА0А0АаАВcd03714, RT_DIRS1, RT_DIRS1: Reverse transcriptases (RTs) occurring in the DIRS1 group of retransposons. Members of the subfamily include the Dictyostelium DIRS-1, Volvox carteri kangaroo, and Panagrellus redivivus PAT elements. These elements differ from LTR and conventional non-LTR retrotransposons. They contain split direct repeat (SDR) termini, and have been proposed to integrate via double-stranded closed-circle DNA intermediates assisted by an encoded recombinase which is similar to gamma-site-specific integrase.бА0АкА0АаАCDDбАаАиDвА0А0АаАВбcd03715, RT_ZFREV_like, RT_ZFREV_like: A subfamily of reverse transcriptases (RTs) found in sequences similar to the intact endogenous retrovirus ZFERV from zebrafish and to Moloney murine leukemia virus RT. An RT gene is usually indicative of a mobile element such as a retrotransposon or retrovirus. RTs occur in a variety of mobile elements, including retrotransposons, retroviruses, group II introns, bacterial msDNAs, hepadnaviruses, and caulimoviruses. These elements can be divided into two major groups. One group contains retroviruses and DNA viruses whose propagation involves an RNA intermediate. They are grouped together with transposable elements containing long terminal repeats (LTRs). The other group, also called poly(A)-type retrotransposons, contain fungal mitochondrial introns and transposable elements that lack LTRs. Phylogenetic analysis suggests that ZFERV belongs to a distinct group of retroviruses.бА0АкА0АаАCDDбАаАиEвА0А0АаАВШcd03716, SOCS_ASB_like, SOCS (suppressors of cytokine signaling) box of ASB (ankyrin repeat and SOCS box) and SSB (SPRY domain-containing SOCS box proteins) protein families. ASB family members have a C-terminal SOCS box and an N-terminal ankyrin-related sequence of a variable number of repeats. SSB proteins contain a central SPRY domain and a C-terminal SOCS. Recently, it has been shown that all four SSB proteins interact with the MET, the receptor protein-tyrosine kinase for hepatocyte growth factor (HGF), and that SSB-1, SSB-2, and SSB-4 interact with prostate apoptosis response protein-4. Both types of interactions are mediated through the SPRY domain.бА0АкА0АаАCDDбАаАиFвА0А0АаАВкcd03717, SOCS_SOCS_like, SOCS (suppressors of cytokine signaling) box of SOCS-like proteins. The CIS/SOCS family of proteins is characterized by the presence of a C-terminal SOCS box and a central SH2 domain. These intracellular proteins regulate the responses of immune cells to cytokines. Identified as negative regulators of the cytokine-JAK-STAT pathway, they seem to play a role in many immunological and pathological processes. The function of the SOCS box is the recruitment of the ubiquitin-transferase system. Related SOCS boxes are also present in Rab40-like proteins and insect proteins of unknown function that also contain a NEUZ (domain in neuralized proteins) domain.бА0АкА0АаАCDDбАаАиGвА0А0АаАВcd03718, SOCS_SSB1_4, SOCS (suppressors of cytokine signaling) box of SSB1 and SSB4 (SPRY domain-containing SOCS box proteins)-like proteins. SSB proteins contain a central SPRY domain and a C-terminal SOCS. SSB1 and SSB4 has been shown to bind to MET, the receptor protein-tyrosine kinase for hepatocyte growth factor (HGF) and also interacts with prostate apoptosis response protein-4. Both types of interactions are mediated through the SPRY domain. The general function of the SOCS box is the recruitment of the ubiquitin-transferase system. The SOCS box interacts with Elongins B and C, Cullin-5 or Cullin-2, Rbx-1, and E2. Therefore, SOCS-box-containing proteins probably function as E3 ubiquitin ligases and mediate the degradation of proteins associated through their N-terminal regions.бА0АкА0АаАCDDбАаАиHвА0А0АаАВcd03719, SOCS_SSB2, SOCS (suppressors of cytokine signaling) box of SSB2 (SPRY domain-containing SOCS box proteins)-like proteins. SSB proteins contain a central SPRY domain and a C-terminal SOCS. SSB2 has been shown to bind to MET, the receptor protein-tyrosine kinase for hepatocyte growth factor (HGF). SSB2, like SSB4 and SSB1, also interacts with prostate apoptosis response protein-4. Both types of interactions are mediated through the SPRY domain. The general function of the SOCS box is the recruitment of the ubiquitin-transferase system. The SOCS box interacts with Elongins B and C, Cullin-5 or Cullin-2, Rbx-1, and E2. Therefore, SOCS-box-containing proteins probably function as E3 ubiquitin ligases and mediate the degradation of proteins associated through their N-terminal regions.бА0АкА0АаАCDDбАаАиIвА0А0АаАВcd03720, SOCS_ASB1, SOCS (suppressors of cytokine signaling) box of ASB1-like proteins. ASB family members have a C-terminal SOCS box and an N-terminal ankyrin-related sequence. The general function of the SOCS box is the recruitment of the ubiquitin-transferase system. The SOCS box interacts with Elongins B and C, Cullin-5 or Cullin-2, Rbx-1, and E2. Therefore, SOCS-box-containing proteins probably function as E3 ubiquitin ligases and mediate the degradation of proteins associated through their N-terminal regions.бА0АкА0АаАCDDбАаАиJвА0А0АаАВГcd03721, SOCS_ASB2, SOCS (suppressors of cytokine signaling) box of ASB2-like proteins. ASB family members have a C-terminal SOCS box and an N-terminal ankyrin-related sequence. ASB2 targets specific proteins to destruction by the proteasome in leukemia cells that have been induced to differentiate. The general function of the SOCS box is the recruitment of the ubiquitin-transferase system. The SOCS box interacts with Elongins B and C, Cullin-5 or Cullin-2, Rbx-1, and E2. Therefore, SOCS-box-containing proteins probably function as E3 ubiquitin ligases and mediate the degradation of proteins associated through their N-terminal regions.бА0АкА0АаАCDDбАаАиKвА0А0АаАВтcd03722, SOCS_ASB3, SOCS (suppressors of cytokine signaling) box of ASB3-like proteins. ASB family members have a C-terminal SOCS box and an N-terminal ankyrin-related sequence. ABS3 has been shown to be negative regulator of TNF-R2-mediated cellular responses to TNF-alpha by direct targeting of tumor necrosis factor receptor II (TNF-R2) for ubiquitination and proteasome-mediated degradation. The general function of the SOCS box is the recruitment of the ubiquitin-transferase system. The SOCS box interacts with Elongins B and C, Cullin-5 or Cullin-2, Rbx-1, and E2. Therefore, SOCS-box-containing proteins probably function as E3 ubiquitin ligases and mediate the degradation of proteins associated through their N-terminal regions.бА0АкА0АаАCDDбАаАиLвА0А0АаАВBcd03723, SOCS_ASB4_ASB18, SOCS (suppressors of cytokine signaling) box of ASB4 and ASB18 proteins. ASB family members have a C-terminal SOCS box and an N-terminal ankyrin-related sequence. Asb4 was identified as imprinted gene in mice. The general function of the SOCS box is the recruitment of the ubiquitin-transferase system. The SOCS box interacts with Elongins B and C, Cullin-5 or Cullin-2, Rbx-1, and E2. Therefore, SOCS-box-containing proteins probably function as E3 ubiquitin ligases and mediate the degradation of proteins associated through their N-terminal regions.бА0АкА0АаАCDDбАаАиMвА0А0АаАВFcd03724, SOCS_ASB5, SOCS (suppressors of cytokine signaling) box of ASB5-like proteins. ASB family members have a C-terminal SOCS box and an N-terminal ankyrin-related sequence. ASB5 has been implicated in the initiation of arteriogenesis. The general function of the SOCS box is the recruitment of the ubiquitin-transferase system. The SOCS box interacts with Elongins B and C, Cullin-5 or Cullin-2, Rbx-1, and E2. Therefore, SOCS-box-containing proteins probably function as E3 ubiquitin ligases and mediate the degradation of proteins associated through their N-terminal regions.бА0АкА0АаАCDDбАаАиNвА0А0АаАВxcd03725, SOCS_ASB6, SOCS (suppressors of cytokine signaling) box of ASB6-like proteins. ASB family members have a C-terminal SOCS box and an N-terminal ankyrin-related sequence. ASB6 interacts with the adaptor protein APS and recruits elongin B/C to the insulin receptor signaling complex. The general function of the SOCS box is the recruitment of the ubiquitin-transferase system. The SOCS box interacts with Elongins B and C, Cullin-5 or Cullin-2, Rbx-1, and E2. Therefore, SOCS-box-containing proteins probably function as E3 ubiquitin ligases and mediate the degradation of proteins associated through their N-terminal regions.бА0АкА0АаАCDDбАаАиOвА0А0АаАВcd03726, SOCS_ASB7, SOCS (suppressors of cytokine signaling) box of ASB7-like proteins. ASB family members have a C-terminal SOCS box and an N-terminal ankyrin-related sequence. The general function of the SOCS box is the recruitment of the ubiquitin-transferase system. The SOCS box interacts with Elongins B and C, Cullin-5 or Cullin-2, Rbx-1, and E2. Therefore, SOCS-box-containing proteins probably function as E3 ubiquitin ligases and mediate the degradation of proteins associated through their N-terminal regions.бА0АкА0АаАCDDбАаАиPвА0А0АаАВ^cd03727, SOCS_ASB8, SOCS (suppressors of cytokine signaling) box of ASB8-like proteins. ASB family members have a C-terminal SOCS box and an N-terminal ankyrin-related sequence. Human ASB8 is highly transcribed in skeletal muscle and in lung carcinoma cell lines. The general function of the SOCS box is the recruitment of the ubiquitin-transferase system. The SOCS box interacts with Elongins B and C, Cullin-5 or Cullin-2, Rbx-1, and E2. Therefore, SOCS-box-containing proteins probably function as E3 ubiquitin ligases and mediate the degradation of proteins associated through their N-terminal regions.бА0АкА0АаАCDDбАаАиQвА0А0АаАВcd03728, SOCS_ASB_9_11, SOCS (suppressors of cytokine signaling) box of ASB9 and 11 proteins. ASB family members have a C-terminal SOCS box and an N-terminal ankyrin-related sequence. The general function of the SOCS box is the recruitment of the ubiquitin-transferase system. The SOCS box interacts with Elongins B and C, Cullin-5 or Cullin-2, Rbx-1, and E2. Therefore, SOCS-box-containing proteins probably function as E3 ubiquitin ligases and mediate the degradation of proteins associated through their N-terminal regions.бА0АкА0АаАCDDбАаАиRвА0А0АаАВ cd03729, SOCS_ASB13, SOCS (suppressors of cytokine signaling) box of ASB13-like proteins. ASB family members have a C-terminal SOCS box and an N-terminal ankyrin-related sequence. The general function of the SOCS box is the recruitment of the ubiquitin-transferase system. The SOCS box interacts with Elongins B and C, Cullin-5 or Cullin-2, Rbx-1, and E2. Therefore, SOCS-box-containing proteins probably function as E3 ubiquitin ligases and mediate the degradation of proteins associated through their N-terminal regions.бА0АкА0АаАCDDбАаАиSвА0А0АаАВ cd03730, SOCS_ASB14, SOCS (suppressors of cytokine signaling) box of ASB14-like proteins. ASB family members have a C-terminal SOCS box and an N-terminal ankyrin-related sequence. The general function of the SOCS box is the recruitment of the ubiquitin-transferase system. The SOCS box interacts with Elongins B and C, Cullin-5 or Cullin-2, Rbx-1, and E2. Therefore, SOCS-box-containing proteins probably function as E3 ubiquitin ligases and mediate the degradation of proteins associated through their N-terminal regions.бА0АкА0АаАCDDбАаАиTвА0А0АаАВшcd03731, SOCS_ASB15, SOCS (suppressors of cytokine signaling) box of ASB15-like proteins. ASB family members have a C-terminal SOCS box and an N-terminal ankyrin-related sequence. Human ASB15 is expressed predominantly in skeletal muscle and participates in the regulation of protein turnover and muscle cell development by stimulating protein synthesis and regulating differentiation of muscle cells. The general function of the SOCS box is the recruitment of the ubiquitin-transferase system. The SOCS box interacts with Elongins B and C, Cullin-5 or Cullin-2, Rbx-1, and E2. Therefore, SOCS-box-containing proteins probably function as E3 ubiquitin ligases and mediate the degradation of proteins associated through their N-terminal regions.бА0АкА0АаАCDDбАаАиUвА0А0АаАВ6cd03733, SOCS_WSB_SWIP, SOCS (suppressors of cytokine signaling) box of WSB/SWiP-like proteins. This subfamily contains WSB-1 (SOCS-box-containing WD-40 protein), part of an E3 ubiquitin ligase for the thyroid-hormone-activating type 2 iodothyronine deiodinase (D2), and SWiP-1 (SOCS box and WD-repeats in Protein), a WD40-containing protein that is expressed in embryonic structures of chickens and regulated by Sonic Hedgehog (Shh), as well as, their isoforms WSB-2 and SWiP-2. The general function of the SOCS box is the recruitment of the ubiquitin-transferase system. The SOCS box interacts with Elongins B and C, Cullin-5 or Cullin-2, Rbx-1, and E2. Therefore, SOCS-box-containing proteins probably function as E3 ubiquitin ligases and mediate the degradation of proteins associated through their N-terminal regions.бА0АкА0АаАCDDбАаАиVвА0А0АаАВ!cd03734, SOCS_CIS1, SOCS (suppressors of cytokine signaling) box of CIS (cytokine-inducible SH2 protein) 1-like proteins. Together with the SOCS proteins, the CIS/SOCS family of proteins is characterized by the presence of a C-terminal SOCS box and a central SH2 domain. CIS1, like SOCS1 and SOCS3, is involved in the down-regulation of the JAK/STAT pathway. CIS1 binds to cytokine receptors at STAT5-docking sites, which prohibits recruitment of STAT5 to the receptor signaling complex and results in the down-regulation of activation by STAT5.бА0АкА0АаАCDDбАаАиWвА0А0АаАВьcd03735, SOCS_SOCS1, SOCS (suppressors of cytokine signaling) box of SOCS1-like proteins. Together with CIS1, the CIS/SOCS family of proteins is characterized by the presence of a C-terminal SOCS box and a central SH2 domain. SOCS1, like CIS1 and SOCS3, is involved in the down-regulation of the JAK/STAT pathway. SOCS1 has a dual function as a direct potent JAK kinase inhibitor and as a component of an E3 ubiquitin-ligase complex recruiting substrates to the protein degradation machinery.бА0АкА0АаАCDDбАаАиXвА0А0АаАВcd03736, SOCS_SOCS2, SOCS (suppressors of cytokine signaling) box of SOCS2-like proteins. Together with CIS1, the CIS/SOCS family of proteins is characterized by the presence of a C-terminal SOCS box and a central SH2 domain. SOCS2 has recently been shown to regulate neuronal differentiation by controlling expression of a neurogenic transcription factor, Neurogenin-1. SOCS2 binds to GH receptors and inhibits the activation of STAT5b induced by GH. The general function of the SOCS box is the recruitment of the ubiquitin-transferase system. The SOCS box interacts with Elongins B and C, Cullin-5 or Cullin-2, Rbx-1, and E2. Therefore, SOCS-box-containing proteins probably function as E3 ubiquitin ligases and mediate the degradation of proteins associated through their N-terminal regions.бА0АкА0АаАCDDбАаАиYвА0А0АаАВ_cd03737, SOCS_SOCS3, SOCS (suppressors of cytokine signaling) box of SOCS3-like proteins. Together with CIS1, the CIS/SOCS family of proteins is characterized by the presence of a C-terminal SOCS box and a central SH2 domain. SOCS3, like CIS1 and SOCS1, is involved in the down-regulation of the JAK/STAT pathway. SOCS3 inhibits JAK activity indirectly through recruitment to the cytokine receptors. SOCS3 has been shown to play an essential role in placental development and a non-essential role in embryo development. The general function of the SOCS box is the recruitment of the ubiquitin-transferase system. The SOCS box interacts with Elongins B and C, Cullin-5 or Cullin-2, Rbx-1, and E2. Therefore, SOCS-box-containing proteins probably function as E3 ubiquitin ligases and mediate the degradation of proteins associated through their N-terminal regions.бА0АкА0АаАCDDбАаАиZвА0А0АаАВ8cd03738, SOCS_SOCS4, SOCS (suppressors of cytokine signaling) box of SOCS4-like proteins. Together with CIS1, the CIS/SOCS family of proteins is characterized by the presence of a C-terminal SOCS box and a central SH2 domain. The general function of the SOCS box is the recruitment of the ubiquitin-transferase system. The SOCS box interacts with Elongins B and C, Cullin-5 or Cullin-2, Rbx-1, and E2. Therefore, SOCS-box-containing proteins probably function as E3 ubiquitin ligases and mediate the degradation of proteins associated through their N-terminal regions.бА0АкА0АаАCDDбАаАи[вА0А0АаАВ{cd03739, SOCS_SOCS5, SOCS (suppressors of cytokine signaling) box of SOCS5-like proteins. Together with CIS1, the CIS/SOCS family of proteins is characterized by the presence of a C-terminal SOCS box and a central SH2 domain. SOCS5 inhibits Th2 differentiation by inhibiting IL-4 signaling. The general function of the SOCS box is the recruitment of the ubiquitin-transferase system. The SOCS box interacts with Elongins B and C, Cullin-5 or Cullin-2, Rbx-1, and E2. Therefore, SOCS-box-containing proteins probably function as E3 ubiquitin ligases and mediate the degradation of proteins associated through their N-terminal regions.бА0АкА0АаАCDDбАаАи\вА0А0АаАВ8cd03740, SOCS_SOCS6, SOCS (suppressors of cytokine signaling) box of SOCS6-like proteins. Together with CIS1, the CIS/SOCS family of proteins is characterized by the presence of a C-terminal SOCS box and a central SH2 domain. The general function of the SOCS box is the recruitment of the ubiquitin-transferase system. The SOCS box interacts with Elongins B and C, Cullin-5 or Cullin-2, Rbx-1, and E2. Therefore, SOCS-box-containing proteins probably function as E3 ubiquitin ligases and mediate the degradation of proteins associated through their N-terminal regions.бА0АкА0АаАCDDбАаАи]вА0А0АаАВqcd03741, SOCS_SOCS7, SOCS (suppressors of cytokine signaling) box of SOCS7-like proteins. Together with CIS1, the CIS/SOCS family of proteins is characterized by the presence of a C-terminal SOCS box and a central SH2 domain. SOCS7 is important in the functioning of neuronal cells. The general function of the SOCS box is the recruitment of the ubiquitin-transferase system. The SOCS box interacts with Elongins B and C, Cullin-5 or Cullin-2, Rbx-1, and E2. Therefore, SOCS-box-containing proteins probably function as E3 ubiquitin ligases and mediate the degradation of proteins associated through their N-terminal regions.бА0АкА0АаАCDDбАаАи^вА0А0АаАВ{cd03742, SOCS_Rab40, SOCS (suppressors of cytokine signaling) box of Rab40-like proteins. Rab40 is part of the Rab family of small GTP-binding proteins that form the largest family within the Ras superfamily. Rab proteins regulate vesicular trafficking pathways, behaving as membrane-associated molecular switches. Rab40 is characterized by a SOCS box c-terminal to the GTPase domain. The SOCS boxes interact with Elongins B and C, Cullin-5 or Cullin-2, Rbx-1, and E2. Therefore, SOCS-box-containing proteins probably function as E3 ubiquitin ligases and mediate the degradation of proteins associated through their N-terminal regions.бА0АкА0АаАCDDбАаАи_вА0А0АаАВcd03743, SOCS_SSB4, SOCS (suppressors of cytokine signaling) box of SSB4 (SPRY domain-containing SOCS box proteins)-like proteins. SSB proteins contain a central SPRY domain and a C-terminal SOCS. SSB4 has been shown to bind to MET, the receptor protein-tyrosine kinase for hepatocyte growth factor (HGF). SSB4, like SSB2 and SSB1, also interacts with prostate apoptosis response protein-4. Both types of interactions are mediated through the SPRY domain. The general function of the SOCS box is the recruitment of the ubiquitin-transferase system. The SOCS box interacts with Elongins B and C, Cullin-5 or Cullin-2, Rbx-1, and E2. Therefore, SOCS-box-containing proteins probably function as E3 ubiquitin ligases and mediate the degradation of proteins associated through their N-terminal regions.бА0АкА0АаАCDDбАаАи`вА0А0АаАВ╨cd03744, SOCS_SSB1, SOCS (suppressors of cytokine signaling) box of SSB1 (SPRY domain-containing SOCS box proteins)-like proteins. SSB proteins contain a central SPRY domain and a C-terminal SOCS. SSB1 has been shown to bind to MET, the receptor protein-tyrosine kinase for hepatocyte growth factor (HGF), both the absence and the presence of HGF and enhances the HGF-MET-induced mitogen-activated protein kinases Erk-transcription factor Elk-1-serum response elements (SRE) pathway. SSB1, like SSB2 and SSB4, also interacts with prostate apoptosis response protein-4. Both types of interactions are mediated through the SPRY domain. The general function of the SOCS box is the recruitment of the ubiquitin-transferase system. The SOCS box interacts with Elongins B and C, Cullin-5 or Cullin-2, Rbx-1, and E2. Therefore, SOCS-box-containing proteins probably function as E3 ubiquitin ligases and mediate the degradation of proteins associated through their N-terminal regions.бА0АкА0АаАCDDбАаАиaвА0А0АаАВ▒cd03745, SOCS_WSB2_SWIP2, SOCS (suppressors of cytokine signaling) box of WSB2/SWiP2-like proteins. This family consists of WSB-2 (SOCS-box-containing WD-40 protein) and SWiP-2 (SOCS box and WD-repeats in Protein). No functional information is available for WSB2 or SWiP-2, but limited information is available for the isoforms WSB-1 and SWiP-1. The general function of the SOCS box is the recruitment of the ubiquitin-transferase system. The SOCS box interacts with Elongins B and C, Cullin-5 or Cullin-2, Rbx-1, and E2. Therefore, SOCS-box-containing proteins probably function as E3 ubiquitin ligases and mediate the degradation of proteins associated through their N-terminal regions.бА0АкА0АаАCDDбАаАиbвА0А0АаАВcd03746, SOCS_WSB1_SWIP1, SOCS (suppressors of cytokine signaling) box of WSB1/SWiP1-like proteins. This subfamily contains WSB-1 (SOCS-box-containing WD-40 protein), part of an E3 ubiquitin ligase for the thyroid-hormone-activating type 2 iodothyronine deiodinase (D2) and SWiP-1 (SOCS box and WD-repeats in Protein), a WD40-containing protein that is expressed in embryonic structures of chickens and regulated by Sonic Hedgehog (Shh). The general function of the SOCS box is the recruitment of the ubiquitin-transferase system. The SOCS box interacts with Elongins B and C, Cullin-5 or Cullin-2, Rbx-1, and E2. Therefore, SOCS-box-containing proteins probably function as E3 ubiquitin ligases and mediate the degradation of proteins associated through their N-terminal regions.бА0АкА0АаАCDDбАаАиcвА0А0АаАВ;cd03747, Ntn_PGA_like, Penicillin G acylase (PGA) belongs to a family of beta-lactam acylases that includes cephalosporin acylase (CA) and aculeacin A acylase. PGA and CA are crucial for the production of backbone chemicals like 6-aminopenicillanic acid and 7-aminocephalosporanic acid (7-ACA), which can be used to synthesize semi-synthetic penicillins and cephalosporins, respectively. While both PGA and CA have a conserved Ntn (N-terminal nucleophile) hydrolase fold and the structural similarity at their active sites is very high, their sequence similarity is low.бА0АкА0АаАCDDбАаАиdвА0А0АаАВ┐cd03748, Ntn_PGA, Penicillin G acylase (PGA) is the key enzyme in the industrial production of beta-lactam antibiotics. PGA hydrolyzes the side chain of penicillin G and related beta-lactam antibiotics releasing 6-amino penicillanic acid (6-APA), a building block in the production of semisynthetic penicillins. PGA is widely distributed among microorganisms, including bacteria, yeast and filamentous fungi but it's in vivo role remains unclear.бА0АкА0АаАCDDбАаАиeвА0А0АаАВЪcd03749, proteasome_alpha_type_1, proteasome_alpha_type_1. The 20S proteasome, multisubunit proteolytic complex, is the central enzyme of nonlysosomal protein degradation in both the cytosol and nucleus. It is composed of 28 subunits arranged as four homoheptameric rings that stack on top of one another forming an elongated alpha-beta-beta-alpha cylinder with a central cavity. The proteasome alpha and beta subunits are members of the N-terminal nucleophile (Ntn)-hydrolase superfamily. Their N-terminal threonine residues are exposed as a nucleophile in peptide bond hydrolysis. Mammals have 7 alpha and 7 beta proteasome subunits while archaea have one of each.бА0АкА0АаАCDDбАаАиfвА0А0АаАВЪcd03750, proteasome_alpha_type_2, proteasome_alpha_type_2. The 20S proteasome, multisubunit proteolytic complex, is the central enzyme of nonlysosomal protein degradation in both the cytosol and nucleus. It is composed of 28 subunits arranged as four homoheptameric rings that stack on top of one another forming an elongated alpha-beta-beta-alpha cylinder with a central cavity. The proteasome alpha and beta subunits are members of the N-terminal nucleophile (Ntn)-hydrolase superfamily. Their N-terminal threonine residues are exposed as a nucleophile in peptide bond hydrolysis. Mammals have 7 alpha and 7 beta proteasome subunits while archaea have one of each.бА0АкА0АаАCDDбАаАиgвА0А0АаАВЪcd03751, proteasome_alpha_type_3, proteasome_alpha_type_3. The 20S proteasome, multisubunit proteolytic complex, is the central enzyme of nonlysosomal protein degradation in both the cytosol and nucleus. It is composed of 28 subunits arranged as four homoheptameric rings that stack on top of one another forming an elongated alpha-beta-beta-alpha cylinder with a central cavity. The proteasome alpha and beta subunits are members of the N-terminal nucleophile (Ntn)-hydrolase superfamily. Their N-terminal threonine residues are exposed as a nucleophile in peptide bond hydrolysis. Mammals have 7 alpha and 7 beta proteasome subunits while archaea have one of each.бА0АкА0АаАCDDбАаАиhвА0А0АаАВЪcd03752, proteasome_alpha_type_4, proteasome_alpha_type_4. The 20S proteasome, multisubunit proteolytic complex, is the central enzyme of nonlysosomal protein degradation in both the cytosol and nucleus. It is composed of 28 subunits arranged as four homoheptameric rings that stack on top of one another forming an elongated alpha-beta-beta-alpha cylinder with a central cavity. The proteasome alpha and beta subunits are members of the N-terminal nucleophile (Ntn)-hydrolase superfamily. Their N-terminal threonine residues are exposed as a nucleophile in peptide bond hydrolysis. Mammals have 7 alpha and 7 beta proteasome subunits while archaea have one of each.бА0АкА0АаАCDDбАаАиiвА0А0АаАВЪcd03753, proteasome_alpha_type_5, proteasome_alpha_type_5. The 20S proteasome, multisubunit proteolytic complex, is the central enzyme of nonlysosomal protein degradation in both the cytosol and nucleus. It is composed of 28 subunits arranged as four homoheptameric rings that stack on top of one another forming an elongated alpha-beta-beta-alpha cylinder with a central cavity. The proteasome alpha and beta subunits are members of the N-terminal nucleophile (Ntn)-hydrolase superfamily. Their N-terminal threonine residues are exposed as a nucleophile in peptide bond hydrolysis. Mammals have 7 alpha and 7 beta proteasome subunits while archaea have one of each.бА0АкА0АаАCDDбАаАиjвА0А0АаАВЪcd03754, proteasome_alpha_type_6, proteasome_alpha_type_6. The 20S proteasome, multisubunit proteolytic complex, is the central enzyme of nonlysosomal protein degradation in both the cytosol and nucleus. It is composed of 28 subunits arranged as four homoheptameric rings that stack on top of one another forming an elongated alpha-beta-beta-alpha cylinder with a central cavity. The proteasome alpha and beta subunits are members of the N-terminal nucleophile (Ntn)-hydrolase superfamily. Their N-terminal threonine residues are exposed as a nucleophile in peptide bond hydrolysis. Mammals have 7 alpha and 7 beta proteasome subunits while archaea have one of each.бА0АкА0АаАCDDбАаАиkвА0А0АаАВЪcd03755, proteasome_alpha_type_7, proteasome_alpha_type_7. The 20S proteasome, multisubunit proteolytic complex, is the central enzyme of nonlysosomal protein degradation in both the cytosol and nucleus. It is composed of 28 subunits arranged as four homoheptameric rings that stack on top of one another forming an elongated alpha-beta-beta-alpha cylinder with a central cavity. The proteasome alpha and beta subunits are members of the N-terminal nucleophile (Ntn)-hydrolase superfamily. Their N-terminal threonine residues are exposed as a nucleophile in peptide bond hydrolysis. Mammals have 7 alpha and 7 beta proteasome subunits while archaea have one of each.бА0АкА0АаАCDDбАаАиlвА0А0АаАВЬcd03756, proteasome_alpha_archeal, proteasome_alpha_archeal. The 20S proteasome, multisubunit proteolytic complex, is the central enzyme of nonlysosomal protein degradation in both the cytosol and nucleus. It is composed of 28 subunits arranged as four homoheptameric rings that stack on top of one another forming an elongated alpha-beta-beta-alpha cylinder with a central cavity. The proteasome alpha and beta subunits are members of the N-terminal nucleophile (Ntn)-hydrolase superfamily. Their N-terminal threonine residues are exposed as a nucleophile in peptide bond hydrolysis. Mammals have 7 alpha and 7 beta proteasome subunits while archaea have one of each.бА0АкА0АаАCDDбАаАиmвА0А0АаАВаcd03757, proteasome_beta_type_1, proteasome beta type-1 subunit. The 20S proteasome, multisubunit proteolytic complex, is the central enzyme of nonlysosomal protein degradation in both the cytosol and nucleus. It is composed of 28 subunits arranged as four homoheptameric rings that stack on top of one another forming an elongated alpha-beta-beta-alpha cylinder with a central cavity. The proteasome alpha and beta subunits are members of the N-terminal nucleophile (Ntn)-hydrolase superfamily. Their N-terminal threonine residues are exposed as a nucleophile in peptide bond hydrolysis. Mammals have 7 alpha and 7 beta proteasome subunits while archaea have one of each.бА0АкА0АаАCDDбАаАиnвА0А0АаАВЯcd03758, proteasome_beta_type_2, proteasome beta type-2 subunit. The 20S proteasome, multisubunit proteolytic complex, is the central enzyme of nonlysosomal protein degradation in both the cytosol and nucleus. It is composed of 28 subunits arranged as four homoheptameric rings that stack on top of one another forming an elongated alpha-beta-beta-alpha cylinder with a central cavity. The proteasome alpha and beta subunits are members of the N-terminal nucleophile (Ntn)-hydrolase superfamily. Their N-terminal threonine residues are exposed as a nucleophile in peptide bond hydrolysis.Mammals have 7 alpha and 7 beta proteasome subunits while archaea have one of each.бА0АкА0АаАCDDбАаАиoвА0А0АаАВаcd03759, proteasome_beta_type_3, proteasome beta type-3 subunit. The 20S proteasome, multisubunit proteolytic complex, is the central enzyme of nonlysosomal protein degradation in both the cytosol and nucleus. It is composed of 28 subunits arranged as four homoheptameric rings that stack on top of one another forming an elongated alpha-beta-beta-alpha cylinder with a central cavity. The proteasome alpha and beta subunits are members of the N-terminal nucleophile (Ntn)-hydrolase superfamily. Their N-terminal threonine residues are exposed as a nucleophile in peptide bond hydrolysis. Mammals have 7 alpha and 7 beta proteasome subunits while archaea have one of each.бА0АкА0АаАCDDбАаАиpвА0А0АаАВЯcd03760, proteasome_beta_type_4, proteasome beta type-4 subunit. The 20S proteasome, multisubunit proteolytic complex, is the central enzyme of nonlysosomal protein degradation in both the cytosol and nucleus. It is composed of 28 subunits arranged as four homoheptameric rings that stack on top of one another forming an elongated alpha-beta-beta-alpha cylinder with a central cavity. The proteasome alpha and beta subunits are members of the N-terminal nucleophile (Ntn)-hydrolase superfamily. Their N-terminal threonine residues are exposed as a nucleophile in peptide bond hydrolysis.Mammals have 7 alpha and 7 beta proteasome subunits while archaea have one of each.бА0АкА0АаАCDDбАаАиqвА0А0АаАВаcd03761, proteasome_beta_type_5, proteasome beta type-5 subunit. The 20S proteasome, multisubunit proteolytic complex, is the central enzyme of nonlysosomal protein degradation in both the cytosol and nucleus. It is composed of 28 subunits arranged as four homoheptameric rings that stack on top of one another forming an elongated alpha-beta-beta-alpha cylinder with a central cavity. The proteasome alpha and beta subunits are members of the N-terminal nucleophile (Ntn)-hydrolase superfamily. Their N-terminal threonine residues are exposed as a nucleophile in peptide bond hydrolysis. Mammals have 7 alpha and 7 beta proteasome subunits while archaea have one of each.бА0АкА0АаАCDDбАаАиrвА0А0АаАВаcd03762, proteasome_beta_type_6, proteasome beta type-6 subunit. The 20S proteasome, multisubunit proteolytic complex, is the central enzyme of nonlysosomal protein degradation in both the cytosol and nucleus. It is composed of 28 subunits arranged as four homoheptameric rings that stack on top of one another forming an elongated alpha-beta-beta-alpha cylinder with a central cavity. The proteasome alpha and beta subunits are members of the N-terminal nucleophile (Ntn)-hydrolase superfamily. Their N-terminal threonine residues are exposed as a nucleophile in peptide bond hydrolysis. Mammals have 7 alpha and 7 beta proteasome subunits while archaea have one of each.бА0АкА0АаАCDDбАаАиsвА0А0АаАВаcd03763, proteasome_beta_type_7, proteasome beta type-7 subunit. The 20S proteasome, multisubunit proteolytic complex, is the central enzyme of nonlysosomal protein degradation in both the cytosol and nucleus. It is composed of 28 subunits arranged as four homoheptameric rings that stack on top of one another forming an elongated alpha-beta-beta-alpha cylinder with a central cavity. The proteasome alpha and beta subunits are members of the N-terminal nucleophile (Ntn)-hydrolase superfamily. Their N-terminal threonine residues are exposed as a nucleophile in peptide bond hydrolysis. Mammals have 7 alpha and 7 beta proteasome subunits while archaea have one of each.бА0АкА0АаАCDDбАаАиtвА0А0АаАВоcd03764, proteasome_beta_archeal, Archeal proteasome, beta subunit. The 20S proteasome, multisubunit proteolytic complex, is the central enzyme for non-lysosomal protein degradation in both the cytosol and the nucleus. It is composed of 28 subunits arranged as four homoheptameric rings that stack on top of one another forming an elongated alpha-beta-beta-alpha cylinder with a central cavity. The proteasome alpha and beta subunits are both members of the N-terminal nucleophile (Ntn)-hydrolase superfamily. Their N-terminal threonine residues are exposed as a nucleophile in peptide bond hydrolysis. Mammals have 7 alpha and 7 beta proteasome subunits while archaea have one of each.бА0АкА0АаАCDDбАаАиuвА0А0АаАВзcd03765, proteasome_beta_bacterial, Bacterial proteasome, beta subunit. The 20S proteasome, multisubunit proteolytic complex, is the central enzyme of nonlysosomal protein degradation in both the cytosol and nucleus. It is composed of 28 subunits arranged as four homoheptameric rings that stack on top of one another forming an elongated alpha-beta-beta-alpha cylinder with a central cavity. The proteasome alpha and beta subunits are members of the N-terminal nucleophile (Ntn)-hydrolase superfamily. Their N-terminal threonine residues are exposed as a nucleophile in peptide bond hydrolysis. Mammals have 7 alpha and 7 beta proteasome subunits while archaea have one of each.бА0АкА0АаАCDDбАаАиvвА0А0АаАВcd03766, Gn_AT_II_novel, Gn_AT_II_novel. This asparagine synthase-related domain is present in eukaryotes but its function has not yet been determined. The glutaminase domain catalyzes an amide nitrogen transfer from glutamine to the appropriate substrate. In this process, glutamine is hydrolyzed to glutamic acid and ammonia. This domain is related to members of the Ntn (N-terminal nucleophile) hydrolase superfamily and is found at the N-terminus of enzymes such as glucosamine-fructose 6-phosphate synthase (GLMS or GFAT), glutamine phosphoribosylpyrophosphate (Prpp) amidotransferase (GPATase), asparagine synthetase B (AsnB), beta lactam synthetase (beta-LS) and glutamate synthase (GltS). GLMS catalyzes the formation of glucosamine 6-phosphate from fructose 6-phosphate and glutamine in amino sugar synthesis. GPATase catalyzes the first step in purine biosynthesis, an amide transfer from glutamine to PRPP, resulting in phosphoribosylamine, pyrophosphate and glutamate. Asparagine synthetase B synthesizes asparagine from aspartate and glutamine. Beta-LS catalyzes the formation of the beta-lactam ring in the beta-lactamase inhibitor clavulanic acid. GltS synthesizes L-glutamate from 2-oxoglutarate and L-glutamine. These enzymes are generally dimers, but GPATase also exists as a homotetramer.бА0АкА0АаАCDDбАаАиwвА0А0АаАВ0cd03767, SR_Res_par, Serine recombinase (SR) family, Partitioning (par)-Resolvase subfamily, catalytic domain; Serine recombinases catalyze site-specific recombination of DNA molecules by a concerted, four-strand cleavage and rejoining mechanism which involves a transient phosphoserine linkage between DNA and the enzyme. They are functionally versatile and include resolvases, invertases, integrases, and transposases. This subgroup is composed of proteins similar to the E. coli resolvase found in the par region of the RP4 plasmid, which encodes a highly efficient partitioning system. This protein is part of a complex stabilization system involved in the resolution of plasmid dimers during cell division. Similar to Tn3 and other resolvases, members of this family may contain a C-terminal DNA binding domain.бА0АкА0АаАCDDбАаАиxвА0А0АаАВ.cd03768, SR_ResInv, Serine Recombinase (SR) family, Resolvase and Invertase subfamily, catalytic domain; members contain a C-terminal DNA binding domain. Serine recombinases catalyze site-specific recombination of DNA molecules by a concerted, four-strand cleavage and rejoining mechanism which involves a transient phosphoserine linkage between DNA and the enzyme. They are functionally versatile and include resolvases, invertases, integrases, and transposases. Resolvases and invertases affect resolution or inversion and comprise a major phylogenic group. Resolvases (e.g. Tn3, gamma-delta, and Tn5044) normally recombine two sites in direct repeat causing deletion of the DNA between the sites. Invertases (e.g. Gin and Hin) recombine sites in inverted repeat to invert the DNA between the sites. Cointegrate resolution with gamma-delta resolvase requires the formation of a synaptosome of three resolvase dimers bound to each of two res sites on the DNA. Also included in this subfamily are some putative integrases including a sequence from bacteriophage phi-FC1.бА0АкА0АаАCDDбАаАиyвА0А0АаАВЩcd03769, SR_IS607_transposase_like, Serine Recombinase (SR) family, IS607-like transposase subfamily, catalytic domain; members contain a DNA binding domain with homology to MerR/SoxR located N-terminal to the catalytic domain. Serine recombinases catalyze site-specific recombination of DNA molecules by a concerted, four-strand cleavage and rejoining mechanism which involves a transient phosphoserine linkage between DNA and the enzyme. They are functionally versatile and include resolvases, invertases, integrases, and transposases. This subfamily is composed of proteins that catalyze the transposition of insertion sequence (IS) elements such as IS607 from Helicobacter and IS1535 from Mycobacterium, and similar proteins from other bacteria and several archaeal species. IS elements are DNA segments that move to new sites in prokaryotic and eukaryotic genomes causing insertion mutations and gene rearrangements.бА0АкА0АаАCDDбАаАиzвА0А0АаАВ}cd03770, SR_TndX_transposase, Serine Recombinase (SR) family, TndX-like transposase subfamily, catalytic domain; composed of large serine recombinases similar to Clostridium TndX and TnpX transposases. Serine recombinases catalyze site-specific recombination of DNA molecules by a concerted, four-strand cleavage and rejoining mechanism which involves a transient phosphoserine linkage between DNA and the enzyme. They are functionally versatile and include resolvases, invertases, integrases, and transposases. TndX mediates the excision and circularization of the conjugative transposon Tn5397 from Clostridium difficile. TnpX is responsible for the movement of the nonconjugative chloramphenicol resistance elements of the Tn4451/3 family. Mobile genetic elements such as transposons are important vehicles for the transmission of virulence and antibiotic resistance in many microorganisms.бА0АкА0АаАCDDбАаАи{вА0А0АаАВbcd03771, MATH_Meprin, Meprin family, MATH domain; Meprins are multidomain, highly glycosylated extracellular metalloproteases, which are either anchored to the membrane or secreted into extracellular spaces. They are expressed in renal and intestinal brush border membranes, leukocytes, and cancer cells, and are capable of cleaving growth factors, cytokines, extracellular matrix proteins, and biologically active peptides. Meprin proteases are composed of two related subunits, alpha and beta, which form homo- or hetro-complexes where the basic unit is a disulfide-linked dimer. Despite their similarity, the two subunits differ in their ability to self-associate, in proteolytic processing during biosynthesis and in substrate specificity. Both subunits are synthesized as membrane spanning proteins, however, the alpha subunit is cleaved during biosynthesis and loses its transmembrane domain. Meprin beta forms homodimers or heterotetramers while meprin alpha oligomerizes into large complexes containing 10-100 subunits. Both alpha and beta subunits contain a catalytic astacin (M12 family) protease domain followed by the adhesion or interaction domains MAM, MATH and AM. The MATH and MAM domains provide symmetrical intersubunit disulfide bonds necessary for the dimerization of meprin subunits. The MATH domain may also be required for folding of an activable zymogen.бА0АкА0АаАCDDбАаАи|вА0А0АаАВcd03772, MATH_HAUSP, Herpesvirus-associated ubiquitin-specific protease (HAUSP, also known as USP7) family, N-terminal MATH (TRAF-like) domain; composed of proteins similar to human HAUSP, an enzyme that specifically catalyzes the deubiquitylation of p53 and MDM2, hence playing an important role in the p53-MDM2 pathway. It contains an N-terminal TRAF-like domain and a C-terminal catalytic protease (C19 family) domain. The tumor suppressor p53 protein is a transcription factor that responds to many cellular stress signals and is regulated primarily through ubiquitylation and subsequent degradation. MDM2 is a RING-finger E3 ubiquitin ligase that promotes p53 ubiquitinylation. p53 and MDM2 bind to the same site in the N-terminal TRAF-like domain of HAUSP in a mutually exclusive manner. HAUSP also interacts with the Epstein-Barr nuclear antigen 1 (EBNA1) protein of the Epstein-Barr virus (EBV), which efficiently immortalizes infected cells predisposing the host to a variety of cancers. EBNA1 plays several important roles in EBV latent infection and cellular transformation. It binds the same pocket as p53 in the HAUSP TRAF-like domain. Through interactions with p53, MDM2 and EBNA1, HAUSP plays a role in cell proliferation, apoptosis and EBV-mediated immortalization.бА0АкА0АаАCDDбАаАи}вА0А0АаАВ=cd03773, MATH_TRIM37, Tripartite motif containing protein 37 (TRIM37) family, MATH domain; TRIM37 is a peroxisomal protein and is a member of the tripartite motif (TRIM) protein subfamily, also known as the RING-B-box-coiled-coil (RBCC) subfamily of zinc-finger proteins. Mutations in the human TRIM37 gene (also known as MUL) cause Mulibrey (muscle-liver-brain-eye) nanism, a rare growth disorder of prenatal onset characterized by dysmorphic features, pericardial constriction and hepatomegaly. TRIM37, similar to other TRIMs, contains a cysteine-rich, zinc-binding RING-finger domain followed by another cysteine-rich zinc-binding domain, the B-box, and a coiled-coil domain. TRIM37 is autoubiquitinated in a RING domain-dependent manner, indicating that it functions as an ubiquitin E3 ligase. In addition to the tripartite motif, TRIM37 also contains a MATH domain C-terminal to the coiled-coil domain. The MATH domain of TRIM37 has been shown to interact with the TRAF domain of six known TRAFs in vitro, however, it is unclear whether this is physiologically relevant. Eleven TRIM37 mutations have been associated with Mulibrey nanism so far. One mutation, Gly322Val, is located in the MATH domain and is the only mutation that does not affect the length of the protein. It results in the incorrect subcellular localization of TRIM37.бА0АкА0АаАCDDбАаАи~вА0А0АаАВIcd03774, MATH_SPOP, Speckle-type POZ protein (SPOP) family, MATH domain; composed of proteins with similarity to human SPOP. SPOP was isolated as a novel antigen recognized by serum from a scleroderma patient, whose overexpression in COS cells results in a discrete speckled pattern in the nuclei. It contains an N-terminal MATH domain and a C-terminal BTB (also called POZ) domain. Together with Cul3, SPOP constitutes an ubiquitin E3 ligase which is able to ubiquitinate the PcG protein BMI1, the variant histone macroH2A1 and the death domain-associated protein Daxx. Therefore, SPOP may be involved in the regulation of these proteins and may play a role in transcriptional regulation, apoptosis and X-chromosome inactivation. Cul3 binds to the BTB domain of SPOP whereas Daxx and the macroH2A1 nonhistone region have been shown to bind to the MATH domain. Both MATH and BTB domains are necessary for the nuclear speckled accumulation of SPOP. There are many proteins, mostly uncharacterized, containing both MATH and BTB domains from C. elegans and plants which are excluded from this family.бА0АкА0АаАCDDбАаАивА0А0АаАВcd03775, MATH_Ubp21p, Ubiquitin-specific protease 21 (Ubp21p) family, MATH domain; composed of fungal proteins with similarity to Ubp21p of fission yeast. Ubp21p is a deubiquitinating enzyme that may be involved in the regulation of the protein kinase Prp4p, which controls the formation of active spliceosomes. Members of this family are similar to human HAUSP (Herpesvirus-associated ubiquitin-specific protease) in that they contain an N-terminal MATH domain and a C-terminal catalytic protease (C19 family) domain. HAUSP is also an ubiquitin-specific protease that specifically catalyzes the deubiquitylation of p53 and MDM2. The MATH domain of HAUSP contains the binding site for p53 and MDM2. Similarly, the MATH domain of members in this family may be involved in substrate binding.бА0АкА0АаАCDDбАаАиАвА0А0АаАВСcd03776, MATH_TRAF6, Tumor Necrosis Factor Receptor (TNFR)-Associated Factor (TRAF) family, TRAF6 subfamily, TRAF domain, C-terminal MATH subdomain; composed of proteins with similarity to human TRAF6, including the Drosophila protein DTRAF2. TRAF molecules serve as adapter proteins that link TNFRs and downstream kinase cascades resulting in the activation of transcription factors and the regulation of cell survival, proliferation and stress responses. TRAF6 is the most divergent in its TRAF domain among the mammalian TRAFs. In addition to mediating TNFR family signaling, it is also an essential signaling molecule of the interleukin-1/Toll-like receptor superfamily. Whereas other TRAF molecules display similar and overlapping TNFR-binding specificities, TRAF6 binds completely different sites on receptors such as CD40 and RANK. TRAF6 serves as a molecular bridge between innate and adaptive immunity and plays a central role in osteoimmunology. DTRAF2, as an activator of nuclear factor-kappaB, plays a pivotal role in Drosophila development and innate immunity. TRAF6 contains a RING finger domain, five zinc finger domains, and a TRAF domain. The TRAF domain can be divided into a more divergent N-terminal alpha helical region (TRAF-N), and a highly conserved C-terminal MATH subdomain (TRAF-C) with an eight-stranded beta-sandwich structure. TRAF-N mediates trimerization while TRAF-C interacts with receptors.бА0АкА0АаАCDDбАаАиБвА0А0АаАВ╡cd03777, MATH_TRAF3, Tumor Necrosis Factor Receptor (TNFR)-Associated Factor (TRAF) family, TRAF3 subfamily, TRAF domain; TRAF molecules serve as adapter proteins that link TNFRs and downstream kinase cascades resulting in the activation of transcription factors and the regulation of cell survival, proliferation and stress responses. TRAF3 was first described as a molecule that binds the cytoplasmic tail of CD40. However, it is not required for CD40 signaling. More recently, TRAF3 has been identified as a key regulator of type I interferon (IFN) production and the mammalian innate antiviral immunity. It mediates IFN responses in Toll-like receptor (TLR)-dependent as well as TLR-independent viral recognition pathways. It is also a key element in immunological homeostasis through its regulation of the anti-inflammatory cytokine interleukin-10. TRAF3 contains a RING finger domain, five zinc finger domains, and a TRAF domain. The TRAF domain can be divided into a more divergent N-terminal alpha helical region (TRAF-N), and a highly conserved C-terminal MATH subdomain (TRAF-C) with an eight-stranded beta-sandwich structure. TRAF-N mediates trimerization while TRAF-C interacts with receptors.бА0АкА0АаАCDDбАаАиВвА0А0АаАВcd03778, MATH_TRAF2, Tumor Necrosis Factor Receptor (TNFR) Associated Factor (TRAF) family, TRAF2 subfamily, TRAF domain; TRAF molecules serve as adapter proteins that link TNFRs and downstream kinase cascades resulting in the activation of transcription factors and the regulation of cell survival, proliferation and stress responses. TRAF2 associates with the receptors TNFR-1, TNFR-2, RANK (which mediates differentiation and maturation of osteoclasts) and CD40 (which is important for the proliferation and activation of B cells), among others. It regulates distinct pathways that lead to the activation of nuclear factor-kappaB and Jun NH2-terminal kinases. TRAF2 also indirectly associates with death receptors through its interaction with TRADD (TNFR-associated death domain protein). It is involved in regulating oxidative stress or ROS-induced cell death and in the preconditioning of cells by sublethal stress for protection from subsequent injury. TRAF2 contains a RING finger domain, five zinc finger domains, and a TRAF domain. The TRAF domain can be divided into a more divergent N-terminal alpha helical region (TRAF-N), and a highly conserved C-terminal MATH subdomain (TRAF-C) with an eight-stranded beta-sandwich structure. TRAF-N mediates trimerization while TRAF-C interacts with receptors.бА0АкА0АаАCDDбАаАиГвА0А0АаАВ@cd03779, MATH_TRAF1, Tumor Necrosis Factor Receptor (TNFR) Associated Factor (TRAF) family, TRAF1 subfamily, TRAF domain, C-terminal MATH subdomain; TRAF molecules serve as adapter proteins that link TNFRs and downstream kinase cascades resulting in the activation of transcription factors and the regulation of cell survival, proliferation and stress responses. TRAF1 expression is the most restricted among the TRAFs. It is found exclusively in activated lymphocytes, dendritic cells and certain epithelia. TRAF1 associates, directly or indirectly through heterodimerization with TRAF2, with the TNFR family receptors TNFR-2, CD30, RANK, CD40 and LMP1, among others. It also binds the intracellular proteins TRADD, TANK, TRIP, RIP1, RIP2 and FLIP. TRAF1 is unique among the TRAFs in that it lacks a RING domain, which is critical for the activation of nuclear factor-kappaB and Jun NH2-terminal kinase. Studies on TRAF1-deficient mice suggest that TRAF1 has a negative regulatory role in TNFR-mediated signaling events. TRAF1 contains one zinc finger and one TRAF domain. The TRAF domain can be divided into a more divergent N-terminal alpha helical region (TRAF-N), and a highly conserved C-terminal MATH subdomain (TRAF-C) with an eight-stranded beta-sandwich structure. TRAF-N mediates trimerization while TRAF-C interacts with receptors.бА0АкА0АаАCDDбАаАиДвА0А0АаАВ╚cd03780, MATH_TRAF5, Tumor Necrosis Factor Receptor (TNFR)-Associated Factor (TRAF) family, TRAF5 subfamily, TRAF domain, C-terminal MATH subdomain; TRAF molecules serve as adapter proteins that link TNFRs and downstream kinase cascades resulting in the activation of transcription factors and the regulation of cell survival, proliferation and stress responses. TRAF5 was identified as an activator of nuclear factor-kappaB and a regulator of lymphotoxin-beta receptor and CD40 signaling. Its interaction with CD40 is indirect, involving hetero-oligomerization with TRAF3. In addition, TRAF5 has been shown to associate with other TNFRs including CD27, CD30, OX40 and GITR (glucocorticoid-induced TNFR). It plays a role in modulating Th2 immune responses (driven by OX40 costimulation) and T-cell activation (triggered by GITR). It is also involved in osteoclastogenesis. TRAF5 contains a RING finger domain, five zinc finger domains, and a TRAF domain. The TRAF domain can be divided into a more divergent N-terminal alpha helical region (TRAF-N), and a highly conserved C-terminal MATH subdomain (TRAF-C) with an eight-stranded beta-sandwich structure. TRAF-N mediates trimerization while TRAF-C interacts with receptors.бА0АкА0АаАCDDбАаАиЕвА0А0АаАВ┴cd03781, MATH_TRAF4, Tumor Necrosis Factor Receptor (TNFR)-Associated Factor (TRAF) family, TRAF4 subfamily, TRAF domain, C-terminal MATH subdomain; composed of proteins with similarity to human TRAF4, including the Drosophila protein DTRAF1. TRAF molecules serve as adapter proteins that link TNFRs and downstream kinase cascades resulting in the activation of transcription factors and the regulation of cell survival, proliferation and stress responses. TRAF4 is highly expressed during embryogenesis, especially in the central and peripheral nervous system. Studies using TRAF4-deficient mice show that TRAF4 is required for neurogenesis, as well as the development of the trachea and the axial skeleton. In addition, TRAF4 augments nuclear factor-kappaB activation triggered by GITR (glucocorticoid-induced TNFR), a receptor expressed in T-cells, B-cells and macrophages. It also participates in counteracting the signaling mediated by Toll-like receptors through its association with TRAF6 and TRIF. DTRAF1 plays a pivotal role in the development of eye imaginal discs and photosensory neuron arrays in Drosophila. TRAF4 contains a RING finger domain, seven zinc finger domains, and a TRAF domain. The TRAF domain can be divided into a more divergent N-terminal alpha helical region (TRAF-N), and a highly conserved C-terminal MATH subdomain (TRAF-C) with an eight-stranded beta-sandwich structure. TRAF-N mediates trimerization while TRAF-C interacts with receptors.бА0АкА0АаАCDDбАаАиЖвА0А0АаАВ cd03782, MATH_Meprin_Beta, Meprin family, Beta subunit, MATH domain; Meprins are multidomain extracellular metalloproteases capable of cleaving growth factors, cytokines, extracellular matrix proteins, and biologically active peptides. They are composed of two related subunits, alpha and beta, which form homo- or hetro-complexes where the basic unit is a disulfide-linked dimer. The beta subunit is a type I membrane protein, which forms homodimers or heterotetramers (alpha2beta2 or alpha3beta). Meprin beta shows preference for acidic residues at the P1 and P1' sites of its substrate. Among its best substrates are growth factors and chemokines such as gastrin and osteopontin. Both alpha and beta subunits contain a catalytic astacin (M12 family) protease domain followed by the adhesion or interaction domains MAM, MATH and AM. The MATH and MAM domains provide symmetrical intersubunit disulfide bonds necessary for the dimerization of meprin subunits. The MATH domain may also be required for folding of an activable zymogen.бА0АкА0АаАCDDбАаАиЗвА0А0АаАВDcd03783, MATH_Meprin_Alpha, Meprin family, Alpha subunit, MATH domain; Meprins are multidomain extracellular metalloproteases capable of cleaving growth factors, cytokines, extracellular matrix proteins, and biologically active peptides. They are composed of two related subunits, alpha and beta, which form homo- or hetro-complexes where the basic unit is a disulfide-linked dimer. The alpha subunit is synthesized as a membrane spanning protein, however, it is cleaved during biosynthesis and loses its transmembrane domain. It oligomerizes into large complexes, containing 10-100 subunits (dimers that associate noncovalently), which are secreted as latent proteases and can move through extracellular spaces in a nondestructive manner. This allows delivery of the concentrated protease to sites containing activating enzymes, such as sites of inflammation, infection or cancerous growth. Meprin alpha shows preference for small or hydrophobic residues at the P1 and P1' sites of its substrate. Both alpha and beta subunits contain a catalytic astacin (M12 family) protease domain followed by the adhesion or interaction domains MAM, MATH and AM. The MATH and MAM domains provide symmetrical intersubunit disulfide bonds necessary for the dimerization of meprin subunits. The MATH domain may also be required for folding of an activable zymogen.бА0АкА0АаАCDDбАаАиИвА0А0АаАВгcd03784, GT1_Gtf_like, This family includes the Gtfs, a group of homologous glycosyltransferases involved in the final stages of the biosynthesis of antibiotics vancomycin and related chloroeremomycin. Gtfs transfer sugar moieties from an activated NDP-sugar donor to the oxidatively cross-linked heptapeptide core of vancomycin group antibiotics. The core structure is important for the bioactivity of the antibiotics.бА0АкА0АаАCDDбАаАЖxвА0А0АаАВcd03785, GT1_MurG, MurG is an N-acetylglucosaminyltransferase, the last enzyme involved in the intracellular phase of peptidoglycan biosynthesis. It transfers N-acetyl-D-glucosamine (GlcNAc) from UDP-GlcNAc to the C4 hydroxyl of a lipid-linked N-acetylmuramoyl pentapeptide (NAM). The resulting disaccharide is then transported across the cell membrane, where it is polymerized into NAG-NAM cell-wall repeat structure. MurG belongs to the GT-B structural superfamily of glycoslytransferases, which have characteristic N- and C-terminal domains, each containing a typical Rossmann fold. The two domains have high structural homology despite minimal sequence homology. The large cleft that separates the two domains includes the catalytic center and permits a high degree of flexibility.бА0АкА0АаАCDDбАаАЖyвА0А0АаАВ=cd03786, GT1_UDP-GlcNAc_2-Epimerase, Bacterial members of the UDP-N-Acetylglucosamine (GlcNAc) 2-Epimerase family are known to catalyze the reversible interconversion of UDP-GlcNAc and UDP-N-acetylmannosamine (UDP-ManNAc). The enzyme serves to produce an activated form of ManNAc residues (UDP-ManNAc) for use in the biosynthesis of a variety of cell surface polysaccharides; The mammalian enzyme is bifunctional, catalyzing both the inversion of stereochemistry at C-2 and the hydrolysis of the UDP-sugar linkage to generate free ManNAc. It also catalyzes the phosphorylation of ManNAc to generate ManNAc 6-phosphate, a precursor to salic acids. In mammals, sialic acids are found at the termini of oligosaccharides in a large variety of cell surface glycoconjugates and are key mediators of cell-cell recognition events. Mutations in human members of this family have been associated with Sialuria, a rare disease caused by the disorders of sialic acid metabolism. This family belongs to the GT-B structural superfamily of glycoslytransferases, which have characteristic N- and C-terminal domains each containing a typical Rossmann fold. The two domains have high structural homology despite minimal sequence homology. The large cleft that separates the two domains includes the catalytic center and permits a high degree of flexibility.бА0АкА0АаАCDDбАаАЖzвА0А0АаАВсcd03788, GT1_TPS, Trehalose-6-Phosphate Synthase (TPS) is a glycosyltransferase that catalyses the synthesis of alpha,alpha-1,1-trehalose-6-phosphate from glucose-6-phosphate using a UDP-glucose donor. It is a key enzyme in the trehalose synthesis pathway. Trehalose is a nonreducing disaccharide present in a wide variety of organisms and may serve as a source of energy and carbon. It is characterized most notably in insect, plant, and microbial cells. Its production is often associated with a variety of stress conditions, including desiccation, dehydration, heat, cold, and oxidation. This family represents the catalytic domain of the TPS. Some members of this domain family coexist with a C-terminal trehalose phosphatase domain.бА0АкА0АаАCDDбАаАЖ{вА0А0АаАВ·cd03789, GT1_LPS_heptosyltransferase, Lipopolysaccharide heptosyltransferase is involved in the biosynthesis of lipooligosaccharide (LOS). Lipopolysaccharide (LPS) is a major component of the outer membrane of gram-negative bacteria. LPS heptosyltransferase transfers heptose molecules from ADP-heptose to 3-deoxy-D-manno-octulosonic acid (KDO), a part of the inner core component of LPS. This family belongs to the GT-B structural superfamily of glycoslytransferases, which have characteristic N- and C-terminal domains each containing a typical Rossmann fold. The two domains have high structural homology despite minimal sequence homology. The large cleft that separates the two domains includes the catalytic center and permits a high degree of flexibility.бА0АкА0АаАCDDбАаАЖ|вА0А0АаАВСcd03791, GT1_Glycogen_synthase_DULL1_like, This family is most closely related to the GT1 family of glycosyltransferases. Glycogen synthase catalyzes the formation and elongation of the alpha-1,4-glucose backbone using ADP-glucose, the second and key step of glycogen biosynthesis. This family includes starch synthases of plants, such as DULL1 in Zea mays and glycogen synthases of various organisms.бА0АкА0АаАCDDбАаАЖ}вА0А0АаАВЬcd03792, GT1_Trehalose_phosphorylase, Trehalose phosphorylase (TP) reversibly catalyzes trehalose synthesis and degradation from alpha-glucose-1-phosphate (alpha-Glc-1-P) and glucose. The catalyzing activity includes the phosphorolysis of trehalose, which produce alpha-Glc-1-P and glucose, and the subsequent synthesis of trehalose. This family is most closely related to the GT1 family of glycosyltransferases.бА0АкА0АаАCDDбАаАЖ~вА0А0АаАВДcd03793, GT1_Glycogen_synthase_GSY2_like, Glycogen synthase, which is most closely related to the GT1 family of glycosyltransferases, catalyzes the transfer of a glucose molecule from UDP-glucose to a terminal branch of a glycogen molecule, a rate-limit step of glycogen biosynthesis. GSY2, the member of this family in S. cerevisiae, has been shown to possess glycogen synthase activity.бА0АкА0АаАCDDбАаАЖвА0А0АаАВcd03794, GT1_wbuB_like, This family is most closely related to the GT1 family of glycosyltransferases. wbuB in E. coli is involved in the biosynthesis of the O26 O-antigen. It has been proposed to function as an N-acetyl-L-fucosamine (L-FucNAc) transferase.бА0АкА0АаАCDDбАаАЖАвА0А0АаАВлcd03795, GT1_like_4, This family is most closely related to the GT1 family of glycosyltransferases. Glycosyltransferases catalyze the transfer of sugar moieties from activated donor molecules to specific acceptor molecules, forming glycosidic bonds. The acceptor molecule can be a lipid, a protein, a heterocyclic compound, or another carbohydrate residue. This group of glycosyltransferases is most closely related to the previously defined glycosyltransferase family 1 (GT1). The members of this family may transfer UDP, ADP, GDP, or CMP-linked sugars. The diverse enzymatic activities among members of this family reflect a wide range of biological functions. The protein structure available for this family has the GTB topology, one of the two protein topologies observed for nucleotide-sugar-dependent glycosyltransferases. GTB proteins have distinct N- and C- terminal domains each containing a typical Rossmann fold. The two domains have high structural homology despite minimal sequence homology. The large cleft that separates the two domains includes the catalytic center and permits a high degree of flexibility. The members of this family are found mainly in bacteria and eukaryotes.бА0АкА0АаАCDDбАаАЖБвА0А0АаАВLcd03796, GT1_PIG-A_like, This family is most closely related to the GT1 family of glycosyltransferases. Phosphatidylinositol glycan-class A (PIG-A), an X-linked gene in humans, is necessary for the synthesis of N-acetylglucosaminyl-phosphatidylinositol, a very early intermediate in glycosyl phosphatidylinositol (GPI)-anchor biosynthesis. The GPI-anchor is an important cellular structure that facilitates the attachment of many proteins to cell surfaces. Somatic mutations in PIG-A have been associated with Paroxysmal Nocturnal Hemoglobinuria (PNH), an acquired hematological disorder.бА0АкА0АаАCDDбАаАЖВвА0А0АаАВ3cd03798, GT1_wlbH_like, This family is most closely related to the GT1 family of glycosyltransferases. wlbH in Bordetella parapertussis has been shown to be required for the biosynthesis of a trisaccharide that, when attached to the B. pertussis lipopolysaccharide (LPS) core (band B), generates band A LPS.бА0АкА0АаАCDDбАаАЖГвА0А0АаАБ¤cd03799, GT1_amsK_like, This is a family of GT1 glycosyltransferases found specifically in certain bacteria. amsK in Erwinia amylovora, has been reported to be involved in the biosynthesis of amylovoran, a exopolysaccharide acting as a virulence factor.бА0АкА0АаАCDDбАаАЖДвА0А0АаАВ°cd03800, GT1_Sucrose_synthase, This family is most closely related to the GT1 family of glycosyltransferases. The sucrose-phosphate synthases in this family may be unique to plants and photosynthetic bacteria. This enzyme catalyzes the synthesis of sucrose 6-phosphate from fructose 6-phosphate and uridine 5'-diphosphate-glucose, a key regulatory step of sucrose metabolism. The activity of this enzyme is regulated by phosphorylation and moderated by the concentration of various metabolites and light.бА0АкА0АаАCDDбАаАЖЕвА0А0АаАВ■cd03801, GT1_YqgM_like, This family is most closely related to the GT1 family of glycosyltransferases and named after YqgM in Bacillus licheniformis about which little is known. Glycosyltransferases catalyze the transfer of sugar moieties from activated donor molecules to specific acceptor molecules, forming glycosidic bonds. The acceptor molecule can be a lipid, a protein, a heterocyclic compound, or another carbohydrate residue. This group of glycosyltransferases is most closely related to the previously defined glycosyltransferase family 1 (GT1). The members of this family may transfer UDP, ADP, GDP, or CMP linked sugars. The diverse enzymatic activities among members of this family reflect a wide range of biological functions. The protein structure available for this family has the GTB topology, one of the two protein topologies observed for nucleotide-sugar-dependent glycosyltransferases. GTB proteins have distinct N- and C- terminal domains each containing a typical Rossmann fold. The two domains have high structural homology despite minimal sequence homology. The large cleft that separates the two domains includes the catalytic center and permits a high degree of flexibility. The members of this family are found mainly in certain bacteria and archaea.бА0АкА0АаАCDDбАаАЖЖвА0А0АаАВocd03802, GT1_AviGT4_like, This family is most closely related to the GT1 family of glycosyltransferases. aviGT4 in Streptomyces viridochromogenes has been shown to be involved in biosynthesis of oligosaccharide antibiotic avilamycin A. Inactivation of aviGT4 resulted in a mutant that accumulated a novel avilamycin derivative lacking the terminal eurekanate residue.бА0АкА0АаАCDDбАаАЖЗвА0А0АаАВcd03804, GT1_wbaZ_like, This family is most closely related to the GT1 family of glycosyltransferases. wbaZ in Salmonella enterica has been shown to possess the mannosyl transferase activity. The members of this family are found in certain bacteria and Archaea.бА0АкА0АаАCDDбАаАЖИвА0А0АаАВcd03805, GT1_ALG2_like, This family is most closely related to the GT1 family of glycosyltransferases. ALG2, a 1,3-mannosyltransferase, in yeast catalyzes the mannosylation of Man(2)GlcNAc(2)-dolichol diphosphate and Man(1)GlcNAc(2)-dolichol diphosphate to form Man(3)GlcNAc(2)-dolichol diphosphate. A deficiency of this enzyme causes an abnormal accumulation of Man1GlcNAc2-PP-dolichol and Man2GlcNAc2-PP-dolichol, which is associated with a type of congenital disorders of glycosylation (CDG), designated CDG-Ii, in humans.бА0АкА0АаАCDDбАаАЖЙвА0А0АаАВ╜cd03806, GT1_ALG11_like, This family is most closely related to the GT1 family of glycosyltransferases. ALG11 in yeast is involved in adding the final 1,2-linked Man to the Man5GlcNAc2-PP-Dol synthesized on the cytosolic face of the ER. The deletion analysis of ALG11 was shown to block the early steps of core biosynthesis that takes place on the cytoplasmic face of the ER and lead to a defect in the assembly of lipid-linked oligosaccharides.бА0АкА0АаАCDDбАаАЖКвА0А0АаАБ╟cd03807, GT1_WbnK_like, This family is most closely related to the GT1 family of glycosyltransferases. WbnK in Shigella dysenteriae has been shown to be involved in the type 7 O-antigen biosynthesis.бА0АкА0АаАCDDбАаАЖЛвА0А0АаАБ╦cd03808, GT1_cap1E_like, This family is most closely related to the GT1 family of glycosyltransferases. cap1E in Streptococcus pneumoniae is required for the synthesis of type 1 capsular polysaccharides.бА0АкА0АаАCDDбАаАЖМвА0А0АаАВ7cd03809, GT1_mtfB_like, This family is most closely related to the GT1 family of glycosyltransferases. mtfB (mannosyltransferase B) in E. coli has been shown to direct the growth of the O9-specific polysaccharide chain. It transfers two mannoses into the position 3 of the previously synthesized polysaccharide.бА0АкА0АаАCDDбАаАЖНвА0А0АаАБ№cd03811, GT1_WabH_like, This family is most closely related to the GT1 family of glycosyltransferases. WabH in Klebsiella pneumoniae has been shown to transfer a GlcNAc residue from UDP-GlcNAc onto the acceptor GalUA residue in the cellular outer core.бА0АкА0АаАCDDбАаАЖОвА0А0АаАБфcd03812, GT1_CapH_like, This family is most closely related to the GT1 family of glycosyltransferases. capH in Staphylococcus aureus has been shown to be required for the biosynthesis of the type 1 capsular polysaccharide (CP1).бА0АкА0АаАCDDбАаАЖПвА0А0АаАВ┘cd03813, GT1_like_3, This family is most closely related to the GT1 family of glycosyltransferases. Glycosyltransferases catalyze the transfer of sugar moieties from activated donor molecules to specific acceptor molecules, forming glycosidic bonds. The acceptor molecule can be a lipid, a protein, a heterocyclic compound, or another carbohydrate residue. This group of glycosyltransferases is most closely related to the previously defined glycosyltransferase family 1 (GT1). The members of this family may transfer UDP, ADP, GDP, or CMP linked sugars. The diverse enzymatic activities among members of this family reflect a wide range of biological functions. The protein structure available for this family has the GTB topology, one of the two protein topologies observed for nucleotide-sugar-dependent glycosyltransferases. GTB proteins have distinct N- and C- terminal domains each containing a typical Rossmann fold. The two domains have high structural homology despite minimal sequence homology. The large cleft that separates the two domains includes the catalytic center and permits a high degree of flexibility. The members of this family are found mainly in bacteria, while some of them are also found in Archaea and eukaryotes.бА0АкА0АаАCDDбАаАЖРвА0А0АаАВлcd03814, GT1_like_2, This family is most closely related to the GT1 family of glycosyltransferases. Glycosyltransferases catalyze the transfer of sugar moieties from activated donor molecules to specific acceptor molecules, forming glycosidic bonds. The acceptor molecule can be a lipid, a protein, a heterocyclic compound, or another carbohydrate residue. This group of glycosyltransferases is most closely related to the previously defined glycosyltransferase family 1 (GT1). The members of this family may transfer UDP, ADP, GDP, or CMP linked sugars. The diverse enzymatic activities among members of this family reflect a wide range of biological functions. The protein structure available for this family has the GTB topology, one of the two protein topologies observed for nucleotide-sugar-dependent glycosyltransferases. GTB proteins have distinct N- and C- terminal domains each containing a typical Rossmann fold. The two domains have high structural homology despite minimal sequence homology. The large cleft that separates the two domains includes the catalytic center and permits a high degree of flexibility. The members of this family are found mainly in bacteria and eukaryotes.бА0АкА0АаАCDDбАаАЖСвА0А0АаАВЎcd03816, GT1_ALG1_like, This family is most closely related to the GT1 family of glycosyltransferases. The yeast gene ALG1 has been shown to function as a mannosyltransferase that catalyzes the formation of dolichol pyrophosphate (Dol-PP)-GlcNAc2Man from GDP-Man and Dol-PP-Glc-NAc2, and participates in the formation of the lipid-linked precursor oligosaccharide for N-glycosylation. In humans ALG1 has been associated with the congenital disorders of glycosylation (CDG) designated as subtype CDG-Ik.бА0АкА0АаАCDDбАаАЖТвА0А0АаАВFcd03817, GT1_UGDG_like, This family is most closely related to the GT1 family of glycosyltransferases. UDP-glucose-diacylglycerol glucosyltransferase (UGDG; also known as 1,2-diacylglycerol 3-glucosyltransferase) catalyzes the transfer of glucose from UDP-glucose to 1,2-diacylglycerol forming 3-D-glucosyl-1,2-diacylglycerol.бА0АкА0АаАCDDбАаАЖУвА0А0АаАБ▄cd03818, GT1_ExpC_like, This family is most closely related to the GT1 family of glycosyltransferases. ExpC in Rhizobium meliloti has been shown to be involved in the biosynthesis of galactoglucan (exopolysaccharide II).бА0АкА0АаАCDDбАаАЖФвА0А0АаАБ╨cd03819, GT1_WavL_like, This family is most closely related to the GT1 family of glycosyltransferases. WavL in Vibrio cholerae has been shown to be involved in the biosynthesis of the lipopolysaccharide core.бА0АкА0АаАCDDбАаАЖХвА0А0АаАВ]cd03820, GT1_amsD_like, This family is most closely related to the GT1 family of glycosyltransferases. AmSD in Erwinia amylovora has been shown to be involved in the biosynthesis of amylovoran, the acidic exopolysaccharide acting as a virulence factor. This enzyme may be responsible for the formation of galactose alpha-1,6 linkages in amylovoran.бА0АкА0АаАCDDбАаАЖЦвА0А0АаАБ╔cd03821, GT1_Bme6_like, This family is most closely related to the GT1 family of glycosyltransferases. Bme6 in Brucella melitensis has been shown to be involved in the biosynthesis of a polysaccharide.бА0АкА0АаАCDDбАаАЖЧвА0А0АаАБ┘cd03822, GT1_ecORF704_like, This family is most closely related to the GT1 family of glycosyltransferases. ORF704 in E. coli has been shown to be involved in the biosynthesis of O-specific mannose homopolysaccharides.бА0АкА0АаАCDDбАаАЖШвА0А0АаАБуcd03823, GT1_ExpE7_like, This family is most closely related to the GT1 family of glycosyltransferases. ExpE7 in Sinorhizobium meliloti has been shown to be involved in the biosynthesis of galactoglucans (exopolysaccharide II).бА0АкА0АаАCDDбАаАЖЩвА0А0АаАБ╬cd03825, GT1_wcfI_like, This family is most closely related to the GT1 family of glycosyltransferases. wcfI in Bacteroides fragilis has been shown to be involved in the capsular polysaccharide biosynthesis.бА0АкА0АаАCDDбАаАЖЪвА0А0АаАВcd03829, Sina, Seven in absentia (Sina) protein family, C-terminal substrate binding domain; composed of the Drosophila Sina protein, the mammalian Sina homolog (Siah), the plant protein SINAT5, and similar proteins. Sina, Siah and SINAT5 are RING-containing proteins that function as E3 ubiquitin ligases, acting either as single proteins or as a part of multiprotein complexes. Sina is expressed in many cells in the developing eye but is essential specifically for R7 photoreceptor cell development. Sina cooperates with Phyllopod (Phyl), Ebi and the E2 ubiquitin-conjugating enzyme Ubcd1 to catalyze the ubiquitination and subsequent degradation of Tramtrack (Ttk88); Ttk88 is a transcriptional repressor that blocks photoreceptor differentiation. Similarly, the mammalian homologue Siah1 cooperates with SIP (Siah-interacting protein), Ebi and the adaptor protein Skp1, to target beta-catenin for ubiquitination and degradation via a p53-dependent mechanism. SINAT5 targets NAC1 for ubiquitin-mediated degradation resulting in the downregulation of auxin, a hormone that controls many aspects of plant development. Other targets of Sina family proteins include c-Myb, synaptophysin, group 1 glutamate receptors, promyelocytic leukemia protein, alpha-synuclein, synphilin-1 and alpha-ketoglutarate dehydrogenase, among others. Sina proteins also bind proteins that are not targets for ubiquitination such as Phyl, adenomatous polyposis coli, VAV, BAG-1 and Dab-1. Siah binds to a consensus motif, PXAXVXP, which is present in Siah-binding proteins. Siah is a dimeric protein consisting of an N-terminal RING domain, two zinc finger motifs and a C-terminal substrate-binding domain (SBD); this SBD contains an eight-stranded antiparallel beta-sandwich fold similar to the MATH (meprin and TRAF-C homology) domain.бА0АкА0АаАCDDбАаАиЙвА0А0АаАВ_cd03855, M14_ASTE, Peptidase M14 Succinylglutamate desuccinylase (ASTE) subfamily. Peptidase M14 Succinylglutamate desuccinylase (ASTE, also known as N-succinyl-L-glutamate amidohydrolase, N2-succinylglutamate desuccinylase, and SGDS; EC 3.5.1.96) belongs to the Succinylglutamate desuccinylase (ASTE)/aspartoacylase (ASPA) subfamily of the M14 family of metallocarboxypeptidases. This group includes succinylglutamate desuccinylase that catalyzes the fifth and last step in arginine catabolism by the arginine succinyltransferase pathway. It hydrolyzes N-succinyl-L-glutamate to succinate and L-glutamate.бА0АкА0АаАCDDбАаАавА0А0АаАВUcd03856, M14_Nna1_like, Peptidase M14-like domain of ATP/GTP binding proteins, cytosolic carboxypeptidases and related proteins. Peptidase M14-like domain of Nna-1 (Nervous system Nuclear protein induced by Axotomy), also known as ATP/GTP binding protein (AGTPBP-1) and cytosolic carboxypeptidase (CCP), and related proteins. The Peptidase M14 family of metallocarboxypeptidases are zinc-binding carboxypeptidases (CPs) which hydrolyze single, C-terminal amino acids from polypeptide chains, and have a recognition site for the free C-terminal carboxyl group, which is a key determinant of specificity. This subfamily includes the human AGTPBP-1 and AGBL -2, -3, -4, and -5, and the mouse Nna1/CCP-1 and CCP -2 through -6. Nna1-like proteins are active metallopeptidases that are thought to act on cytosolic proteins such as alpha-tubulin, to remove a C-terminal tyrosine. Nna1 is widely expressed in the developing and adult nervous systems, including cerebellar Purkinje and granule neurons, miral cells of the olfactory bulb and retinal photoreceptors. Nna1 is also induced in axotomized motor neurons. Mutations in Nna1 cause Purkinje cell degeneration (pcd). The Nna1 CP domain is required to prevent the retinal photoreceptor loss and cerebellar ataxia phenotypes of pcd mice, and a functional zinc-binding domain is needed for Nna-1 to support neuron survival in these mice. Nna1-like proteins from the different phyla are highly diverse, but they all contain a characteristic N-terminal conserved domain right before the CP domain. It has been suggested that this N-terminal domain might act as a folding domain.бА0АкА0АаАCDDбАаАбвА0А0АаАВ ═cd03857, M14-like_1, Peptidase M14-like domain; uncharacterized subfamily. Peptidase M14-like domain of a functionally uncharacterized subgroup of the M14 family of metallocarboxypeptidases (MCPs). The M14 family are zinc-binding carboxypeptidases (CPs) which hydrolyze single, C-terminal amino acids from polypeptide chains, and have a recognition site for the free C-terminal carboxyl group, which is a key determinant of specificity. Two major subfamilies of the M14 family, defined based on sequence and structural homology, are the A/B and N/E subfamilies. Enzymes belonging to the A/B subfamily are normally synthesized as inactive precursors containing preceding signal peptide, followed by an N-terminal pro-region linked to the enzyme; these proenzymes are called procarboxypeptidases. The A/B enzymes can be further divided based on their substrate specificity; Carboxypeptidase A-like (CPA-like) enzymes favor hydrophobic residues while carboxypeptidase B-like (CPB-like) enzymes only cleave the basic residues lysine or arginine. The A forms have slightly different specificities, with Carboxypeptidase A1 (CPA1) preferring aliphatic and small aromatic residues, and CPA2 preferring the bulky aromatic side chains. Enzymes belonging to the N/E subfamily enzymes are not produced as inactive precursors and instead rely on their substrate specificity and subcellular compartmentalization to prevent inappropriate cleavage. They contain an extra C-terminal transthyretin-like domain, thought to be involved in folding or formation of oligomers. MCPs can also be classified based on their involvement in specific physiological processes; the pancreatic MCPs participate only in alimentary digestion and include carboxypeptidase A and B (A/B subfamily), while others, namely regulatory MCPs or the N/E subfamily, are involved in more selective reactions, mainly in non-digestive tissues and fluids, acting on blood coagulation/fibrinolysis, inflammation and local anaphylaxis, pro-hormone and neuropeptide processing, cellular response and others. Another MCP subfamily, is that of succinylglutamate desuccinylase /aspartoacylase, which hydrolyzes N-acetyl-L-aspartate (NAA), and deficiency in which is the established cause of Canavan disease. Another subfamily (referred to as subfamily C) includes an exceptional type of activity in the MCP family, that of dipeptidyl-peptidase activity of gamma-glutamyl-(L)-meso-diaminopimelate peptidase I which is involved in bacterial cell wall metabolism.бА0АкА0АаАCDDбАаА═вА0А0АаАВ3cd03858, M14_CP_N-E_like, Peptidase M14 carboxypeptidase subfamily N/E-like. Carboxypeptidase (CP) N/E-like subfamily of the M14 family of metallocarboxypeptidases (MCPs). The M14 family are zinc-binding CPs which hydrolyze single, C-terminal amino acids from polypeptide chains, and have a recognition site for the free C-terminal carboxyl group, which is a key determinant of specificity. The N/E subfamily includes eight members, of which five (CPN, CPE, CPM, CPD, CPZ) are considered enzymatically active, while the other three are non-active (CPX1, PCX2, ACLP/AEBP1) and lack the critical active site and substrate-binding residues considered necessary for CP activity. These non-active members may function as binding proteins or display catalytic activity towards other substrates. Unlike the A/B CP subfamily, enzymes belonging to the N/E subfamily are not produced as inactive precursors that require proteolysis to produce the active form; rather, they rely on their substrate specificity and subcellular compartmentalization to prevent inappropriate cleavages that would otherwise damage the cell. In addition, all members of the N/E subfamily contain an extra C-terminal domain that is not present in the A/B subfamily. This domain has structural homology to transthyretin and other proteins and has been proposed to function as a folding domain. The active N/E enzymes fulfill a variety of cellular functions, including prohormone processing, regulation of peptide hormone activity, alteration of protein-protein or protein-cell interactions and transcriptional regulation.бА0АкА0АаАCDDбАаАввА0А0АаАВcd03859, M14_CPT, Peptidase M14 Carboxypeptidase T subfamily. Peptidase M14-like domain of carboxypeptidase (CP) T (CPT), CPT belongs to the M14 family of metallocarboxypeptidases (MCPs). The M14 family are zinc-binding CPs which hydrolyze single, C-terminal amino acids from polypeptide chains, and have a recognition site for the free C-terminal carboxyl group, which is a key determinant of specificity. CPT has moderate similarity to CPA and CPB, and exhibits dual-substrate specificity by cleaving C-terminal hydrophobic amino acid residues like CPA and C-terminal positively charged residues like CPB. CPA and CPB are M14 family peptidases but do not belong to this CPT group. The substrate specificity difference between CPT and CPA and CPB is ascribed to a few amino acid substitutions at the substrate-binding pocket while the spatial organization of the binding site remains the same as in all Zn-CPs. CPT has increased thermal stability in presence of Ca2+ ions, and two disulfide bridges which give an additional stabilization factor.бА0АкА0АаАCDDбАаАгвА0А0АаАВРcd03860, M14_CP_A-B_like, Peptidase M14 carboxypeptidase subfamily A/B-like. The Peptidase M14 Carboxypeptidase (CP) A/B subfamily is one of two main M14 CP subfamilies defined by sequence and structural homology, the other being the N/E subfamily. CPs hydrolyze single, C-terminal amino acids from polypeptide chains. They have a recognition site for the free C-terminal carboxyl group, which is a key determinant of specificity. Enzymes belonging to the A/B subfamily are normally synthesized as inactive precursors containing preceding signal peptide, followed by a globular N-terminal pro-region linked to the enzyme; these proenzymes are called procarboxypeptidases. The A/B enzymes can be further divided based on their substrate specificity; Carboxypeptidase A-like (CPA-like) enzymes favor hydrophobic residues while carboxypeptidase B-like (CPB-like) enzymes only cleave the basic residues lysine or arginine. There are nine members in the A/B family: CPA1, CPA2, CPA3, CPA4, CPA5, CPA6, CPB, CPO and CPU. CPA1, CPA2 and CPB are produced by the pancreas. The A forms have slightly different specificities, with CPA1 preferring aliphatic and small aromatic residues, and CPA2 preferring the bulkier aromatic side chains. CPA3 is found in secretory granules of mast cells and functions in inflammatory processes. CPA4 is detected in hormone-regulated tissues, and is thought to play a role in prostate cancer. CPA5 is present in discrete regions of pituitary and other tissues, and cleaves aliphatic C-terminal residues. CPA6 is highly expressed in embryonic brain and optic muscle, suggesting that it may play a specific role in cell migration and axonal guidance. CPU (also called CPB2) is produced and secreted by the liver as the inactive precursor, PCPU, commonly referred to as thrombin-activatable fibrinolysis inhibitor (TAFI). Little is known about CPO but it has been suggested to have specificity for acidic residues.бА0АкА0АаАCDDбАаАдвА0А0АаАВ ▒cd03862, M14-like_7, Peptidase M14-like domain; uncharacterized subfamily. A functionally uncharacterized subgroup of the M14 family of metallocarboxypeptidases (MCPs). The M14 family are zinc-binding carboxypeptidases (CPs) which hydrolyze single, C-terminal amino acids from polypeptide chains, and have a recognition site for the free C-terminal carboxyl group, which is a key determinant of specificity. Two major subfamilies of the M14 family, defined based on sequence and structural homology, are the A/B and N/E subfamilies. Enzymes belonging to the A/B subfamily are normally synthesized as inactive precursors containing preceding signal peptide, followed by an N-terminal pro-region linked to the enzyme; these proenzymes are called procarboxypeptidases. The A/B enzymes can be further divided based on their substrate specificity; Carboxypeptidase A-like (CPA-like) enzymes favor hydrophobic residues while carboxypeptidase B-like (CPB-like) enzymes only cleave the basic residues lysine or arginine. The A forms have slightly different specificities, with Carboxypeptidase A1 (CPA1) preferring aliphatic and small aromatic residues, and CPA2 preferring the bulky aromatic side chains. Enzymes belonging to the N/E subfamily enzymes are not produced as inactive precursors and instead rely on their substrate specificity and subcellular compartmentalization to prevent inappropriate cleavages. They contain an extra C-terminal transthyretin-like domain, thought to be involved in folding or formation of oligomers. MCPs can also be classified based on their involvement in specific physiological processes; the pancreatic MCPs participate only in alimentary digestion and include carboxypeptidase A and B (A/B subfamily), while others, namely regulatory MCPs or the N/E subfamily, are involved in more selective reactions, mainly in non-digestive tissues and fluids, acting on blood coagulation/fibrinolysis, inflammation and local anaphylaxis, pro-hormone and neuropeptide processing, cellular response and others. Another MCP subfamily, is that of succinylglutamate desuccinylase /aspartoacylase, which hydrolyzes N-acetyl-L-aspartate (NAA), and deficiency in which is the established cause of Canavan disease. Another subfamily (referred to as subfamily C) includes an exceptional type of activity in the MCP family, that of dipeptidyl-peptidase activity of gamma-glutamyl-(L)-meso-diaminopimelate peptidase I which is involved in bacterial cell wall metabolism.бА0АкА0АаАCDDбАаА╤вА0А0АаАВ3cd03863, M14_CPD_II, Peptidase M14 carboxypeptidase subfamily N/E-like; Carboxypeptidase D, domain II subgroup. The second carboxypeptidase (CP)-like domain of Carboxypeptidase D (CPD; EC 3.4.17.22), domain II. CPD differs from all other metallocarboxypeptidases in that it contains multiple CP-like domains. CPD belongs to the N/E-like subfamily of the M14 family of metallocarboxypeptidases (MCPs).The M14 family are zinc-binding CPs which hydrolyze single, C-terminal amino acids from polypeptide chains, and have a recognition site for the free C-terminal carboxyl group, which is a key determinant of specificity. CPD is a single-chain protein containing a signal peptide, three tandem repeats of CP-like domains separated by short bridge regions, followed by a transmembrane domain, and a C-terminal cytosolic tail. The first two CP-like domains of CPD contain all of the essential active site and substrate-binding residues, while the third CP-like domain lacks critical residues necessary for enzymatic activity and is inactive towards standard CP substrates. Domain I is optimally active at pH 6.3-7.5 and prefers substrates with C-terminal Arg, whereas domain II is active at pH 5.0-6.5 and prefers substrates with C-terminal Lys. CPD functions in the processing of proteins that transit the secretory pathway, and is present in all vertebrates as well as Drosophila. It is broadly distributed in all tissue types. Within cells, CPD is present in the trans-Golgi network and immature secretory vesicles, but is excluded from mature vesicles. It is thought to play a role in the processing of proteins that are initially processed by furin or related endopeptidases present in the trans-Golgi network, such as growth factors and receptors. CPD is implicated in the pathogenesis of lupus erythematosus (LE), it is regulated by TGF-beta in various cell types of murine and human origin and is significantly down-regulated in CD14 positive cells isolated from patients with LE. As down -regulation of CPD leads to down-modulation of TGF-beta, CPD may have a role in a positive feedback loop.бА0АкА0АаАCDDбАаАевА0А0АаАВьcd03864, M14_CPN, Peptidase M14 carboxypeptidase subfamily N/E-like; Carboxypeptidase N subgroup. Peptidase M14 Carboxypeptidase N (CPN, also known as kininase I, creatine kinase conversion factor, plasma carboxypeptidase B, arginine carboxypeptidase, and protaminase; EC 3.4.17.3) is an extracellular glycoprotein synthesized in the liver and released into the blood, where it is present in high concentrations. CPN belongs to the N/E subfamily of the M14 family of metallocarboxypeptidases (MCPs).The M14 family are zinc-binding carboxypeptidases (CPs) which hydrolyze single, C-terminal amino acids from polypeptide chains, and have a recognition site for the free C-terminal carboxyl group, which is a key determinant of specificity. CPN plays an important role in protecting the body from excessive buildup of potentially deleterious peptides that normally act as local autocrine or paracrine hormones. It specifically removes C-terminal basic residues. As CPN can cleave lysine more avidly than arginine residues it is also called lysine carboxypeptidase. CPN substrates include peptides found in the bloodstream, such as kinins (e.g. bradykinin, kalinin, met-lys-bradykinin), complement anaphylatoxins and creatine kinase MM (CK-MM). By removing just one amino acid, CPN can alter peptide activity and receptor binding. For example Bradykinin, a nine-residue peptide released from kiningen in response to tissue injury which is inactivated by CPN, anaphylatoxins which are regulated by CPN by the cleaving and removal of their C-terminal arginines resulting in a reduction in their biological activities of 10-100-fold, and creatine kinase MM, a cytosolic enzyme that catalyzes the reversible transfer of a phosphate group from ATP to creatine, and is regulated by CPN by the cleavage of C-terminal lysines. Like the other N/E subfamily members, two surface loops surrounding the active-site groove restrict access to the catalytic center, thus restricting larger protein carboxypeptidase inhibitors from inhibiting CPN.бА0АкА0АаАCDDбАаАжвА0А0АаАВ_cd03865, M14_CPE, Peptidase M14 carboxypeptidase subfamily N/E-like; Carboxypeptidase E subgroup. Peptidase M14 Carboxypeptidase (CP) E (CPE, also known as carboxypeptidase H, and enkephalin convertase; EC 3.4.17.10) belongs to the N/E subfamily of the M14 family of metallocarboxypeptidases (MCPs).The M14 family are zinc-binding CPs which hydrolyze single, C-terminal amino acids from polypeptide chains, and have a recognition site for the free C-terminal carboxyl group, which is a key determinant of specificity. CPE is an important enzyme responsible for the proteolytic processing of prohormone intermediates (such as pro-insulin, pro-opiomelanocortin, or pro-gonadotropin-releasing hormone) by specifically removing C-terminal basic residues. In addition, it has been proposed that the regulated secretory pathway (RSP) of the nervous and endocrine systems utilizes membrane-bound CPE as a sorting receptor. A naturally occurring point mutation in CPE reduces the stability of the enzyme and causes its degradation, leading to an accumulation of numerous neuroendocrine peptides that result in obesity and hyperglycemia. Reduced CPE enzyme and receptor activity could underlie abnormal placental phenotypes from the observation that CPE is down-regulated in enlarged placentas of interspecific hybrid (interspecies hybrid placental dysplasia, IHPD) and cloned mice.бА0АкА0АаАCDDбАаАзвА0А0АаАВчcd03866, M14_CPM, Peptidase M14 carboxypeptidase subfamily N/E-like; Carboxypeptidase M subgroup. Peptidase M14 Carboxypeptidase (CP) M (CPM) belongs to the N/E subfamily of the M14 family of metallocarboxypeptidases (MCPs).The M14 family are zinc-binding CPs which hydrolyze single, C-terminal amino acids from polypeptide chains, and have a recognition site for the free C-terminal carboxyl group, which is a key determinant of specificity. CPM is an extracellular glycoprotein, bound to cell membranes via a glycosyl-phosphatidylinositol on the C-terminus of the protein. It specifically removes C-terminal basic residues such as lysine and arginine from peptides and proteins. The highest levels of CPM have been found in human lung and placenta, but significant amounts are present in kidney, blood vessels, intestine, brain, and peripheral nerves. CPM has also been found in soluble form in various body fluids, including amniotic fluid, seminal plasma and urine. Due to its wide distribution in a variety of tissues, it is believed that it plays an important role in the control of peptide hormones and growth factor activity on the cell surface and in the membrane-localized degradation of extracellular proteins, for example it hydrolyses the C-terminal arginine of epidermal growth factor (EGF) resulting in des-Arg-EGF which binds to the EGF receptor (EGFR) with an equal or greater affinity than native EGF. CPM is a required processing enzyme that generates specific agonists for the B1 receptor.бА0АкА0АаАCDDбАаАивА0А0АаАВЁcd03867, M14_CPZ, Peptidase M14 carboxypeptidase subfamily N/E-like; Carboxypeptidase Z subgroup. Peptidase M14-like domain of carboxypeptidase (CP) Z (CPZ), CPZ belongs to the N/E subfamily of the M14 family of metallocarboxypeptidases (MCPs). The M14 family are zinc-binding CPs which hydrolyze single, C-terminal amino acids from polypeptide chains, and have a recognition site for the free C-terminal carboxyl group, which is a key determinant of specificity. CPZ is a secreted Zn-dependent enzyme whose biological function is largely unknown. Unlike other members of the N/E subfamily, CPZ has a bipartite structure, which consists of an N-terminal cysteine-rich domain (CRD) whose sequence is similar to Wnt-binding proteins, and a C-terminal CP catalytic domain that removes C-terminal Arg residues from substrates. CPZ is enriched in the extracellular matrix and is widely distributed during early embryogenesis. That the CRD of CPZ can bind to Wnt4 suggests that CPZ plays a role in Wnt signaling.бА0АкА0АаАCDDбАаАйвА0А0АаАВ Hcd03868, M14_CPD_I, Peptidase M14 carboxypeptidase subfamily N/E-like; Carboxypeptidase D, domain I subgroup. The first carboxypeptidase (CP)-like domain of Carboxypeptidase D (CPD; EC 3.4.17.22), domain I. CPD differs from all other metallocarboxypeptidases in that it contains multiple CP-like domains. CPD belongs to the N/E-like subfamily of the M14 family of metallocarboxypeptidases (MCPs).The M14 family are zinc-binding CPs which hydrolyze single, C-terminal amino acids from polypeptide chains, and have a recognition site for the free C-terminal carboxyl group, which is a key determinant of specificity. CPD is a single-chain protein containing a signal peptide, three tandem repeats of CP-like domains separated by short bridge regions, followed by a transmembrane domain, and a C-terminal cytosolic tail. The first two CP-like domains of CPD contain all of the essential active site and substrate-binding residues, the third CP-like domain lacks critical residues necessary for enzymatic activity and is inactive towards standard CP substrates. Domain I is optimally active at pH 6.3-7.5 and prefers substrates with C-terminal Arg, whereas domain II is active at pH 5.0-6.5 and prefers substrates with C-terminal Lys. This Domain I family contains two contiguous surface cysteines that may become palmitoylated and target the enzyme to membranes, thus regulating intracellular trafficking. CPD functions in the processing of proteins that transit the secretory pathway, and is present in all vertebrates as well as Drosophila. It is broadly distributed in all tissue types. Within cells, CPD is present in the trans Golgi network and immature secretory vesicles, but is excluded from mature vesicles. It is thought to play a role in the processing of proteins that are initially processed by furin or related endopeptidases present in the trans Golgi network, such as growth factors and receptors. CPD is implicated in the pathogenesis of lupus erythematosus (LE), it is regulated by TGF-beta in various cell types of murine and human origin and is significantly down-regulated in CD14 positive cells isolated from patients with LE. As down-regulation of CPD leads to down-modulation of TGF-beta, CPD may have a role in a positive feedback loop. In D. melanogaster, the CPD variant 1B short (DmCPD1Bs) is necessary and sufficient for viability of the fruit fly.бА0АкА0АаАCDDбАаАквА0А0АаАВcd03869, M14_CPX_like, Peptidase M14 carboxypeptidase subfamily N/E-like; Carboxypeptidase X subgroup. Peptidase M14-like domain of carboxypeptidase (CP)-like protein X (CPX), CPX forms a distinct subgroup of the N/E subfamily of the M14 family of metallocarboxypeptidases (MCPs). The M14 family are zinc-binding CPs which hydrolyze single, C-terminal amino acids from polypeptide chains, and have a recognition site for the free C-terminal carboxyl group, which is a key determinant of specificity. Proteins belonging to this subgroup include CP-like protein X1 (CPX1), CP-like protein X2 (CPX2), and aortic CP-like protein (ACLP) and its isoform adipocyte enhancer binding protein-1 (AEBP1). AEBP1 is a truncated form of ACLP, which may arise from alternative splicing of the gene. These proteins are inactive towards standard CP substrates because they lack one or more critical active site and substrate-binding residues that are necessary for activity. They may function as binding proteins rather than as active CPs or display catalytic activity toward other substrates. Proteins in this subgroup also contain an N-terminal discoidin domain. The CP domain is important for the function of AEBP1 as a transcriptional repressor. AEBP1 is involved in several biological processes including adipogenesis, macrophage cholesterol homeostasis, and inflammation. In macrophages, AEBP1 promotes the expression of IL-6, TNF-alpha, MCP-1, and iNOS whose expression is tightly regulated by NF-kappaB activity. ACLP, a secreted protein that associates with the extracellular matrix, is essential for abdominal wall development and contributes to dermal wound healing.бА0АкА0АаАCDDбАаАлвА0А0АаАВ┴cd03870, M14_CPA, Peptidase M14 carboxypeptidase subfamily A/B-like; Carboxypeptidase A subgroup. Peptidase M14 Carboxypeptidase (CP) A (CPA) belongs to the A/B subfamily of the M14 family of metallocarboxypeptidases (MCPs). The M14 family are zinc-binding CPs which hydrolyze single, C-terminal amino acids from polypeptide chains, and have a recognition site for the free C-terminal carboxyl group, which is a key determinant of specificity. CPA enzymes generally favor hydrophobic residues. A/B subfamily enzymes are normally synthesized as inactive precursors containing preceding signal peptide, followed by a globular N-terminal pro-region linked to the enzyme; these proenzymes are called procarboxypeptidases. The procarboxypeptidase A (PCPA) is produced by the exocrine pancreas and stored as a stable zymogen in the pancreatic granules until secretion into the digestive tract occurs. This subfamily includes CPA1, CPA2 and CPA4 forms. Within these A forms, there are slightly different specificities, with CPA1 preferring aliphatic and small aromatic residues, and CPA2 preferring the bulkier aromatic side chains. CPA4, detected in hormone-regulated tissues, is thought to play a role in prostate cancer.бА0АкА0АаАCDDбАаА┘вА0А0АаАВ;cd03871, M14_CPB, Peptidase M14 carboxypeptidase subfamily A/B-like; Carboxypeptidase B subgroup. Peptidase M14 Carboxypeptidase B (CPB) belongs to the carboxypeptidase A/B subfamily of the M14 family of metallocarboxypeptidases (MCPs). The M14 family are zinc-binding CPs which hydrolyze single, C-terminal amino acids from polypeptide chains, and have a recognition site for the free C-terminal carboxyl group, which is a key determinant of specificity. Carboxypeptidase B (CPB) enzymes only cleave the basic residues lysine or arginine. A/B subfamily enzymes are normally synthesized as inactive precursors containing preceding signal peptide, followed by a globular N-terminal pro-region linked to the enzyme; these proenzymes are called procarboxypeptidases. The procarboxypeptidase B (PCPB) is produced by the exocrine pancreas and stored as stable zymogen in the pancreatic granules until secretion into the digestive tract occurs. PCPB has been reported to be a good serum marker for the diagnosis of acute pancreatitis and graft rejection in pancreas transplant recipients.бА0АкА0АаАCDDбАаАмвА0А0АаАВBcd03872, M14_CPA6, Peptidase M14 carboxypeptidase subfamily A/B-like; Carboxypeptidase A6 subgroup. Carboxypeptidase (CP) A6 (CPA6, also known as CPAH; EC 3.4.17.1), belongs to the carboxypeptidase A/B subfamily of the M14 family of metallocarboxypeptidases (MCPs). The M14 family are zinc-binding CPs which hydrolyze single, C-terminal amino acids from polypeptide chains, and have a recognition site for the free C-terminal carboxyl group, which is a key determinant of specificity. CPA6 prefers large hydrophobic C-terminal amino acids as well as histidine, while peptides with a penultimate glycine or proline are very poorly cleaved. Several neuropeptides are processed by CPA6, including Met- and Leu-enkephalin, angiotensin I, and neurotensin. CPA6 converts enkephalin and neurotensin into forms known to be inactive toward their receptors, but converts inactive angiotensin I into the biologically active angiotensin II. Thus, CPA6 plays a possible role in the regulation of neuropeptides in the extracellular environment within the olfactory bulb where it is highly expressed. It is also broadly expressed in embryonic tissue, being found in neuronal tissues, bone, skin as well as the lateral rectus eye muscle. A disruption in the CPA6 gene is linked to Duane syndrome, a defect in the abducens nerve/lateral rectus muscle connection.бА0АкА0АаАCDDбАаАнвА0А0АаАВ█cd03873, Zinc_peptidase_like, Zinc peptidases M18, M20, M28, and M42. Zinc peptidases play vital roles in metabolic and signaling pathways throughout all kingdoms of life. This family corresponds to several clans in the MEROPS database, including the MH clan, which contains 4 families (M18, M20, M28, M42). The peptidase M20 family includes carboxypeptidases such as the glutamate carboxypeptidase from Pseudomonas, the thermostable carboxypeptidase Ss1 of broad specificity from archaea and yeast Gly-X carboxypeptidase. The dipeptidases include bacterial dipeptidase, peptidase V (PepV), a eukaryotic, non-specific dipeptidase, and two Xaa-His dipeptidases (carnosinases). There is also the bacterial aminopeptidase, peptidase T (PepT) that acts only on tripeptide substrates and has therefore been termed a tripeptidase. Peptidase family M28 contains aminopeptidases and carboxypeptidases, and has co-catalytic zinc ions. However, several enzymes in this family utilize other first row transition metal ions such as cobalt and manganese. Each zinc ion is tetrahedrally co-ordinated, with three amino acid ligands plus activated water; one aspartate residue binds both metal ions. The aminopeptidases in this family are also called bacterial leucyl aminopeptidases, but are able to release a variety of N-terminal amino acids. IAP aminopeptidase and aminopeptidase Y preferentially release basic amino acids while glutamate carboxypeptidase II preferentially releases C-terminal glutamates. Glutamate carbxypeptidase II and plasma glutamate carboxypeptidase hydrolyze dipeptides. Peptidase families M18 and M42 contain metalloaminopeptidases. M18 is widely distributed in bacteria and eukaryotes. However, only yeast aminopeptidase I and mammalian aspartyl aminopeptidase have been characterized in detail. Some of M42 (also known as glutamyl aminopeptidase) enzymes exhibit aminopeptidase specificity while others also have acylaminoacylpeptidase activity (i.e. hydrolysis of acylated N-terminal residues).бА0АкА0АаАCDDбАаАє╫вА0А0АаАВ ═cd03874, M28_PMSA_TfR_like, M28 Zn-peptidase Transferrin Receptor-like family. Peptidase M28 family; Transferrin Receptor (TfR) and prostate-specific membrane antigen (PSMA, also called glutamate carboxypeptidase or GCP-II) subfamily. TfR and PSMA are homodimeric type II transmembrane proteins containing three distinct domains: protease-like, apical or protease-associated (PA) and helical domains. The protease-like domain is a large extracellular portion (ectodomain). In TfR, it contains a binding site for the transferrin molecule and has 28% identity to membrane glutamate carboxypeptidase II (mGCP-II or PSMA). The PA domain is inserted between the first and second strands of the central beta sheet in the protease-like domain. TfR1 is widely expressed, and is a key player in the uptake of iron-loaded transferrin (Tf) into cells. The TfR1 homodimer binds two molecules of Tf and the complex is then internalized. TfR1 may also participate in cell growth and proliferation. TfR2 binds Tf but with a significantly lower affinity than TfR1. It is expressed chiefly in hepatocytes, hematopoietic cells, and duodenal crypt cells; its expression overlaps with that of hereditary hemochromatosis protein (HFE). TfR2 is involved in iron homeostasis; in humans, mutations in TfR2 are associated with a form of hemochromatosis (HFE3). PSMA is over-expressed predominantly in prostate cancer (PCa) as well as neovasculature of most solid tumors, but not in the vasculature of normal tissues. PSMA is considered a biomarker for PCa and possibly for use as an imaging and therapeutic target. The extracellular domain of PSMA possesses two unique enzymatic functions: N-acetylated, alpha-linked acidic dipeptidase (NAALADase) which cleaves terminal glutamate from the neurodipeptide N-acetyl-aspartyl-glutamate (NAAG), and folate hydrolase (FOLH) which cleaves the terminal glutamates from gamma-linked polyglutamates (carboxypeptidase). A mutation in this gene may be associated with impaired intestinal absorption of dietary folates, resulting in low blood folate levels and consequent hyperhomocysteinemia. Expression of this protein in the brain may be involved in a number of pathological conditions associated with glutamate excitotoxicity. This gene likely arose from a duplication event of a nearby chromosomal region. Alternative splicing gives rise to multiple transcript variants. While related in sequence to peptidase M28 GCP-II, TfR lacks the metal ion coordination centers and protease activity.бА0АкА0АаАCDDбАаАє╪вА0А0АаАВacd03875, M28_Fxna_like, M28 Zn-peptidase Endoplasmic reticulum metallopeptidase 1. Peptidase family M28; Endoplasmic reticulum metallopeptidase 1 (ERMP1; Felix-ina, FXNA or Fxna peptidase; KIAA1815) subfamily. ERMP1 is a multi-pass membrane protein located in the endoplasmic reticulum membrane. In humans, Fxna may play a crucial role in processing proteins required for the organization of somatic cells and oocytes into discrete follicular structures, although which proteins are hydrolyzed has not yet been determined. Another member of this cluster is the 24-kDa vacuolar protein (VP24) which is probably involved in the formation of intravacuolar pigmented globules (cyanoplasts) in highly anthocyanin-containing vacuoles; however, the biological function of the C-terminal region which includes the putative transmembrane metallopeptidase domain is unknown.бА0АкА0АаАCDDбАаАє┘вА0А0АаАВHcd03876, M28_SGAP_like, M28 Zn-peptidase Streptomyces griseus Aminopeptidase and similar proteins. Peptidase family M28; Streptomyces griseus Aminopeptidase (SGAP, Leucine aminopeptidase (LAP), aminopeptidase S, Mername-AA022 peptidase) subfamily. SGAP is a di-zinc exopeptidase with high preference towards large hydrophobic amino-terminal residues, with Leu being the most efficiently cleaved. It can accommodate all except Pro and Glu residues in the P1' position. It is a monomeric (30 kDa), calcium-activated and calcium-stabilized enzyme; its activation by calcium correlates with substrate specificity and it has thermal stability only in the presence of calcium. Although SGAP contains a calcium binding site, it is not conserved in many members of this subfamily. SGAP is present in the extracellular fluid of S. griseus cultures.бА0АкА0АаАCDDбАаАє┌вА0А0АаАВ\cd03877, M28_like_PA, M28 Zn-Peptidases containing a PA domain insert. Peptidase family M28 (also called aminopeptidase Y family), uncharacterized subfamily. The M28 family contains aminopeptidases as well as carboxypeptidases. They have co-catalytic zinc ions; each zinc ion is tetrahedrally co-ordinated, with three amino acid ligands plus activated water; one aspartate residue binds both metal ions. This subfamily is composed of uncharacterized proteins, many of which contain a protease-associated (PA) domain insert which may participate in substrate binding and/or promote conformational changes, influencing the stability and accessibility of the site to substrate. Some proteins in this subfamily are also associated with the PDZ domain, a widespread protein module that has been recruited to serve multiple functions during the course of evolution.бА0АкА0АаАCDDбАаАє█вА0А0АаАВюcd03879, M28_AAP, M28 Zn-Peptidase Aeromonas (Vibrio) proteolytica aminopeptidase. Peptidase family M28; Aeromonas (Vibrio) proteolytica aminopeptidase (AAP; leucine aminopeptidase from Vibrio proteolyticus; Bacterial leucyl aminopeptidase; E.C. 3.4.11.10) subfamily. AAP is a small (32kDa), heat stable leucine aminopeptidase and is active as a monomer. Similar forms of the enzyme have been isolated from Escherichia coli and Staphylococcus thermophilus. Leucine aminopeptidases, in general, play important roles in many biological processes such as protein catabolism, hormone degradation, regulation of migration and cell proliferation, as well as HIV infection and proliferation. AAP is a broad-specificity enzyme, utilizing two zinc(II) ions in its active site to remove N-terminal amino acids, with preference for large hydrophobic amino acids in the P1 position of the substrate, Leu being the most efficiently cleaved. It can accommodate all residues, except Pro, Asp and Glu in the P1' position.бА0АкА0АаАCDDбАаАє▄вА0А0АаАВcd03880, M28_QC_like, M28 Zn-Peptidase Glutaminyl Cyclase. Peptidase M28 family; Glutaminyl Cyclase (QC; EC 2.3.2.5) subfamily. QC is involved in N-terminal glutamine cyclization of many endocrine peptides and is typically abundant in brain tissue. N-terminal glutamine residue cyclization is an important post-translational event in the processing of numerous bioactive proteins, including neuropeptides, hormones, and cytokines during their maturation in the secretory pathway. The N-terminal pGlu protects them from exopeptidase degradation and/or enables them to have proper conformation for binding to the receptors. QCs are highly conserved from yeast to human. In humans, several genetic diseases, such as osteoporosis, appear to result from mutations of the QC gene. N-terminal glutamate cyclization into pyroglutamate (pGlu) is a reaction that may be related to the formation of several plaque-forming peptides, such as amyloid-(A) peptides and collagen-like Alzheimer amyloid plaque component, which play a pivotal role in Alzheimer's disease.бА0АкА0АаАCDDбАаАє▌вА0А0АаАВ.cd03881, M28_Nicastrin, M28 Zn-Peptidase Nicastrin, a main component of gamma-secretase complex. Peptidase M28 family, Nicastrin subfamily. Nicastrin is a main component of gamma-secretase complex. Its extracellular domain sequence resembles aminopeptidases, but certain catalytic residues are not conserved. It is mainly localized to the endoplasmic reticulum and Golgi. It is highly glycosylated (Mr 120 kDa) and is essential for substrate recognition of the N-terminus of gamma-secretase substrates derived from APP and Notch. Nicastrin facilitates substrate cleavage by the catalytic presenilin subunit in the gamma-secretase complex. One conserved glutamate is especially important, probably because this residue forms an ion pair with the amino terminus of the substrate. This substrate-binding domain is often called the DAP domain (named after DYIGS, the amino acid stretch that modulates amyloid precursor protein (APP) processing, and Peptidase homologous region). The sequence of the substrate N-terminus is apparently not critical for the interaction, but a free amino group is. Thus, nicastrin can be considered a kind of gatekeeper for the gamma-secretase complex: type I membrane proteins that have not shed their ectodomains cannot interact properly with nicastrin and do not gain access to the active site.бА0АкА0АаАCDDбАаАє▐вА0А0АаАВ═cd03882, M28_nicalin_like, M28 Zn-Peptidase Nicalin, Nicastrin-like protein. Peptidase M28 family, Nicalin (nicastrin-like protein) subfamily. Nicalin is distantly related to Nicastrin, a component of the Alzheimer's disease-associated gamma-secretase, and forms a complex with Nomo (nodal modulator) pM5. Similar to Nicastrin, Nicalin lacks the amino-acid conservation required for catalytically active aminopeptidases. Functional studies in zebrafish embryos and cultured human cells reveal that nicalin and Nomo collaborate to antagonize the Nodal/TGFbeta signaling pathway. Thus, nicastrin and nicalin are both associated with protein complexes involved in cell fate decisions during early embryonic development.бА0АкА0АаАCDDбАаАє▀вА0А0АаАВ!cd03883, M28_Pgcp_like, M28 Zn-Peptidase Plasma glutamate carboxypeptidase. Peptidase M28 family; Plasma glutamate carboxypeptidase (PGCP; blood plasma glutamate carboxypeptidase; EC 3.4.17.21) subfamily. PGCP is a 56kDa glutamate carboxypeptidase that is mainly produced in mammalian placenta and kidney, the majority of which is thought to be secreted into the bloodstream. Similar proteins are also found in other species, including bacteria. These proteins contain protease-associated (PA) domain inserts between the first and second strands of the central beta sheet in the protease-like domain. The PA domains may participate in substrate binding and/or promoting conformational changes, which influence the stability and accessibility of the site to substrate. The exact physiological substrates of PGCP are unknown, although this enzyme may play an important role in the hydrolysis of circulating peptides. Its closest homolog encodes an important brain glutamate carboxypeptidase II (NAALADase) identical to the prostate-specific membrane antigen (PSMA), which serves as a marker for prostatic cancer metastasis. However, PGCP has not been linked to any type of cancer. It provides an attractive target for serological analysis in hepatitis C virus (HCV)-induced hepatocellular carcinoma (HCC) patients.бА0АкА0АаАCDDбАаАєрвА0А0АаАВ№cd03884, M20_bAS, M20 Peptidase beta-alanine synthase, an amidohydrolase. Peptidase M20 family, beta-alanine synthase (bAS; N-carbamoyl-beta-alanine amidohydrolase and beta-ureidopropionase; EC 3.5.1.6) subfamily. bAS is an amidohydrolase and is the final enzyme in the pyrimidine catabolic pathway, which is involved in the regulation of the cellular pyrimidine pool. The bAS catalyzes the irreversible hydrolysis of the N-carbamylated beta-amino acids to beta-alanine or aminoisobutyrate under the release of carbon dioxide and ammonia. Also included in this subfamily is allantoate amidohydrolase (allantoate deiminase), which catalyzes the conversion of allantoate to (S)-ureidoglycolate, one of the crucial alternate steps in purine metabolism. It is possible that these two enzymes arose from the same ancestral peptidase that evolved into two structurally related enzymes with distinct catalytic properties and biochemical roles within the cell. Yeast requires beta-alanine as a precursor of pantothenate and coenzyme A biosynthesis, but generates it mostly via degradation of spermine. Disorders in pyrimidine degradation and beta-alanine metabolism caused by beta-ureidopropionase deficiency (UPB1 gene) in humans are normally associated with neurological disorders.бА0АкА0АаАCDDбАаАєсвА0А0АаАВecd03885, M20_CPDG2, M20 Peptidase Glutamate carboxypeptidase, a periplasmic enzyme. Peptidase M20 family, Glutamate carboxypeptidase (carboxypeptidase G; carboxypeptidase G1; carboxypeptidase G2; CPDG2; CPG2; Folate hydrolase G2; Pteroylmonoglutamic acid hydrolase G2; Glucarpidase; E.C. 3.4.17.11) subfamily. CPDG2 is a periplasmic enzyme that is synthesized with a signal peptide. It is a dimeric zinc-dependent exopeptidase, with two domains, a catalytic domain, which provides the ligands for the two zinc ions in the active site, and a dimerization domain. CPDG2 cleaves the C-terminal glutamate moiety from a wide range of N-acyl groups, including peptidyl, aminoacyl, benzoyl, benzyloxycarbonyl, folyl, and pteroyl groups to release benzoic acid, phenol, and aniline mustards. It is used clinically to treat methotrexate toxicity by hydrolyzing it to inactive and non-toxic metabolites. It is also proposed for use in antibody-directed enzyme prodrug therapy; for example, glutamate can be cleaved from glutamated benzoyl nitrogen mustards, producing nitrogen mustards with effective cytotoxicity against tumor cells.бА0АкА0АаАCDDбАаАєтвА0А0АаАВcd04042, C2A_MCTP_PRT, C2 domain first repeat found in Multiple C2 domain and Transmembrane region Proteins (MCTP). MCTPs are involved in Ca2+ signaling at the membrane. MCTP is composed of a variable N-terminal sequence, three C2 domains, two transmembrane regions (TMRs), and a short C-terminal sequence. It is one of four protein classes that are anchored to membranes via a transmembrane region; the others being synaptotagmins, extended synaptotagmins, and ferlins. MCTPs are the only membrane-bound C2 domain proteins that contain two functional TMRs. MCTPs are unique in that they bind Ca2+ but not phospholipids. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the first C2 repeat, C2A, and has a type-II topology.бА0АкА0АаАCDDбАаАпЗвА0А0АаАВcd04043, C2_Munc13_fungal, C2 domain in Munc13 (mammalian uncoordinated) proteins; fungal group. C2-like domains are thought to be involved in phospholipid binding in a Ca2+ independent manner in both Unc13 and Munc13. Caenorabditis elegans Unc13 has a central domain with sequence similarity to PKC, which includes C1 and C2-related domains. Unc13 binds phorbol esters and DAG with high affinity in a phospholipid manner. Mutations in Unc13 results in abnormal neuronal connections and impairment in cholinergic neurotransmission in the nematode. Munc13 is the mammalian homolog which are expressed in the brain. There are 3 isoforms (Munc13-1, -2, -3) and are thought to play a role in neurotransmitter release and are hypothesized to be high-affinity receptors for phorbol esters. Unc13 and Munc13 contain both C1 and C2 domains. There are two C2 related domains present, one central and one at the carboxyl end. Munc13-1 contains a third C2-like domain. Munc13 interacts with syntaxin, synaptobrevin, and synaptotagmin suggesting a role for these as scaffolding proteins. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the second C2 repeat, C2B, and has a type-II topology.бА0АкА0АаАCDDбАаАпИвА0А0АаАВ╗cd04044, C2A_Tricalbin-like, C2 domain first repeat present in Tricalbin-like proteins. 5 to 6 copies of the C2 domain are present in Tricalbin, a yeast homolog of Synaptotagmin, which is involved in membrane trafficking and sorting. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the first C2 repeat, C2A, and has a type-II topology.бА0АкА0АаАCDDбАаАпЙвА0А0АаАВ╗cd04045, C2C_Tricalbin-like, C2 domain third repeat present in Tricalbin-like proteins. 5 to 6 copies of the C2 domain are present in Tricalbin, a yeast homolog of Synaptotagmin, which is involved in membrane trafficking and sorting. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the third C2 repeat, C2C, and has a type-II topology.бА0АкА0АаАCDDбАаАпКвА0А0АаАВ╡cd04046, C2_Calpain, C2 domain present in Calpain proteins. A single C2 domain is found in calpains (EC 3.4.22.52, EC 3.4.22.53), calcium-dependent, non-lysosomal cysteine proteases. Caplains are classified as belonging to Clan CA by MEROPS and include six families: C1, C2, C10, C12, C28, and C47. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions.бА0АкА0АаАCDDбАаАпЛвА0А0АаАВ┤cd04047, C2B_Copine, C2 domain second repeat in Copine. There are 2 copies of the C2 domain present in copine, a protein involved in membrane trafficking, protein-protein interactions, and perhaps even cell division and growth. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the second C2 repeat, C2B, and has a type-I topology.бА0АкА0АаАCDDбАаАпМвА0А0АаАВ▓cd04048, C2A_Copine, C2 domain first repeat in Copine. There are 2 copies of the C2 domain present in copine, a protein involved in membrane trafficking, protein-protein interactions, and perhaps even cell division and growth. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the first C2 repeat, C2A, and has a type-I topology.бА0АкА0АаАCDDбАаАпНвА0А0АаАВ╩cd04049, C2_putative_Elicitor-responsive_gene, C2 domain present in the putative elicitor-responsive gene. In plants elicitor-responsive proteins are triggered in response to specific elicitor molecules such as glycolproteins, peptides, carbohydrates and lipids. A host of defensive responses are also triggered resulting in localized cell death. Antimicrobial secondary metabolites, such as phytoalexins, or defense-related proteins, including pathogenesis-related (PR) proteins are also produced. There is a single C2 domain present here. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. Members have a type-II topology.бА0АкА0АаАCDDбАаАпОвА0А0АаАВ+cd04050, C2B_Synaptotagmin-like, C2 domain second repeat present in Synaptotagmin-like proteins. Synaptotagmin is a membrane-trafficking protein characterized by a N-terminal transmembrane region, a linker, and 2 C-terminal C2 domains. Previously all synaptotagmins were thought to be calcium sensors in the regulation of neurotransmitter release and hormone secretion, but it has been shown that not all of them bind calcium. Of the 17 identified synaptotagmins only 8 bind calcium (1-3, 5-7, 9, 10). The function of the two C2 domains that bind calcium are: regulating the fusion step of synaptic vesicle exocytosis (C2A) and binding to phosphatidyl-inositol-3,4,5-triphosphate (PIP3) in the absence of calcium ions and to phosphatidylinositol bisphosphate (PIP2) in their presence (C2B). C2B also regulates also the recycling step of synaptic vesicles. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the second C2 repeat, C2B, and has a type-I topology.бА0АкА0АаАCDDбАаАпПвА0А0АаАВ,cd04051, C2_SRC2_like, C2 domain present in Soybean genes Regulated by Cold 2 (SRC2)-like proteins. SRC2 production is a response to pathogen infiltration. The initial response of increased Ca2+ concentrations are coupled to downstream signal transduction pathways via calcium binding proteins. SRC2 contains a single C2 domain which localizes to the plasma membrane and is involved in Ca2+ dependent protein binding. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions.бА0АкА0АаАCDDбАаАпРвА0А0АаАВ╝cd04052, C2B_Tricalbin-like, C2 domain second repeat present in Tricalbin-like proteins. 5 to 6 copies of the C2 domain are present in Tricalbin, a yeast homolog of Synaptotagmin, which is involved in membrane trafficking and sorting. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the second C2 repeat, C2B, and has a type-II topology.бА0АкА0АаАCDDбАаАпСвА0А0АаАВ9cd04054, C2A_Rasal1_RasA4, C2 domain first repeat present in RasA1 and RasA4. Rasal1 and RasA4 are both members of GAP1 (GTPase activating protein 1). Rasal1 responds to repetitive Ca2+ signals by associating with the plasma membrane and deactivating Ras. RasA4 suppresses Ras function by enhancing the GTPase activity of Ras proteins resulting in the inactive GDP-bound form of Ras. In this way it can control cellular proliferation and differentiation. Both of these proteins contains two C2 domains, a Ras-GAP domain, a plextrin homology (PH)-like domain, and a Bruton's Tyrosine Kinase (BTK) zinc binding domain. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the first C2 repeat, C2A, and has a type-I topology.бА0АкА0АаАCDDбАаАпТвА0А0АаАВ╠cd04056, Peptidases_S53, Peptidase domain in the S53 family. Members of the peptidases S53 (sedolisin) family include endopeptidases and exopeptidases sedolisin, kumamolysin, and (PSCP) Pepstatin-insensitive Carboxyl Proteinase. The S53 family contains a catalytic triad Glu/Asp/Ser with an additional acidic residue Asp in the oxyanion hole, similar to that of Asn in subtilisin. The stability of these enzymes may be enhanced by calcium, some members have been shown to bind up to 4 ions via binding sites with different affinity. Some members of this clan contain disulfide bonds. These enzymes can be intra- and extracellular, some function at extreme temperatures and pH values. Characterized sedolisins include Kumamolisin, an extracellular calcium-dependent thermostable endopeptidase from Bacillus. The enzyme is synthesized with a 188 amino acid N-terminal preprotein region which is cleaved after the extraction into the extracellular space with low pH. One kumamolysin paralog, kumamolisin-As, is believed to be a collagenase. TPP1 is a serine protease that functions as a tripeptidyl exopeptidase as well as an endopeptidase. Less is known about PSCP from Pseudomonas which is thought to be an aspartic proteinase.бА0АкА0АаАCDDбАаАж▄вА0А0АаАВjcd04059, Peptidases_S8_Protein_convertases_Kexins_Furin-like, Peptidase S8 family domain in Protein convertases. Protein convertases, whose members include furins and kexins, are members of the peptidase S8 or Subtilase clan of proteases. They have an Asp/His/Ser catalytic triad that is not homologous to trypsin. Kexins are involved in the activation of peptide hormones, growth factors, and viral proteins. Furin cleaves cell surface vasoactive peptides and proteins involved in cardiovascular tissue remodeling in the TGN, at cell surface, or in endosomes but rarely in the ER. Furin also plays a key role in blood pressure regulation though the activation of transforming growth factor (TGF)-beta. High specificity is seen for cleavage after dibasic (Lys-Arg or Arg-Arg) or multiple basic residues in protein convertases. There is also strong sequence conservation.бА0АкА0АаАCDDбАаАж▌вА0А0АаАВ╥cd04077, Peptidases_S8_PCSK9_ProteinaseK_like, Peptidase S8 family domain in ProteinaseK-like proteins. The peptidase S8 or Subtilase clan of proteases have a Asp/His/Ser catalytic triad that is not homologous to trypsin. This CD contains several members of this clan including: PCSK9 (Proprotein convertase subtilisin/kexin type 9), Proteinase_K, Proteinase_T, and other subtilisin-like serine proteases. PCSK9 posttranslationally regulates hepatic low-density lipoprotein receptors (LDLRs) by binding to LDLRs on the cell surface, leading to their degradation. The binding site of PCSK9 has been localized to the epidermal growth factor-like repeat A (EGF-A) domain of the LDLR. Characterized Proteinases K are secreted endopeptidases with a high degree of sequence conservation. Proteinases K are not substrate-specific and function in a wide variety of species in different pathways. It can hydrolyze keratin and other proteins with subtilisin-like specificity. The number of calcium-binding motifs found in these differ. Proteinase T is a novel proteinase from the fungus Tritirachium album Limber. The amino acid sequence of proteinase T as deduced from the nucleotide sequence is about 56% identical to that of proteinase K.бА0АкА0АаАCDDбАаАж▐вА0А0АаАВ┐cd04078, CBM36_xylanase-like, Carbohydrate Binding Module family 36 (CBM36); appended mainly to glycoside hydrolase family 11 (GH11) domains; xylan binding. This family includes carbohydrate binding module family 36 (CBM36) most of which appear appended to glycoside hydrolase family 11 (GH11) domains. These CBMs are non-catalytic carbohydrate binding domains that facilitate the strong binding of the GH11 catalytic modules with their dedicated, insoluble substrates. GH11 domains have xylanase (endo-1,4-beta-xylanase) activity which catalyzes the hydrolysis of beta-1,4 bonds of xylan, the major component of hemicelluloses, to generate xylooligosaccharides and xylose. This family includes XynB from Dictyoglomus thermophilum Rt46B.1 and Xyn11A from Pseudobutyrivibrio xylanivorans Mz5T. Xyn11A is a multicatalytic enzyme with an N-terminal GH11 domain, a CBM36 domain, and a C-terminal putative NodB-like polysaccharide deacetylase which is predicted to be an acetyl esterase involved in debranching activity in the xylan backbone. CBM6 is an unusual CBM as it represents a chimera of two distinct binding sites with different modes of binding: binding site I within the loop regions and binding site II on the concave face of the beta-sandwich fold. Consistent with its structural and sequence similarity to CBM6, CBM36 binds xylan, but only at binding site I, and in a calcium-dependent manner; the latter suggests its potential application in affinity labeling.бА0АкА0АаАCDDбАаА#(вА0А0АаАВ╥cd04079, CBM6_agarase-like, Carbohydrate Binding Module 6 (CBM6); appended mainly to glycoside hydrolase (GH) family 16 alpha- and beta agarases. This family includes carbohydrate binding module 6 (CBM6) domains that are appended mainly to glycoside hydrolase (GH) family 16 agarases. These CBM6s are non-catalytic carbohydrate binding domains that facilitate the activity of alpha- and beta-agarase catalytic modules which are involved in the hydrolysis of 1,4-beta-D-galactosidic linkages. These CBM6s bind specifically to the non-reducing end of agarose chains, recognizing only the first repeat of the disaccharide, and directing the appended catalytic modules to areas of the plant cell wall attacked by beta-agarases. CBM6 is an unusual CBM as it represents a chimera of two distinct binding sites with different modes of binding: binding site I within the loop regions and binding site II on the concave face of the beta-sandwich fold. This family includes three tandem CBM6s from the Saccharophagus degradans agarase Aga86E, and three tandem CBM6s from Vibrio sp. strain PO-303 AgaA; in both these proteins these are appended to a GH16 domain. Vibrio AgaA also contains a Big-2-like protein-protein interaction domain. This family also includes two tandem CBM6s from an endo-type beta-agarase from a deep-sea Microbulbifer-like isolate, which are appended to a GH16 domain, and two of three CBM6s of Alteromonas agarilytica AgaA alpha-agarase, which are appended to a GH96 domain.бА0АкА0АаАCDDбАаА#)вА0А0АаАВCcd04080, CBM6_cellulase-like, Carbohydrate Binding Module 6 (CBM6); appended to glycoside hydrolase (GH) domains, including GH5 (cellulase). This family includes carbohydrate binding module 6 (CBM6) domains that are appended to several glycoside hydrolase (GH) domains, including GH5 (cellulase) and GH16, as well as to coagulation factor 5/8 carbohydrate-binding domains. CBM6s are non-catalytic carbohydrate binding domains that facilitate the strong binding of the GH catalytic modules with their dedicated, insoluble substrates. The CBM6s are appended to GHs that display a diversity of substrate specificities. For some members of this family information is available about the specific substrates of the appended GH domains. It includes the CBM domains of various enzymes involved in cell wall degradation including, an extracellular beta-1,3-glucanase from Lysobacter enzymogenes encoded by the gluC gene (its catalytic domain belongs to the GH16 family), the tandem CBM domains of Pseudomonas sp. PE2 beta-1,3(4)-glucanase A (its catalytic domain also belongs to GH16), and a family 6 CBM from Cellvibrio mixtus Endoglucanase 5A (CmCBM6) which binds to the beta1,4-beta1,3-mixed linked glucans lichenan, and barley beta-glucan, cello-oligosaccharides, insoluble forms of cellulose, the beta1,3-glucan laminarin, and xylooligosaccharides, and the CBM6 of Fibrobacter succinogenes S85 XynD xylanase, appended to a GH10 domain, and Cellvibrio japonicas Cel5G appended to a GH5 (cellulase) domain. GH5 (cellulase) family includes enzymes with several known activities such as endoglucanase, beta-mannanase, and xylanase, which are involved in the degradation of cellulose and xylans. GH16 family includes enzymes with lichenase, xyloglucan endotransglycosylase (XET), and beta-agarase activities. CBM6 is an unusual CBM as it represents a chimera of two distinct binding sites with different modes of binding: binding site I within the loop regions and binding site II on the concave face of the beta-sandwich fold. For CmCBM6 it has been shown that these two binding sites have different ligand specificities.бА0АкА0АаАCDDбАаА#*вА0А0АаАВдcd04081, CBM35_galactosidase-like, Carbohydrate Binding Module family 35 (CBM35); appended mainly to enzymes that bind alpha-D-galactose (CBM35-Gal), including glycoside hydrolase (GH) families GH27 and GH43. This family includes carbohydrate binding module family 35 (CBM35); these are non-catalytic carbohydrate binding domains that are appended mainly to enzymes that bind alpha-D-galactose (CBM35-Gal), including glycoside hydrolase (GH) families GH27 and GH43. Examples of proteins which contain CBM35s belonging to this family includes the CBM35 of an exo-beta-1,3-galactanase from Phanerochaete chrysosporium 9 (Pc1,3Gal43A) which is appended to a GH43 domain, and the CBM35 domain of two bifunctional proteins with beta-L-arabinopyranosidase/alpha-D-galactopyranosidase activities from Fusarium oxysporum 12S, Foap1 and Foap2 (Fo/AP1 and Fo/AP2), that are appended to GH27 domains. CBM35s are unique in that they display conserved specificity through extensive sequence similarity but divergent function through their appended catalytic modules. They are known to bind alpha-D-galactose (Gal), mannan (Man), xylan, glucuronic acid (GlcA), a beta-polymer of mannose, and possibly glucans, forming four subfamilies based on general ligand specificities (galacto, urono, manno, and gluco configurations). Some CBM35s bind their ligands in a calcium-dependent manner. In contrast to most CBMs that are generally rigid proteins, CBM35 undergoes significant conformational change upon ligand binding. GH43 includes beta-xylosidases and beta-xylanases, using aryl-glycosides as substrates, while family GH27 includes alpha-galactosidases, alpha-N-acetylgalactosaminidases, and isomaltodextranases.бА0АкА0АаАCDDбАаА#+вА0А0АаАВQcd04082, CBM35_pectate_lyase-like, Carbohydrate Binding Module family 35 (CBM35), pectate lyase-like; appended mainly to enzymes that bind mannan (Man), xylan, glucuronic acid (GlcA) and possibly glucans. This family includes carbohydrate binding module family 35 (CBM35) domains that are non-catalytic carbohydrate binding domains that are appended mainly to enzymes that bind mannan (Man), xylan, glucuronic acid (GlcA) and possibly glucans. Included in this family are CBM35s of pectate lyases, including pectate lyase 10A from Cellvibrio japonicas, these enzymes release delta-4,5-anhydrogalaturonic acid (delta4,5-GalA) from pectin, thus identifying a signature molecule for plant cell wall degradation. CBM35s are unique in that they display conserved specificity through extensive sequence similarity but divergent function through their appended catalytic modules. They are known to bind alpha-D-galactose (Gal), mannan (Man), xylan, glucuronic acid (GlcA), a beta-polymer of mannose, and possibly glucans, forming four subfamilies based on general ligand specificities (galacto, urono, manno, and gluco configurations). In contrast to most CBMs that are generally rigid proteins, CBM35 undergoes significant conformational change upon ligand binding. Some CBM35s bind their ligands in a calcium-dependent manner, especially those binding uronic acids.бА0АкА0АаАCDDбАаА#,вА0А0АаАВпcd04083, CBM35_Lmo2446-like, Carbohydrate Binding Module 35 (CBM35) domains similar to Lmo2446. This family includes carbohydrate binding module 35 (CBM35) domains that are appended to several carbohydrate binding enzymes. Some CBM35 domains belonging to this family are appended to glycoside hydrolase (GH) family domains, including glycoside hydrolase family 31 (GH31), for example the CBM35 domain of Lmo2446, an uncharacterized protein from Listeria monocytogenes EGD-e. These CBM35s are non-catalytic carbohydrate binding domains that facilitate the strong binding of the GH catalytic modules with their dedicated, insoluble substrates. GH31 has a wide range of hydrolytic activities such as alpha-glucosidase, alpha-xylosidase, 6-alpha-glucosyltransferase, or alpha-1,4-glucan lyase, cleaving a terminal carbohydrate moiety from a substrate that may be a starch or a glycoprotein. Most characterized GH31 enzymes are alpha-glucosidases.бА0АкА0АаАCDDбАаА#-вА0А0АаАВйcd04084, CBM6_xylanase-like, Carbohydrate Binding Module 6 (CBM6); many are appended to glycoside hydrolase (GH) family 11 and GH43 xylanase domains. This family includes carbohydrate binding module 6 (CBM6) domains that are appended mainly to glycoside hydrolase (GH) family domains, including GH3, GH11, and GH43 domains. These CBM6s are non-catalytic carbohydrate binding domains that facilitate the strong binding of the GH catalytic modules with their dedicated, insoluble substrates. Examples of proteins having CMB6s belonging to this family are Microbispora bispora GghA, a 1,4-beta-D-glucan glucohydrolase (GH3); Clostridium thermocellum xylanase U (GH11), and Penicillium purpurogenum ABF3, a bifunctional alpha-L-arabinofuranosidase/xylobiohydrolase (GH43). GH3 comprises enzymes with activities including beta-glucosidase (hydrolyzes beta-galactosidase) and beta-xylosidase (hydrolyzes 1,4-beta-D-xylosidase). GH11 family comprises enzymes with xylanase (endo-1,4-beta-xylanase) activity which catalyze the hydrolysis of beta-1,4 bonds of xylan, the major component of hemicelluloses, to generate xylooligosaccharides and xylose. GH43 includes beta-xylosidases and beta-xylanases, using aryl-glycosides as substrates. CBM6 is an unusual CBM as it represents a chimera of two distinct binding sites with different modes of binding: binding site I within the loop regions and binding site II on the concave face of the beta-sandwich fold.бА0АкА0АаАCDDбАаА#.вА0А0АаАВcd04085, delta_endotoxin_C, delta-endotoxin C-terminal domain may be associated with carbohydrate binding functionality. Delta-endotoxin C-terminal domain (delta endotoxin domain III) is part of the activated region of delta endotoxins, which are insecticidal toxins produced during sporulation by Bacillus species of bacteria. The activated endotoxin binds to the gut epithelium and causes cell lysis leading to death. This activated region of the delta endotoxin is composed of three structural domains. The N-terminal helical domain (I) is involved in membrane insertion and pore formation, while the second and third domains (II and III) are involved in receptor binding. Domain III structurally resembles the carbohydrate binding domain 6 (CBM6) and it is possible that insect specificity is determined by protein-protein or protein-carbohydrate interactions mediated by both domains II and III of the toxin. Delta-endotoxins are of great interest for development of new bioinsecticides and in the control of mosquitoes.бА0АкА0АаАCDDбАаА#/вА0А0АаАВ cd04086, CBM35_mannanase-like, Carbohydrate Binding Module 35 (CBM35); appended to several carbohydrate binding enzymes, including several glycoside hydrolase (GH) family 26 mannanase domains. This family includes carbohydrate binding module 35 (CBM35) domains that are appended to several carbohydrate binding enzymes, including periplasmic component of ABC-type sugar transport system involved in carbohydrate transport and metabolism, and several glycoside hydrolase (GH) domains, including GH26. These CBM6s are non-catalytic carbohydrate binding domains that facilitate the strong binding of the GH catalytic modules with their dedicated, insoluble substrates. Examples of proteins having CMB35s belonging to this family are mannanase A from Clostridium thermocellum (GH26), Man26B from Paenibacillus sp. BME-14 (GH26), and the multifunctional Cel44C-Man26A from Paenibacillus polymyxa GS01 (which has two GH domains, GH44 and GH26). GH26 mainly includes mannan endo-1,4-beta-mannosidase which hydrolyzes 1,4-beta-D-linkages in mannans, galacto-mannans, glucomannans, and galactoglucomannans, but displays little activity towards other plant cell wall polysaccharides. A few proteins belonging to this family have additional CBM3 domains; these CBM3s are not found in the CBM6-CBM35-CBM36_like superfamily.бА0АкА0АаАCDDбАаА#0вА0А0АаАВ{cd04087, PTPA, Phosphotyrosyl phosphatase activator (PTPA) is also known as protein phosphatase 2A (PP2A) phosphatase activator. PTPA is an essential, well conserved protein that stimulates the tyrosyl phosphatase activity of PP2A. It also reactivates the serine/threonine phosphatase activity of an inactive form of PP2A. Together, PTPA and PP2A constitute an ATPase. It has been suggested that PTPA alters the relative specificity of PP2A from phosphoserine/phosphothreonine substrates to phosphotyrosine substrates in an ATP-hydrolysis-dependent manner. Basal expression of PTPA is controlled by the transcription factor Yin Yang1 (YY1). PTPA has been suggested to play a role in the insertion of metals to the PP2A catalytic subunit (PP2Ac) active site, to act as a chaperone, and more recently, to have peptidyl prolyl cis/trans isomerase activity that specifically targets human PP2Ac.бА0АкА0АаАCDDбАаАиКвА0А0АаАВ╜cd04088, EFG_mtEFG_II, Domain II of bacterial elongation factor G and C-terminal domain of mitochondrial Elongation factors G1 and G2. This family represents the domain II of bacterial Elongation factor G (EF-G)and mitochondrial Elongation factors G1 (mtEFG1) and G2 (mtEFG2). During the process of peptide synthesis and tRNA site changes, the ribosome is moved along the mRNA a distance equal to one codon with the addition of each amino acid. In bacteria this translocation step is catalyzed by EF-G_GTP, which is hydrolyzed to provide the required energy. Thus, this action releases the uncharged tRNA from the P site and transfers the newly formed peptidyl-tRNA from the A site to the P site. Eukaryotic cells harbor 2 protein synthesis systems: one localized in the cytoplasm, the other in the mitochondria. Most factors regulating mitochondrial protein synthesis are encoded by nuclear genes, translated in the cytoplasm, and then transported to the mitochondria. The eukaryotic system of elongation factor (EF) components is more complex than that in prokaryotes, with both cytoplasmic and mitochondrial elongation factors and multiple isoforms being expressed in certain species. mtEFG1 and mtEFG2 show significant homology to bacterial EF-Gs. Mutants in yeast mtEFG1 have impaired mitochondrial protein synthesis, respiratory defects and a tendency to lose mitochondrial DNA. No clear phenotype has been found for mutants in the yeast homolog of mtEFG2, MEF2.бА0АкА0АаАCDDбАаА|вА0А0АаАВcd04089, eRF3_II, Domain II of the eukaryotic class II release factor. In eukaryotes, translation termination is mediated by two interacting release factors, eRF1 and eRF3, which act as class I and II factors, respectively. eRF1 functions as an omnipotent release factor, decoding all three stop codons and triggering the release of the nascent peptide catalyzed by the ribosome. eRF3 is a GTPase, which enhances termination efficiency by stimulating eRF1 activity in a GTP-dependent manner. Sequence comparison of class II release factors with elongation factors shows that eRF3 is more similar to eEF-1alpha whereas prokaryote RF3 is more similar to EF-G, implying that their precise function may differ. Only eukaryote RF3s are found in this group. Saccharomyces cerevisiae eRF3 (Sup35p) is a translation termination factor which is divided into three regions N, M and a C-terminal eEF1a-like region essential for translation termination. Sup35NM is a non-pathogenic prion-like protein with the property of aggregating into polymer-like fibrils.бА0АкА0АаАCDDбАаА|вА0А0АаАВЇcd04090, EF2_II_snRNP, Domain II of the spliceosomal 116kD U5 small nuclear ribonucleoprotein (snRNP) component. This subfamily includes domain II of the spliceosomal human 116kD U5 small nuclear ribonucleoprotein (snRNP) protein (U5-116 kD) and its yeast counterpart Snu114p. This domain is homologous to domain II of the eukaryotic translational elongation factor EF-2. U5-116 kD is a GTPase which is a component of the spliceosome complex which processes precursor mRNAs to produce mature mRNAs.бА0АкА0АаАCDDбАаА|вА0А0АаАВcd04091, mtEFG1_II_like, Domain II of mitochondrial elongation factor G1-like proteins found in eukaryotes. Eukaryotic cells harbor 2 protein synthesis systems: one localized in the cytoplasm, the other in the mitochondria. Most factors regulating mitochondrial protein synthesis are encoded by nuclear genes, translated in the cytoplasm, and then transported to the mitochondria. The eukaryotic system of elongation factor (EF) components is more complex than that in prokaryotes, with both cytoplasmic and mitochondrial elongation factors and multiple isoforms being expressed in certain species. Eukaryotic EF-2 operates in the cytosolic protein synthesis machinery of eukaryotes, EF-Gs in protein synthesis in bacteria. Eukaryotic mtEFG1 proteins show significant homology to bacterial EF-Gs. Mutants in yeast mtEFG1 have impaired mitochondrial protein synthesis, respiratory defects and a tendency to lose mitochondrial DNA. There are two forms of mtEFG present in mammals (designated mtEFG1s and mtEFG2s); mtEFG2s are not present in this group.бА0АкА0АаАCDDбАаА|вА0А0АаАВыcd04092, mtEFG2_II_like, Domain II of mitochondrial elongation factor G2-like proteins found in eukaryotes. Eukaryotic cells harbor 2 protein synthesis systems: one localized in the cytoplasm, the other in the mitochondria. Most factors regulating mitochondrial protein synthesis are encoded by nuclear genes, translated in the cytoplasm, and then transported to the mitochondria. The eukaryotic system of elongation factor (EF) components is more complex than that in prokaryotes, with both cytoplasmic and mitochondrial elongation factors and multiple isoforms being expressed in certain species. Eukaryotic EF-2 operates in the cytosolic protein synthesis machinery of eukaryotes, EF-Gs in protein synthesis in bacteria. Eukaryotic mtEFG1 proteins show significant homology to bacterial EF-Gs. No clear phenotype has been found for mutants in the yeast homolog of mtEFG2, MEF2. There are two forms of mtEFG present in mammals (designated mtEFG1s and mtEFG2s); mtEFG1s are not present in this group.бА0АкА0АаАCDDбАаА|вА0А0АаАВрcd04093, HBS1_C_III, C-terminal domain of Hsp70 subfamily B suppressor 1 (HBS1). This model represents the C-terminal domain of Hsp70 subfamily B suppressor 1 (HBS1), which is homologous to the domain III of EF-1alpha. This group contains proteins similar to yeast Hbs1, which together with Dom34, promotes the No-go decay (NGD) of mRNA. The NGD targets mRNAs whose elongation stalled for degradation initiated by endonucleolytic cleavage in the vicinity of the stalled ribosome.бА0АкА0АаАCDDбАаА|xвА0А0АаАВcd04094, eSelB_III, Domain III of eukaryotic and archaeal elongation factor SelB. This model represents the domain III of archaeal and eukaryotic selenocysteine (Sec)-specific eukaryotic elongation factor (eEFSec or eSelB), which is homologous to domain III of EF-Tu. SelB is a specialized translation elongation factor responsible for the co-translational incorporation of selenocysteine into proteins by recoding of a UGA stop codon in the presence of a downstream mRNA hairpin loop, called Sec insertion sequence (SECIS) element.бА0АкА0АаАCDDбАаА|yвА0А0АаАВ┼cd04095, CysN_NoDQ_III, Domain III of the large subunit of ATP sulfurylase (ATPS). This model represents domain III of the large subunit of ATP sulfurylase (ATPS): CysN or the N-terminal portion of NodQ, found mainly in proteobacteria and is homologous to domain III of EF-Tu. Escherichia coli ATPS consists of CysN and a smaller subunit CysD and CysN. ATPS produces adenosine-5'-phosphosulfate (APS) from ATP and sulfate, coupled with GTP hydrolysis. In the subsequent reaction APS is phosphorylated by an APS kinase (CysC), to produce 3'-phosphoadenosine-5'-phosphosulfate (PAPS) for use in amino acid (aa) biosynthesis. The Rhizobiaceae group (alpha-proteobacteria) appears to carry out the same chemistry for the sulfation of a nodulation factor. In Rhizobium meliloti, the heterodimeric complex comprised of NodP and NodQ appears to possess both ATPS and APS kinase activities. The N- and C-termini of NodQ correspond to CysN and CysC, respectively. Other eubacteria, archaea, and eukaryotes use a different ATP sulfurylase, which shows no amino acid sequence similarity to CysN or NodQ. CysN and the N-terminal portion of NodQ show similarity to GTPases involved in translation, in particular, EF-Tu and EF-1alpha.бА0АкА0АаАCDDбАаА|zвА0А0АаАВ cd04096, eEF2_snRNP_like_C, eEF2_snRNP_like_C: this family represents a C-terminal domain of eukaryotic elongation factor 2 (eEF-2) and a homologous domain of the spliceosomal human 116kD U5 small nuclear ribonucleoprotein (snRNP) protein (U5-116 kD) and, its yeast counterpart Snu114p. Yeast Snu114p is essential for cell viability and for splicing in vivo. U5-116 kD binds GTP. Experiments suggest that GTP binding and probably GTP hydrolysis is important for the function of the U5-116 kD/Snu114p. In complex with GTP, EF-2 promotes the translocation step of translation. During translocation the peptidyl-tRNA is moved from the A site to the P site, the uncharged tRNA from the P site to the E-site and, the mRNA is shifted one codon relative to the ribosome.бА0АкА0АаАCDDбАаАиУвА0А0АаАВ+cd04097, mtEFG1_C, mtEFG1_C: C-terminus of mitochondrial Elongation factor G1 (mtEFG1)-like proteins found in eukaryotes. Eukaryotic cells harbor 2 protein synthesis systems: one localized in the cytoplasm, the other in the mitochondria. Most factors regulating mitochondrial protein synthesis are encoded by nuclear genes, translated in the cytoplasm, and then transported to the mitochondria. The eukaryotic system of elongation factor (EF) components is more complex than that in prokaryotes, with both cytoplasmic and mitochondrial elongation factors and multiple isoforms being expressed in certain species. Eukaryotic EF-2 operates in the cytosolic protein synthesis machinery of eukaryotes, EF-Gs in protein synthesis in bacteria. Eukaryotic mtEFG1 proteins show significant homology to bacterial EF-Gs. Mutants in yeast mtEFG1 have impaired mitochondrial protein synthesis, respiratory defects and a tendency to lose mitochondrial DNA. There are two forms of mtEFG present in mammals (designated mtEFG1s and mtEFG2s) mtEFG2s are not present in this group.бА0АкА0АаАCDDбАаАиФвА0А0АаАВcd04098, eEF2_C_snRNP, eEF2_C_snRNP: This family includes a C-terminal portion of the spliceosomal human 116kD U5 small nuclear ribonucleoprotein (snRNP) protein (U5-116 kD) and, its yeast counterpart Snu114p. This domain is homologous to the C-terminal domain of the eukaryotic translational elongation factor EF-2. Yeast Snu114p is essential for cell viability and for splicing in vivo. U5-116 kD binds GTP. Experiments suggest that GTP binding and probably GTP hydrolysis is important for the function of the U5-116 kD/Snu114p. In complex with GTP, EF-2 promotes the translocation step of translation. During translocation the peptidyl-tRNA is moved from the A site to the P site, the uncharged tRNA from the P site to the E-site and, the mRNA is shifted one codon relative to the ribosome.бА0АкА0АаАCDDбАаАиХвА0А0АаАВcd04100, Asp_Lys_Asn_RS_N, Asp_Lys_Asn_RS_N: N-terminal, anticodon recognition domain of class 2b aminoacyl-tRNA synthetases (aaRSs). This domain is a beta-barrel domain (OB fold) involved in binding the tRNA anticodon stem-loop. Class 2b aaRSs include the homodimeric aspartyl-, asparaginyl-, and lysyl-tRNA synthetases (AspRS, AsnRS, and LysRS). aaRSs catalyze the specific attachment of amino acids (AAs) to their cognate tRNAs during protein biosynthesis. This 2-step reaction involves i) the activation of the AA by ATP in the presence of magnesium ions, followed by ii) the transfer of the activated AA to the terminal ribose of tRNA. In the case of the class2b aaRSs, the activated AA is attached to the 3'OH of the terminal ribose. Eukaryotes contain 2 sets of aaRSs, both of which are encoded by the nuclear genome. One set concerns with cytoplasmic protein synthesis, whereas the other exclusively with mitochondrial protein synthesis. Included in this group are archeal and archeal-like AspRSs which are non-discriminating and can charge both tRNAAsp and tRNAAsn. E. coli cells have two isoforms of LysRSs (LysS and LysU) encoded by two distinct genes, which are differentially regulated. The cytoplasmic and the mitochondrial isoforms of human LysRS are encoded by a single gene. Yeast cytoplasmic and mitochondrial LysRSs participate in mitochondrial import of cytoplasmic tRNAlysCUU. In addition to their housekeeping role, human LysRS may function as a signaling molecule that activates immune cells. Tomato LysRS may participate in a process possibly connected to conditions of oxidative-stress conditions or heavy metal uptake. It is known that human tRNAlys and LysRS are specifically packaged into HIV-1 suggesting a role for LysRS in tRNA packaging. AsnRS is immunodominant antigen of the filarial nematode Brugia malayai and is of interest as a target for anti-parasitic drug design. Human AsnRS has been shown to be a pro-inflammatory chemokine which interacts with CCR3 chemokine receptors on T cells, immature dendritic cells and macrophages.бА0АкА0АаАCDDбАаАиЦвА0А0АаАВ{cd04101, RabL4, Rab GTPase-like family 4 (Rab-like4). RabL4 (Rab-like4) subfamily. RabL4s are novel proteins that have high sequence similarity with Rab family members, but display features that are distinct from Rabs, and have been termed Rab-like. As in other Rab-like proteins, RabL4 lacks a prenylation site at the C-terminus. The specific function of RabL4 remains unknown.бА0АкА0АаАCDDбАаА'`вА0А0АаАВ{cd04102, RabL3, Rab GTPase-like family 3 (Rab-like3). RabL3 (Rab-like3) subfamily. RabL3s are novel proteins that have high sequence similarity with Rab family members, but display features that are distinct from Rabs, and have been termed Rab-like. As in other Rab-like proteins, RabL3 lacks a prenylation site at the C-terminus. The specific function of RabL3 remains unknown.бА0АкА0АаАCDDбАаА'aвА0А0АаАВ[cd04103, Centaurin_gamma, Centaurin gamma (CENTG) GTPase. The centaurins (alpha, beta, gamma, and delta) are large, multi-domain proteins that all contain an ArfGAP domain and ankyrin repeats, and in some cases, numerous additional domains. Centaurin gamma contains an additional GTPase domain near its N-terminus. The specific function of this GTPase domain has not been well characterized, but centaurin gamma 2 (CENTG2) may play a role in the development of autism. Centaurin gamma 1 is also called PIKE (phosphatidyl inositol (PI) 3-kinase enhancer) and centaurin gamma 2 is also known as AGAP (ArfGAP protein with a GTPase-like domain, ankyrin repeats and a Pleckstrin homology domain) or GGAP. Three isoforms of PIKE have been identified. PIKE-S (short) and PIKE-L (long) are brain-specific isoforms, with PIKE-S restricted to the nucleus and PIKE-L found in multiple cellular compartments. A third isoform, PIKE-A was identified in human glioblastoma brain cancers and has been found in various tissues. GGAP has been shown to have high GTPase activity due to a direct intramolecular interaction between the N-terminal GTPase domain and the C-terminal ArfGAP domain. In human tissue, AGAP mRNA was detected in skeletal muscle, kidney, placenta, brain, heart, colon, and lung. Reduced expression levels were also observed in the spleen, liver, and small intestine.бА0АкА0АаАCDDбАаА╖вА0А0АаАВ_cd04104, p47_IIGP_like, p47 GTPase family includes IGTP, TGTP/Mg21, IRG-47, GTPI, LRG-47, and IIGP1. The p47 GTPase family consists of several highly homologous proteins, including IGTP, TGTP/Mg21, IRG-47, GTPI, LRG-47, and IIGP1. They are found in higher eukaryotes where they play a role in immune resistance against intracellular pathogens. p47 proteins exist at low resting levels in mouse cells, but are strongly induced by Type II interferon (IFN-gamma). ITGP is critical for resistance to Toxoplasma gondii infection and in involved in inhibition of Coxsackievirus-B3-induced apoptosis. TGTP was shown to limit vesicular stomatitis virus (VSV) infection of fibroblasts in vitro. IRG-47 is involved in resistance to T. gondii infection. LRG-47 has been implicated in resistance to T. gondii, Listeria monocytogenes, Leishmania, and mycobacterial infections. IIGP1 has been shown to localize to the ER and to the Golgi membranes in IFN-induced cells and inflamed tissues. In macrophages, IIGP1 interacts with hook3, a microtubule binding protein that participates in the organization of the cis-Golgi compartment.бА0АкА0АаАCDDбАаА'bвА0А0АаАВВcd04105, SR_beta, Signal recognition particle receptor, beta subunit (SR-beta), together with SR-alpha, forms the heterodimeric signal recognition particle (SRP). Signal recognition particle receptor, beta subunit (SR-beta). SR-beta and SR-alpha form the heterodimeric signal recognition particle (SRP or SR) receptor that binds SRP to regulate protein translocation across the ER membrane. Nascent polypeptide chains are synthesized with an N-terminal hydrophobic signal sequence that binds SRP54, a component of the SRP. SRP directs targeting of the ribosome-nascent chain complex (RNC) to the ER membrane via interaction with the SR, which is localized to the ER membrane. The RNC is then transferred to the protein-conducting channel, or translocon, which facilitates polypeptide translation across the ER membrane or integration into the ER membrane. SR-beta is found only in eukaryotes; it is believed to control the release of the signal sequence from SRP54 upon binding of the ribosome to the translocon. High expression of SR-beta has been observed in human colon cancer, suggesting it may play a role in the development of this type of cancer.бА0АкА0АаАCDDбАаА'cвА0А0АаАВпcd04106, Rab23_like, Rab GTPase family 23 (Rab23)-like. Rab23-like subfamily. Rab23 is a member of the Rab family of small GTPases. In mouse, Rab23 has been shown to function as a negative regulator in the sonic hedgehog (Shh) signaling pathway. Rab23 mediates the activity of Gli2 and Gli3, transcription factors that regulate Shh signaling in the spinal cord, primarily by preventing Gli2 activation in the absence of Shh ligand. Rab23 also regulates a step in the cytoplasmic signal transduction pathway that mediates the effect of Smoothened (one of two integral membrane proteins that are essential components of the Shh signaling pathway in vertebrates). In humans, Rab23 is expressed in the retina. Mice contain an isoform that shares 93% sequence identity with the human Rab23 and an alternative splicing isoform that is specific to the brain. This isoform causes the murine open brain phenotype, indicating it may have a role in the development of the central nervous system. GTPase activating proteins (GAPs) interact with GTP-bound Rab and accelerate the hydrolysis of GTP to GDP. Guanine nucleotide exchange factors (GEFs) interact with GDP-bound Rabs to promote the formation of the GTP-bound state. Rabs are further regulated by guanine nucleotide dissociation inhibitors (GDIs), which facilitate Rab recycling by masking C-terminal lipid binding and promoting cytosolic localization. Most Rab GTPases contain a lipid modification site at the C-terminus, with sequence motifs CC, CXC, or CCX. Lipid binding is essential for membrane attachment, a key feature of most Rab proteins. Due to the presence of truncated sequences in this CD, the lipid modification site is not available for annotation.бА0АкА0АаАCDDбАаА║вА0А0АаАВ╚cd04107, Rab32_Rab38, Rab GTPase families 18 (Rab18) and 32 (Rab32). Rab38/Rab32 subfamily. Rab32 and Rab38 are members of the Rab family of small GTPases. Human Rab32 was first identified in platelets but it is expressed in a variety of cell types, where it functions as an A-kinase anchoring protein (AKAP). Rab38 has been shown to be melanocyte-specific. GTPase activating proteins (GAPs) interact with GTP-bound Rab and accelerate the hydrolysis of GTP to GDP. Guanine nucleotide exchange factors (GEFs) interact with GDP-bound Rabs to promote the formation of the GTP-bound state. Rabs are further regulated by guanine nucleotide dissociation inhibitors (GDIs), which facilitate Rab recycling by masking C-terminal lipid binding and promoting cytosolic localization. Most Rab GTPases contain a lipid modification site at the C-terminus, with sequence motifs CC, CXC, or CCX. Lipid binding is essential for membrane attachment, a key feature of most Rab proteins.бА0АкА0АаАCDDбАаА'dвА0А0АаАВcd04108, Rab36_Rab34, Rab GTPase families 34 (Rab34) and 36 (Rab36). Rab34/Rab36 subfamily. Rab34, found primarily in the Golgi, interacts with its effector, Rab-interacting lysosomal protein (RILP). This enables its participation in microtubular dynenin-dynactin-mediated repositioning of lysosomes from the cell periphery to the Golgi. A Rab34 (Rah) isoform that lacks the consensus GTP-binding region has been identified in mice. This isoform is associated with membrane ruffles and promotes macropinosome formation. Rab36 has been mapped to human chromosome 22q11.2, a region that is homozygously deleted in malignant rhabdoid tumors (MRTs). However, experimental assessments do not implicate Rab36 as a tumor suppressor that would enable tumor formation through a loss-of-function mechanism. GTPase activating proteins (GAPs) interact with GTP-bound Rab and accelerate the hydrolysis of GTP to GDP. Guanine nucleotide exchange factors (GEFs) interact with GDP-bound Rabs to promote the formation of the GTP-bound state. Rabs are further regulated by guanine nucleotide dissociation inhibitors (GDIs), which facilitate Rab recycling by masking C-terminal lipid binding and promoting cytosolic localization. Most Rab GTPases contain a lipid modification site at the C-terminus, with sequence motifs CC, CXC, or CCX. Lipid binding is essential for membrane attachment, a key feature of most Rab proteins.бА0АкА0АаАCDDбАаА'eвА0А0АаАВ{cd04109, Rab28, Rab GTPase family 28 (Rab28). Rab28 subfamily. First identified in maize, Rab28 has been shown to be a late embryogenesis-abundant (Lea) protein that is regulated by the plant hormone abcisic acid (ABA). In Arabidopsis, Rab28 is expressed during embryo development and is generally restricted to provascular tissues in mature embryos. Unlike maize Rab28, it is not ABA-inducible. Characterization of the human Rab28 homolog revealed two isoforms, which differ by a 95-base pair insertion, producing an alternative sequence for the 30 amino acids at the C-terminus. The two human isoforms are presumably the result of alternative splicing. Since they differ at the C-terminus but not in the GTP-binding region, they are predicted to be targeted to different cellular locations. GTPase activating proteins (GAPs) interact with GTP-bound Rab and accelerate the hydrolysis of GTP to GDP. Guanine nucleotide exchange factors (GEFs) interact with GDP-bound Rabs to promote the formation of the GTP-bound state. Rabs are further regulated by guanine nucleotide dissociation inhibitors (GDIs), which facilitate Rab recycling by masking C-terminal lipid binding and promoting cytosolic localization. Most Rab GTPases contain a lipid modification site at the C-terminus, with sequence motifs CC, CXC, or CCX. Lipid binding is essential for membrane attachment, a key feature of most Rab proteins.бА0АкА0АаАCDDбАаА'fвА0А0АаАВ:cd04110, Rab35, Rab GTPase family 35 (Rab35). Rab35 is one of several Rab proteins to be found to participate in the regulation of osteoclast cells in rats. In addition, Rab35 has been identified as a protein that interacts with nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) in human cells. Overexpression of NPM-ALK is a key oncogenic event in some anaplastic large-cell lymphomas; since Rab35 interacts with N|PM-ALK, it may provide a target for cancer treatments. GTPase activating proteins (GAPs) interact with GTP-bound Rab and accelerate the hydrolysis of GTP to GDP. Guanine nucleotide exchange factors (GEFs) interact with GDP-bound Rabs to promote the formation of the GTP-bound state. Rabs are further regulated by guanine nucleotide dissociation inhibitors (GDIs), which facilitate Rab recycling by masking C-terminal lipid binding and promoting cytosolic localization. Most Rab GTPases contain a lipid modification site at the C-terminus, with sequence motifs CC, CXC, or CCX. Lipid binding is essential for membrane attachment, a key feature of most Rab proteins.бА0АкА0АаАCDDбАаА╛вА0А0АаАВЪcd04111, Rab39, Rab GTPase family 39 (Rab39). Found in eukaryotes, Rab39 is mainly found in epithelial cell lines, but is distributed widely in various human tissues and cell lines. It is believed to be a novel Rab protein involved in regulating Golgi-associated vesicular transport during cellular endocytosis. GTPase activating proteins (GAPs) interact with GTP-bound Rab and accelerate the hydrolysis of GTP to GDP. Guanine nucleotide exchange factors (GEFs) interact with GDP-bound Rabs to promote the formation of the GTP-bound state. Rabs are further regulated by guanine nucleotide dissociation inhibitors (GDIs), which facilitate Rab recycling by masking C-terminal lipid binding and promoting cytosolic localization. Most Rab GTPases contain a lipid modification site at the C-terminus, with sequence motifs CC, CXC, or CCX. Lipid binding is essential for membrane attachment, a key feature of most Rab proteins.бА0АкА0АаАCDDбАаА┐вА0А0АаАВ╙cd04112, Rab26, Rab GTPase family 26 (Rab26). Rab26 subfamily. First identified in rat pancreatic acinar cells, Rab26 is believed to play a role in recruiting mature granules to the plasma membrane upon beta-adrenergic stimulation. Rab26 belongs to the Rab functional group III, which are considered key regulators of intracellular vesicle transport during exocytosis. GTPase activating proteins (GAPs) interact with GTP-bound Rab and accelerate the hydrolysis of GTP to GDP. Guanine nucleotide exchange factors (GEFs) interact with GDP-bound Rabs to promote the formation of the GTP-bound state. Rabs are further regulated by guanine nucleotide dissociation inhibitors (GDIs), which facilitate Rab recycling by masking C-terminal lipid binding and promoting cytosolic localization. Most Rab GTPases contain a lipid modification site at the C-terminus, with sequence motifs CC, CXC, or CCX. Lipid binding is essential for membrane attachment, a key feature of most Rab proteins.бА0АкА0АаАCDDбАаА'gвА0А0АаАВ cd04113, Rab4, Rab GTPase family 4 (Rab4). Rab4 subfamily. Rab4 has been implicated in numerous functions within the cell. It helps regulate endocytosis through the sorting, recycling, and degradation of early endosomes. Mammalian Rab4 is involved in the regulation of many surface proteins including G-protein-coupled receptors, transferrin receptor, integrins, and surfactant protein A. Experimental data implicate Rab4 in regulation of the recycling of internalized receptors back to the plasma membrane. It is also believed to influence receptor-mediated antigen processing in B-lymphocytes, in calcium-dependent exocytosis in platelets, in alpha-amylase secretion in pancreatic cells, and in insulin-induced translocation of Glut4 from internal vesicles to the cell surface. Rab4 is known to share effector proteins with Rab5 and Rab11. GTPase activating proteins (GAPs) interact with GTP-bound Rab and accelerate the hydrolysis of GTP to GDP. Guanine nucleotide exchange factors (GEFs) interact with GDP-bound Rabs to promote the formation of the GTP-bound state. Rabs are further regulated by guanine nucleotide dissociation inhibitors (GDIs), which facilitate Rab recycling by masking C-terminal lipid binding and promoting cytosolic localization. Most Rab GTPases contain a lipid modification site at the C-terminus, with sequence motifs CC, CXC, or CCX. Lipid binding is essential for membrane attachment, a key feature of most Rab proteins. Due to the presence of truncated sequences in this CD, the lipid modification site is not available for annotation.бА0АкА0АаАCDDбАаА'hвА0А0АаАВбcd04114, Rab30, Rab GTPase family 30 (Rab30). Rab30 subfamily. Rab30 appears to be associated with the Golgi stack. It is expressed in a wide variety of tissue types and in humans maps to chromosome 11. GTPase activating proteins (GAPs) interact with GTP-bound Rab and accelerate the hydrolysis of GTP to GDP. Guanine nucleotide exchange factors (GEFs) interact with GDP-bound Rabs to promote the formation of the GTP-bound state. Rabs are further regulated by guanine nucleotide dissociation inhibitors (GDIs), which facilitate Rab recycling by masking C-terminal lipid binding and promoting cytosolic localization. Most Rab GTPases contain a lipid modification site at the C-terminus, with sequence motifs CC, CXC, or CCX. Lipid binding is essential for membrane attachment, a key feature of most Rab proteins. Due to the presence of truncated sequences in this CD, the lipid modification site is not available for annotation.бА0АкА0АаАCDDбАаА┬вА0А0АаАВтcd04115, Rab33B_Rab33A, Rab GTPase family 33 includes Rab33A and Rab33B. Rab33B/Rab33A subfamily. Rab33B is ubiquitously expressed in mouse tissues and cells, where it is localized to the medial Golgi cisternae. It colocalizes with alpha-mannose II. Together with the other cisternal Rabs, Rab6A and Rab6A', it is believed to regulate the Golgi response to stress and is likely a molecular target in stress-activated signaling pathways. Rab33A (previously known as S10) is expressed primarily in the brain and immune system cells. In humans, it is located on the X chromosome at Xq26 and its expression is down-regulated in tuberculosis patients. Experimental evidence suggests that Rab33A is a novel CD8+ T cell factor that likely plays a role in tuberculosis disease processes. GTPase activating proteins (GAPs) interact with GTP-bound Rab and accelerate the hydrolysis of GTP to GDP. Guanine nucleotide exchange factors (GEFs) interact with GDP-bound Rabs to promote the formation of the GTP-bound state. Rabs are further regulated by guanine nucleotide dissociation inhibitors (GDIs), which facilitate Rab recycling by masking C-terminal lipid binding and promoting cytosolic localization. Most Rab GTPases contain a lipid modification site at the C-terminus, with sequence motifs CC, CXC, or CCX. Lipid binding is essential for membrane attachment, a key feature of most Rab proteins. Due to the presence of truncated sequences in this CD, the lipid modification site is not available for annotation.бА0АкА0АаАCDDбАаА├вА0А0АаАВ╟cd04116, Rab9, Rab GTPase family 9 (Rab9). Rab9 is found in late endosomes, together with mannose 6-phosphate receptors (MPRs) and the tail-interacting protein of 47 kD (TIP47). Rab9 is a key mediator of vesicular transport from late endosomes to the trans-Golgi network (TGN) by redirecting the MPRs. Rab9 has been identified as a key component for the replication of several viruses, including HIV1, Ebola, Marburg, and measles, making it a potential target for inhibiting a variety of viruses. GTPase activating proteins (GAPs) interact with GTP-bound Rab and accelerate the hydrolysis of GTP to GDP. Guanine nucleotide exchange factors (GEFs) interact with GDP-bound Rabs to promote the formation of the GTP-bound state. Rabs are further regulated by guanine nucleotide dissociation inhibitors (GDIs), which facilitate Rab recycling by masking C-terminal lipid binding and promoting cytosolic localization. Most Rab GTPases contain a lipid modification site at the C-terminus, with sequence motifs CC, CXC, or CCX. Lipid binding is essential for membrane attachment, a key feature of most Rab proteins. Due to the presence of truncated sequences in this CD, the lipid modification site is not available for annotation.бА0АкА0АаАCDDбАаА'iвА0А0АаАВ`cd04117, Rab15, Rab GTPase family 15 (Rab15). Rab15 colocalizes with the transferrin receptor in early endosome compartments, but not with late endosomal markers. It codistributes with Rab4 and Rab5 on early/sorting endosomes, and with Rab11 on pericentriolar recycling endosomes. It is believed to function as an inhibitory GTPase that regulates distinct steps in early endocytic trafficking. GTPase activating proteins (GAPs) interact with GTP-bound Rab and accelerate the hydrolysis of GTP to GDP. Guanine nucleotide exchange factors (GEFs) interact with GDP-bound Rabs to promote the formation of the GTP-bound state. Rabs are further regulated by guanine nucleotide dissociation inhibitors (GDIs), which facilitate Rab recycling by masking C-terminal lipid binding and promoting cytosolic localization. Most Rab GTPases contain a lipid modification site at the C-terminus, with sequence motifs CC, CXC, or CCX. Lipid binding is essential for membrane attachment, a key feature of most Rab proteins. Due to the presence of truncated sequences in this CD, the lipid modification site is not available for annotation.бА0АкА0АаАCDDбАаА'jвА0А0АаАВcd04118, Rab24, Rab GTPase family 24 (Rab24). Rab24 is distinct from other Rabs in several ways. It exists primarily in the GTP-bound state, having a low intrinsic GTPase activity; it is not efficiently geranyl-geranylated at the C-terminus; it does not form a detectable complex with Rab GDP-dissociation inhibitors (GDIs); and it has recently been shown to undergo tyrosine phosphorylation when overexpressed in vitro. The specific function of Rab24 still remains unknown. It is found in a transport route between ER-cis-Golgi and late endocytic compartments. It is putatively involved in an autophagic pathway, possibly directing misfolded proteins in the ER to degradative pathways. GTPase activating proteins (GAPs) interact with GTP-bound Rab and accelerate the hydrolysis of GTP to GDP. Guanine nucleotide exchange factors (GEFs) interact with GDP-bound Rabs to promote the formation of the GTP-bound state. Rabs are further regulated by guanine nucleotide dissociation inhibitors (GDIs), which facilitate Rab recycling by masking C-terminal lipid binding and promoting cytosolic localization. Most Rab GTPases contain a lipid modification site at the C-terminus, with sequence motifs CC, CXC, or CCX. Lipid binding is essential for membrane attachment, a key feature of most Rab proteins.бА0АкА0АаАCDDбАаА╞вА0А0АаАВicd04119, RJL, Rab GTPase family J-like (RabJ-like). RJLs are found in many protists and as chimeras with C-terminal DNAJ domains in deuterostome metazoa. They are not found in plants, fungi, and protostome metazoa, suggesting a horizontal gene transfer between protists and deuterostome metazoa. RJLs lack any known membrane targeting signal and contain a degenerate phosphate/magnesium-binding 3 (PM3) motif, suggesting an impaired ability to hydrolyze GTP. GTPase activating proteins (GAPs) interact with GTP-bound Rab and accelerate the hydrolysis of GTP to GDP. Guanine nucleotide exchange factors (GEFs) interact with GDP-bound Rabs to promote the formation of the GTP-bound state. Rabs are further regulated by guanine nucleotide dissociation inhibitors (GDIs), which facilitate Rab recycling by masking C-terminal lipid binding and promoting cytosolic localization.бА0АкА0АаАCDDбАаА╟вА0А0АаАВ┼cd04120, Rab12, Rab GTPase family 12 (Rab12). Rab12 was first identified in canine cells, where it was localized to the Golgi complex. The specific function of Rab12 remains unknown, and inconsistent results about its cellular localization have been reported. More recent studies have identified Rab12 associated with post-Golgi vesicles, or with other small vesicle-like structures but not with the Golgi complex. Most Rab GTPases contain a lipid modification site at the C-terminus, with sequence motifs CC, CXC, or CCX. Lipid binding is essential for membrane attachment, a key feature of most Rab proteins. GTPase activating proteins (GAPs) interact with GTP-bound Rab and accelerate the hydrolysis of GTP to GDP. Guanine nucleotide exchange factors (GEFs) interact with GDP-bound Rabs to promote the formation of the GTP-bound state. Rabs are further regulated by guanine nucleotide dissociation inhibitors (GDIs), which facilitate Rab recycling by masking C-terminal lipid binding and promoting cytosolic localization. Most Rab GTPases contain a lipid modification site at the C-terminus, with sequence motifs CC, CXC, or CCX. Lipid binding is essential for membrane attachment, a key feature of most Rab proteins.бА0АкА0АаАCDDбАаА'kвА0А0АаАВfcd04121, Rab40, Rab GTPase family 40 (Rab40) contains Rab40a, Rab40b and Rab40c. The Rab40 subfamily contains Rab40a, Rab40b, and Rab40c, which are all highly homologous. In rat, Rab40c is localized to the perinuclear recycling compartment (PRC), and is distributed in a tissue-specific manor, with high expression in brain, heart, kidney, and testis, low expression in lung and liver, and no expression in spleen and skeletal muscle. Rab40c is highly expressed in differentiated oligodendrocytes but minimally expressed in oligodendrocyte progenitors, suggesting a role in the vesicular transport of myelin components. Unlike most other Ras-superfamily proteins, Rab40c was shown to have a much lower affinity for GTP, and an affinity for GDP that is lower than for GTP. GTPase activating proteins (GAPs) interact with GTP-bound Rab and accelerate the hydrolysis of GTP to GDP. Guanine nucleotide exchange factors (GEFs) interact with GDP-bound Rabs to promote the formation of the GTP-bound state. Rabs are further regulated by guanine nucleotide dissociation inhibitors (GDIs), which facilitate Rab recycling by masking C-terminal lipid binding and promoting cytosolic localization. Most Rab GTPases contain a lipid modification site at the C-terminus, with sequence motifs CC, CXC, or CCX. Lipid binding is essential for membrane attachment, a key feature of most Rab proteins.бА0АкА0АаАCDDбАаА╔вА0А0АаАВcd04122, Rab14, Rab GTPase family 14 (Rab14). Rab14 GTPases are localized to biosynthetic compartments, including the rough ER, the Golgi complex, and the trans-Golgi network, and to endosomal compartments, including early endosomal vacuoles and associated vesicles. Rab14 is believed to function in both the biosynthetic and recycling pathways between the Golgi and endosomal compartments. Rab14 has also been identified on GLUT4 vesicles, and has been suggested to help regulate GLUT4 translocation. In addition, Rab14 is believed to play a role in the regulation of phagocytosis. GTPase activating proteins (GAPs) interact with GTP-bound Rab and accelerate the hydrolysis of GTP to GDP. Guanine nucleotide exchange factors (GEFs) interact with GDP-bound Rabs to promote the formation of the GTP-bound state. Rabs are further regulated by guanine nucleotide dissociation inhibitors (GDIs), which facilitate Rab recycling by masking C-terminal lipid binding and promoting cytosolic localization. Most Rab GTPases contain a lipid modification site at the C-terminus, with sequence motifs CC, CXC, or CCX. Lipid binding is essential for membrane attachment, a key feature of most Rab proteins. Due to the presence of truncated sequences in this CD, the lipid modification site is not available for annotation.бА0АкА0АаАCDDбАаА╩вА0А0АаАВ°cd04123, Rab21, Rab GTPase family 21 (Rab21). The localization and function of Rab21 are not clearly defined, with conflicting data reported. Rab21 has been reported to localize in the ER in human intestinal epithelial cells, with partial colocalization with alpha-glucosidase, a late endosomal/lysosomal marker. More recently, Rab21 was shown to colocalize with and affect the morphology of early endosomes. In Dictyostelium, GTP-bound Rab21, together with two novel LIM domain proteins, LimF and ChLim, has been shown to regulate phagocytosis. GTPase activating proteins (GAPs) interact with GTP-bound Rab and accelerate the hydrolysis of GTP to GDP. Guanine nucleotide exchange factors (GEFs) interact with GDP-bound Rabs to promote the formation of the GTP-bound state. Rabs are further regulated by guanine nucleotide dissociation inhibitors (GDIs), which facilitate Rab recycling by masking C-terminal lipid binding and promoting cytosolic localization. Most Rab GTPases contain a lipid modification site at the C-terminus, with sequence motifs CC, CXC, or CCX. Lipid binding is essential for membrane attachment, a key feature of most Rab proteins. Due to the presence of truncated sequences in this CD, the lipid modification site is not available for annotation.бА0АкА0АаАCDDбАаА╦вА0А0АаАВ├cd04124, RabL2, Rab GTPase-like family 2 (Rab-like2). RabL2 (Rab-like2) subfamily. RabL2s are novel Rab proteins identified recently which display features that are distinct from other Rabs, and have been termed Rab-like. RabL2 contains RabL2a and RabL2b, two very similar Rab proteins that share > 98% sequence identity in humans. RabL2b maps to the subtelomeric region of chromosome 22q13.3 and RabL2a maps to 2q13, a region that suggests it is also a subtelomeric gene. Both genes are believed to be expressed ubiquitously, suggesting that RabL2s are the first example of duplicated genes in human proximal subtelomeric regions that are both expressed actively. Like other Rab-like proteins, RabL2s lack a prenylation site at the C-terminus. The specific functions of RabL2a and RabL2b remain unknown. GTPase activating proteins (GAPs) interact with GTP-bound Rab and accelerate the hydrolysis of GTP to GDP. Guanine nucleotide exchange factors (GEFs) interact with GDP-bound Rabs to promote the formation of the GTP-bound state. Rabs are further regulated by guanine nucleotide dissociation inhibitors (GDIs), which facilitate Rab recycling by masking C-terminal lipid binding and promoting cytosolic localization.бА0АкА0АаАCDDбАаА╠вА0А0АаАВ|cd04126, Rab20, Rab GTPase family 20 (Rab20). Rab20 is one of several Rab proteins that appear to be restricted in expression to the apical domain of murine polarized epithelial cells. It is expressed on the apical side of polarized kidney tubule and intestinal epithelial cells, and in non-polarized cells. It also localizes to vesico-tubular structures below the apical brush border of renal proximal tubule cells and in the apical region of duodenal epithelial cells. Rab20 has also been shown to colocalize with vacuolar H+-ATPases (V-ATPases) in mouse kidney cells, suggesting a role in the regulation of V-ATPase traffic in specific portions of the nephron. It was also shown to be one of several proteins whose expression is upregulated in human myelodysplastic syndrome (MDS) patients. GTPase activating proteins (GAPs) interact with GTP-bound Rab and accelerate the hydrolysis of GTP to GDP. Guanine nucleotide exchange factors (GEFs) interact with GDP-bound Rabs to promote the formation of the GTP-bound state. Rabs are further regulated by guanine nucleotide dissociation inhibitors (GDIs), which facilitate Rab recycling by masking C-terminal lipid binding and promoting cytosolic localization. Most Rab GTPases contain a lipid modification site at the C-terminus, with sequence motifs CC, CXC, or CCX. Lipid binding is essential for membrane attachment, a key feature of most Rab proteins.бА0АкА0АаАCDDбАаА╬вА0А0АаАВГcd04127, Rab27A, Rab GTPase family 27a (Rab27a). The Rab27a subfamily consists of Rab27a and its highly homologous isoform, Rab27b. Unlike most Rab proteins whose functions remain poorly defined, Rab27a has many known functions. Rab27a has multiple effector proteins, and depending on which effector it binds, Rab27a has different functions as well as tissue distribution and/or cellular localization. Putative functions have been assigned to Rab27a when associated with the effector proteins Slp1, Slp2, Slp3, Slp4, Slp5, DmSlp, rabphilin, Dm/Ce-rabphilin, Slac2-a, Slac2-b, Slac2-c, Noc2, JFC1, and Munc13-4. Rab27a has been associated with several human diseases, including hemophagocytic syndrome (Griscelli syndrome or GS), Hermansky-Pudlak syndrome, and choroidermia. In the case of GS, a rare, autosomal recessive disease, a Rab27a mutation is directly responsible for the disorder. When Rab27a is localized to the secretory granules of pancreatic beta cells, it is believed to mediate glucose-stimulated insulin secretion, making it a potential target for diabetes therapy. When bound to JFC1 in prostate cells, Rab27a is believed to regulate the exocytosis of prostate- specific markers. GTPase activating proteins (GAPs) interact with GTP-bound Rab and accelerate the hydrolysis of GTP to GDP. Guanine nucleotide exchange factors (GEFs) interact with GDP-bound Rabs to promote the formation of the GTP-bound state. Rabs are further regulated by guanine nucleotide dissociation inhibitors (GDIs), which facilitate Rab recycling by masking C-terminal lipid binding and promoting cytosolic localization. Most Rab GTPases contain a lipid modification site at the C-terminus, with sequence motifs CC, CXC, or CCX. Lipid binding is essential for membrane attachment, a key feature of most Rab proteins. Due to the presence of truncated sequences in this CD, the lipid modification site is not available for annotation.бА0АкА0АаАCDDбАаА'lвА0А0АаАВ┤cd04128, Spg1, Septum-promoting GTPase (Spg1). Spg1p. Spg1p (septum-promoting GTPase) was first identified in the fission yeast S. pombe, where it regulates septum formation in the septation initiation network (SIN) through the cdc7 protein kinase. Spg1p is an essential gene that localizes to the spindle pole bodies. When GTP-bound, it binds cdc7 and causes it to translocate to spindle poles. Sid4p (septation initiation defective) is required for localization of Spg1p to the spindle pole body, and the ability of Spg1p to promote septum formation from any point in the cell cycle depends on Sid4p. Spg1p is negatively regulated by Byr4 and cdc16, which form a two-component GTPase activating protein (GAP) for Spg1p. The existence of a SIN-related pathway in plants has been proposed. GTPase activating proteins (GAPs) interact with GTP-bound Rab and accelerate the hydrolysis of GTP to GDP. Guanine nucleotide exchange factors (GEFs) interact with GDP-bound Rabs to promote the formation of the GTP-bound state. Rabs are further regulated by guanine nucleotide dissociation inhibitors (GDIs), which facilitate Rab recycling by masking C-terminal lipid binding and promoting cytosolic localization.бА0АкА0АаАCDDбАаА'mвА0А0АаАВ╫cd04129, Rho2, Ras homology family 2 (Rho2) of small guanosine triphosphatases (GTPases). Rho2 is a fungal GTPase that plays a role in cell morphogenesis, control of cell wall integrity, control of growth polarity, and maintenance of growth direction. Rho2 activates the protein kinase C homolog Pck2, and Pck2 controls Mok1, the major (1-3) alpha-D-glucan synthase. Together with Rho1 (RhoA), Rho2 regulates the construction of the cell wall. Unlike Rho1, Rho2 is not an essential protein, but its overexpression is lethal. Most Rho proteins contain a lipid modification site at the C-terminus, with a typical sequence motif CaaX, where a = an aliphatic amino acid and X = any amino acid. Lipid binding is essential for proper intracellular localization via membrane attachment. As with other Rho family GTPases, the GDP/GTP cycling is regulated by GEFs (guanine nucleotide exchange factors), GAPs (GTPase-activating proteins) and GDIs (guanine nucleotide dissociation inhibitors).бА0АкА0АаАCDDбАаА'nвА0А0АаАВLcd04130, Wrch_1, Wnt-1 responsive Cdc42 homolog (Wrch-1) is a Rho family GTPase similar to Cdc42. Wrch-1 (Wnt-1 responsive Cdc42 homolog) is a Rho family GTPase that shares significant sequence and functional similarity with Cdc42. Wrch-1 was first identified in mouse mammary epithelial cells, where its transcription is upregulated in Wnt-1 transformation. Wrch-1 contains N- and C-terminal extensions relative to cdc42, suggesting potential differences in cellular localization and function. The Wrch-1 N-terminal extension contains putative SH3 domain-binding motifs and has been shown to bind the SH3 domain-containing protein Grb2, which increases the level of active Wrch-1 in cells. Unlike Cdc42, which localizes to the cytosol and perinuclear membranes, Wrch-1 localizes extensively with the plasma membrane and endosomes. The membrane association, localization, and biological activity of Wrch-1 indicate an atypical model of regulation distinct from other Rho family GTPases. Most Rho proteins contain a lipid modification site at the C-terminus, with a typical sequence motif CaaX, where a = an aliphatic amino acid and X = any amino acid. Lipid binding is essential for membrane attachment, a key feature of most Rho proteins. Due to the presence of truncated sequences in this CD, the lipid modification site is not available for annotation.бА0АкА0АаАCDDбАаА╥вА0А0АаАВЇcd04131, Rnd, Rho family GTPase subfamily Rnd includes Rnd1/Rho6, Rnd2/Rho7, and Rnd3/RhoE/Rho8. The Rnd subfamily contains Rnd1/Rho6, Rnd2/Rho7, and Rnd3/RhoE/Rho8. These novel Rho family proteins have substantial structural differences compared to other Rho members, including N- and C-terminal extensions relative to other Rhos. Rnd3/RhoE is farnesylated at the C-terminal prenylation site, unlike most other Rho proteins that are geranylgeranylated. In addition, Rnd members are unable to hydrolyze GTP and are resistant to GAP activity. They are believed to exist only in the GTP-bound conformation, and are antagonists of RhoA activity. Most Rho proteins contain a lipid modification site at the C-terminus, with a typical sequence motif CaaX, where a = an aliphatic amino acid and X = any amino acid. Lipid binding is essential for membrane attachment, a key feature of most Rho proteins. Due to the presence of truncated sequences in this CD, the lipid modification site is not available for annotation.бА0АкА0АаАCDDбАаА'oвА0А0АаАВЗcd04132, Rho4_like, Ras homology family 4 (Rho4) of small guanosine triphosphatases (GTPases)-like. Rho4 is a GTPase that controls septum degradation by regulating secretion of Eng1 or Agn1 during cytokinesis. Rho4 also plays a role in cell morphogenesis. Rho4 regulates septation and cell morphology by controlling the actin cytoskeleton and cytoplasmic microtubules. The localization of Rho4 is modulated by Rdi1, which may function as a GDI, and by Rga9, which is believed to function as a GAP. In S. pombe, both Rho4 deletion and Rho4 overexpression result in a defective cell wall, suggesting a role for Rho4 in maintaining cell wall integrity. Most Rho proteins contain a lipid modification site at the C-terminus, with a typical sequence motif CaaX, where a = an aliphatic amino acid and X = any amino acid. Lipid binding is essential for membrane attachment, a key feature of most Rho proteins.бА0АкА0АаАCDDбАаА'pвА0А0АаАВ√cd04133, Rop_like, Rho-related protein from plants (Rop)-like. The Rop (Rho-related protein from plants) subfamily plays a role in diverse cellular processes, including cytoskeletal organization, pollen and vegetative cell growth, hormone responses, stress responses, and pathogen resistance. Rops are able to regulate several downstream pathways to amplify a specific signal by acting as master switches early in the signaling cascade. They transmit a variety of extracellular and intracellular signals. Rops are involved in establishing cell polarity in root-hair development, root-hair elongation, pollen-tube growth, cell-shape formation, responses to hormones such as abscisic acid (ABA) and auxin, responses to abiotic stresses such as oxygen deprivation, and disease resistance and disease susceptibility. An individual Rop can have a unique function or an overlapping function shared with other Rop proteins; in addition, a given Rop-regulated function can be controlled by one or multiple Rop proteins. For example, Rop1, Rop3, and Rop5 are all involved in pollen-tube growth; Rop2 plays a role in response to low-oxygen environments, cell-morphology, and root-hair development; root-hair development is also regulated by Rop4 and Rop6; Rop6 is also responsible for ABA response, and ABA response is also regulated by Rop10. Plants retain some of the regulatory mechanisms that are shared by other members of the Rho family, but have also developed a number of unique modes for regulating Rops. Unique RhoGEFs have been identified that are exclusively active toward Rop proteins, such as those containing the domain PRONE (plant-specific Rop nucleotide exchanger). Most Rho proteins contain a lipid modification site at the C-terminus, with a typical sequence motif CaaX, where a = an aliphatic amino acid and X = any amino acid. Lipid binding is essential for membrane attachment, a key feature of most Rho proteins. Due to the presence of truncated sequences in this CD, the lipid modification site is not available for annotation.бА0АкА0АаАCDDбАаА'qвА0А0АаАВ▒cd04134, Rho3, Ras homology family 3 (Rho3) of small guanosine triphosphatases (GTPases). Rho3 is a member of the Rho family found only in fungi. Rho3 is believed to regulate cell polarity by interacting with the diaphanous/formin family protein For3 to control both the actin cytoskeleton and microtubules. Rho3 is also believed to have a direct role in exocytosis that is independent of its role in regulating actin polarity. The function in exocytosis may be two-pronged: first, in the transport of post-Golgi vesicles from the mother cell to the bud, mediated by myosin (Myo2); second, in the docking and fusion of vesicles to the plasma membrane, mediated by an exocyst (Exo70) protein. Most Rho proteins contain a lipid modification site at the C-terminus, with a typical sequence motif CaaX, where a = an aliphatic amino acid and X = any amino acid. Lipid binding is essential for membrane attachment, a key feature of most Rho proteins.бА0АкА0АаАCDDбАаА'rвА0А0АаАВHcd04135, Tc10, Rho GTPase TC10 (Tc10). TC10 is a Rho family protein that has been shown to induce microspike formation and neurite outgrowth in vitro. Its expression changes dramatically after peripheral nerve injury, suggesting an important role in promoting axonal outgrowth and regeneration. TC10 regulates translocation of insulin-stimulated GLUT4 in adipocytes and has also been shown to bind directly to Golgi COPI coat proteins. GTP-bound TC10 in vitro can bind numerous potential effectors. Depending on its subcellular localization and distinct functional domains, TC10 can differentially regulate two types of filamentous actin in adipocytes. TC10 mRNAs are highly expressed in three types of mouse muscle tissues: leg skeletal muscle, cardiac muscle, and uterus; they were also present in brain, with higher levels in adults than in newborns. TC10 has also been shown to play a role in regulating the expression of cystic fibrosis transmembrane conductance regulator (CFTR) through interactions with CFTR-associated ligand (CAL). The GTP-bound form of TC10 directs the trafficking of CFTR from the juxtanuclear region to the secretory pathway toward the plasma membrane, away from CAL-mediated DFTR degradation in the lysosome. Most Rho proteins contain a lipid modification site at the C-terminus, with a typical sequence motif CaaX, where a = an aliphatic amino acid and X = any amino acid. Lipid binding is essential for membrane attachment, a key feature of most Rho proteins. Due to the presence of truncated sequences in this CD, the lipid modification site is not available for annotation.бА0АкА0АаАCDDбАаА'sвА0А0АаАВ cd04136, Rap_like, Rap-like family consists of Rap1, Rap2 and RSR1. The Rap subfamily consists of the Rap1, Rap2, and RSR1. Rap subfamily proteins perform different cellular functions, depending on the isoform and its subcellular localization. For example, in rat salivary gland, neutrophils, and platelets, Rap1 localizes to secretory granules and is believed to regulate exocytosis or the formation of secretory granules. Rap1 has also been shown to localize in the Golgi of rat fibroblasts, zymogen granules, plasma membrane, and microsomal membrane of the pancreatic acini, as well as in the endocytic compartment of skeletal muscle cells and fibroblasts. Rap1 localizes in the nucleus of human oropharyngeal squamous cell carcinomas (SCCs) and cell lines. Rap1 plays a role in phagocytosis by controlling the binding of adhesion receptors (typically integrins) to their ligands. In yeast, Rap1 has been implicated in multiple functions, including activation and silencing of transcription and maintenance of telomeres. Rap2 is involved in multiple functions, including activation of c-Jun N-terminal kinase (JNK) to regulate the actin cytoskeleton and activation of the Wnt/beta-catenin signaling pathway in embryonic Xenopus. A number of effector proteins for Rap2 have been identified, including isoform 3 of the human mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) and Traf2- and Nck-interacting kinase (TNIK), and the RalGEFs RalGDS, RGL, and Rlf, which also interact with Rap1 and Ras. RSR1 is the fungal homolog of Rap1 and Rap2. In budding yeasts, it is involved in selecting a site for bud growth, which directs the establishment of cell polarization. The Rho family GTPase Cdc42 and its GEF, Cdc24, then establish an axis of polarized growth. It is believed that Cdc42 interacts directly with RSR1 in vivo. In filamentous fungi such as Ashbya gossypii, RSR1 is a key regulator of polar growth in the hypha. Most Ras proteins contain a lipid modification site at the C-terminus, with a typical sequence motif CaaX, where a = an aliphatic amino acid and X = any amino acid. Lipid binding is essential for membrane attachment, a key feature of most Ras proteins. Due to the presence of truncated sequences in this CD, the lipid modification site is not available for annotation.бА0АкА0АаАCDDбАаА'tвА0А0АаАВGcd04137, RheB, Ras Homolog Enriched in Brain (RheB) is a small GTPase. Rheb (Ras Homolog Enriched in Brain) subfamily. Rheb was initially identified in rat brain, where its expression is elevated by seizures or by long-term potentiation. It is expressed ubiquitously, with elevated levels in muscle and brain. Rheb functions as an important mediator between the tuberous sclerosis complex proteins, TSC1 and TSC2, and the mammalian target of rapamycin (TOR) kinase to stimulate cell growth. TOR kinase regulates cell growth by controlling nutrient availability, growth factors, and the energy status of the cell. TSC1 and TSC2 form a dimeric complex that has tumor suppressor activity, and TSC2 is a GTPase activating protein (GAP) for Rheb. The TSC1/TSC2 complex inhibits the activation of TOR kinase through Rheb. Rheb has also been shown to induce the formation of large cytoplasmic vacuoles in a process that is dependent on the GTPase cycle of Rheb, but independent of the TOR kinase, suggesting Rheb plays a role in endocytic trafficking that leads to cell growth and cell-cycle progression. Most Ras proteins contain a lipid modification site at the C-terminus, with a typical sequence motif CaaX, where a = an aliphatic amino acid and X = any amino acid. Lipid binding is essential for membrane attachment, a key feature of most Ras proteins.бА0АкА0АаАCDDбАаА'uвА0А0АаАВёcd04138, H_N_K_Ras_like, Ras GTPase family containing H-Ras,N-Ras and K-Ras4A/4B. H-Ras/N-Ras/K-Ras subfamily. H-Ras, N-Ras, and K-Ras4A/4B are the prototypical members of the Ras family. These isoforms generate distinct signal outputs despite interacting with a common set of activators and effectors, and are strongly associated with oncogenic progression in tumor initiation. Mutated versions of Ras that are insensitive to GAP stimulation (and are therefore constitutively active) are found in a significant fraction of human cancers. Many Ras guanine nucleotide exchange factors (GEFs) have been identified. They are sequestered in the cytosol until activation by growth factors triggers recruitment to the plasma membrane or Golgi, where the GEF colocalizes with Ras. Active (GTP-bound) Ras interacts with several effector proteins that stimulate a variety of diverse cytoplasmic signaling activities. Some are known to positively mediate the oncogenic properties of Ras, including Raf, phosphatidylinositol 3-kinase (PI3K), RalGEFs, and Tiam1. Others are proposed to play negative regulatory roles in oncogenesis, including RASSF and NORE/MST1. Most Ras proteins contain a lipid modification site at the C-terminus, with a typical sequence motif CaaX, where a = an aliphatic amino acid and X = any amino acid. Lipid binding is essential for membrane attachment, a key feature of most Ras proteins. Due to the presence of truncated sequences in this CD, the lipid modification site is not available for annotation.бА0АкА0АаАCDDбАаА┌вА0А0АаАВ╜cd04139, RalA_RalB, Ral (Ras-like) family containing highly homologous RalA and RalB. The Ral (Ras-like) subfamily consists of the highly homologous RalA and RalB. Ral proteins are believed to play a crucial role in tumorigenesis, metastasis, endocytosis, and actin cytoskeleton dynamics. Despite their high sequence similarity (>80% sequence identity), nonoverlapping and opposing functions have been assigned to RalA and RalBs in tumor migration. In human bladder and prostate cancer cells, RalB promotes migration while RalA inhibits it. A Ral-specific set of GEFs has been identified that are activated by Ras binding. This RalGEF activity is enhanced by Ras binding to another of its target proteins, phosphatidylinositol 3-kinase (PI3K). Ral effectors include RLIP76/RalBP1, a Rac/cdc42 GAP, and the exocyst (Sec6/8) complex, a heterooctomeric protein complex that is involved in tethering vesicles to specific sites on the plasma membrane prior to exocytosis. In rat kidney cells, RalB is required for functional assembly of the exocyst and for localizing the exocyst to the leading edge of migrating cells. In human cancer cells, RalA is required to support anchorage-independent proliferation and RalB is required to suppress apoptosis. RalA has been shown to localize to the plasma membrane while RalB is localized to the intracellular vesicles. Most Ras proteins contain a lipid modification site at the C-terminus, with a typical sequence motif CaaX, where a = an aliphatic amino acid and X = any amino acid. Lipid binding is essential for membrane attachment, a key feature of most Ras proteins. Due to the presence of truncated sequences in this CD, the lipid modification site is not available for annotation.бА0АкА0АаАCDDбАаА'vвА0А0АаАВ^cd04140, ARHI_like, A Ras homolog member I (ARHI). ARHI (A Ras homolog member I) is a member of the Ras family with several unique structural and functional properties. ARHI is expressed in normal human ovarian and breast tissue, but its expression is decreased or eliminated in breast and ovarian cancer. ARHI contains an N-terminal extension of 34 residues (human) that is required to retain its tumor suppressive activity. Unlike most other Ras family members, ARHI is maintained in the constitutively active (GTP-bound) state in resting cells and has modest GTPase activity. ARHI inhibits STAT3 (signal transducers and activators of transcription 3), a latent transcription factor whose abnormal activation plays a critical role in oncogenesis. Most Ras proteins contain a lipid modification site at the C-terminus, with a typical sequence motif CaaX, where a = an aliphatic amino acid and X = any amino acid. Lipid binding is essential for membrane attachment, a key feature of most Ras proteins. Due to the presence of truncated sequences in this CD, the lipid modification site is not available for annotation.бА0АкА0АаАCDDбАаА'wвА0А0АаАВєcd04141, Rit_Rin_Ric, Ras-like protein in all tissues (Rit), Ras-like protein in neurons (Rin) and Ras-related protein which interacts with calmodulin (Ric). Rit (Ras-like protein in all tissues), Rin (Ras-like protein in neurons) and Ric (Ras-related protein which interacts with calmodulin) form a subfamily with several unique structural and functional characteristics. These proteins all lack a the C-terminal CaaX lipid-binding motif typical of Ras family proteins, and Rin and Ric contain calmodulin-binding domains. Rin, which is expressed only in neurons, induces neurite outgrowth in rat pheochromocytoma cells through its association with calmodulin and its activation of endogenous Rac/cdc42. Rit, which is ubiquitously expressed in mammals, inhibits growth-factor withdrawl-mediated apoptosis and induces neurite extension in pheochromocytoma cells. Rit and Rin are both able to form a ternary complex with PAR6, a cell polarity-regulating protein, and Rac/cdc42. This ternary complex is proposed to have physiological function in processes such as tumorigenesis. Activated Ric is likely to signal in parallel with the Ras pathway or stimulate the Ras pathway at some upstream point, and binding of calmodulin to Ric may negatively regulate Ric activity.бА0АкА0АаАCDDбАаА'xвА0А0АаАВ√cd04142, RRP22, Ras-related protein on chromosome 22 (RRP22) family. RRP22 (Ras-related protein on chromosome 22) subfamily consists of proteins that inhibit cell growth and promote caspase-independent cell death. Unlike most Ras proteins, RRP22 is down-regulated in many human tumor cells due to promoter methylation. RRP22 localizes to the nucleolus in a GTP-dependent manner, suggesting a novel function in modulating transport of nucleolar components. Most Ras proteins contain a lipid modification site at the C-terminus, with a typical sequence motif CaaX, where a = an aliphatic amino acid and X = any amino acid. Lipid binding is essential for membrane attachment, a key feature of most Ras proteins. Like most Ras family proteins, RRP22 is farnesylated.бА0АкА0АаАCDDбАаА▐вА0А0АаАВ╚cd04143, Rhes_like, Ras homolog enriched in striatum (Rhes) and activator of G-protein signaling 1 (Dexras1/AGS1). This subfamily includes Rhes (Ras homolog enriched in striatum) and Dexras1/AGS1 (activator of G-protein signaling 1). These proteins are homologous, but exhibit significant differences in tissue distribution and subcellular localization. Rhes is found primarily in the striatum of the brain, but is also expressed in other areas of the brain, such as the cerebral cortex, hippocampus, inferior colliculus, and cerebellum. Rhes expression is controlled by thyroid hormones. In rat PC12 cells, Rhes is farnesylated and localizes to the plasma membrane. Rhes binds and activates PI3K, and plays a role in coupling serpentine membrane receptors with heterotrimeric G-protein signaling. Rhes has recently been shown to be reduced under conditions of dopamine supersensitivity and may play a role in determining dopamine receptor sensitivity. Dexras1/AGS1 is a dexamethasone-induced Ras protein that is expressed primarily in the brain, with low expression levels in other tissues. Dexras1 localizes primarily to the cytoplasm, and is a critical regulator of the circadian master clock to photic and nonphotic input. Most Ras proteins contain a lipid modification site at the C-terminus, with a typical sequence motif CaaX, where a = an aliphatic amino acid and X = any amino acid. Lipid binding is essential for membrane attachment, a key feature of most Ras proteins.бА0АкА0АаАCDDбАаА▀вА0А0АаАВ╞cd04144, Ras2, Rat sarcoma (Ras) family 2 of small guanosine triphosphatases (GTPases). The Ras2 subfamily, found exclusively in fungi, was first identified in Ustilago maydis. In U. maydis, Ras2 is regulated by Sql2, a protein that is homologous to GEFs (guanine nucleotide exchange factors) of the CDC25 family. Ras2 has been shown to induce filamentous growth, but the signaling cascade through which Ras2 and Sql2 regulate cell morphology is not known. Most Ras proteins contain a lipid modification site at the C-terminus, with a typical sequence motif CaaX, where a = an aliphatic amino acid and X = any amino acid. Lipid binding is essential for membrane attachment, a key feature of most Ras proteins.бА0АкА0АаАCDDбАаАрвА0А0АаАВшcd04145, M_R_Ras_like, R-Ras2/TC21, M-Ras/R-Ras3. The M-Ras/R-Ras-like subfamily contains R-Ras2/TC21, M-Ras/R-Ras3, and related members of the Ras family. M-Ras is expressed in lympho-hematopoetic cells. It interacts with some of the known Ras effectors, but appears to also have its own effectors. Expression of mutated M-Ras leads to transformation of several types of cell lines, including hematopoietic cells, mammary epithelial cells, and fibroblasts. Overexpression of M-Ras is observed in carcinomas from breast, uterus, thyroid, stomach, colon, kidney, lung, and rectum. In addition, expression of a constitutively active M-Ras mutant in murine bone marrow induces a malignant mast cell leukemia that is distinct from the monocytic leukemia induced by H-Ras. TC21, along with H-Ras, has been shown to regulate the branching morphogenesis of ureteric bud cell branching in mice. Most Ras proteins contain a lipid modification site at the C-terminus, with a typical sequence motif CaaX, where a = an aliphatic amino acid and X = any amino acid. Lipid binding is essential for membrane attachment, a key feature of most Ras proteins. Due to the presence of truncated sequences in this CD, the lipid modification site is not available for annotation.бА0АкА0АаАCDDбАаАсвА0А0АаАВCcd04146, RERG_RasL11_like, Ras-related and Estrogen-Regulated Growth inhibitor (RERG) and Ras-like 11 (RasL11)-like families. RERG (Ras-related and Estrogen- Regulated Growth inhibitor) and Ras-like 11 are members of a novel subfamily of Ras that were identified based on their behavior in breast and prostate tumors, respectively. RERG expression was decreased or lost in a significant fraction of primary human breast tumors that lack estrogen receptor and are correlated with poor clinical prognosis. Elevated RERG expression correlated with favorable patient outcome in a breast tumor subtype that is positive for estrogen receptor expression. In contrast to most Ras proteins, RERG overexpression inhibited the growth of breast tumor cells in vitro and in vivo. RasL11 was found to be ubiquitously expressed in human tissue, but down-regulated in prostate tumors. Both RERG and RasL11 lack the C-terminal CaaX prenylation motif, where a = an aliphatic amino acid and X = any amino acid, and are localized primarily in the cytoplasm. Both are believed to have tumor suppressor activity.бА0АкА0АаАCDDбАаА'yвА0А0АаАВ■cd04147, Ras_dva, Ras - dorsal-ventral anterior localization (Ras-dva) family. Ras-dva subfamily. Ras-dva (Ras - dorsal-ventral anterior localization) subfamily consists of a set of proteins characterized only in Xenopus leavis, to date. In Xenopus Ras-dva expression is activated by the transcription factor Otx2 and begins during gastrulation throughout the anterior ectoderm. Ras-dva expression is inhibited in the anterior neural plate by factor Xanf1. Downregulation of Ras-dva results in head development abnormalities through the inhibition of several regulators of the anterior neural plate and folds patterning, including Otx2, BF-1, Xag2, Pax6, Slug, and Sox9. Downregulation of Ras-dva also interferes with the FGF-8a signaling within the anterior ectoderm. Most Ras proteins contain a lipid modification site at the C-terminus, with a typical sequence motif CaaX, where a = an aliphatic amino acid and X = any amino acid. Lipid binding is essential for membrane attachment, a key feature of most Ras proteins.бА0АкА0АаАCDDбАаА'zвА0А0АаАВucd04148, RGK, Rem, Rem2, Rad, Gem/Kir (RGK) subfamily of Ras GTPases. RGK subfamily. The RGK (Rem, Rem2, Rad, Gem/Kir) subfamily of Ras GTPases are expressed in a tissue-specific manner and are dynamically regulated by transcriptional and posttranscriptional mechanisms in response to environmental cues. RGK proteins bind to the beta subunit of L-type calcium channels, causing functional down-regulation of these voltage-dependent calcium channels, and either termination of calcium-dependent secretion or modulation of electrical conduction and contractile function. Inhibition of L-type calcium channels by Rem2 may provide a mechanism for modulating calcium-triggered exocytosis in hormone-secreting cells, and has been proposed to influence the secretion of insulin in pancreatic beta cells. RGK proteins also interact with and inhibit the Rho/Rho kinase pathway to modulate remodeling of the cytoskeleton. Two characteristics of RGK proteins cited in the literature are N-terminal and C-terminal extensions beyond the GTPase domain typical of Ras superfamily members. The N-terminal extension is not conserved among family members; the C-terminal extension is reported to be conserved among the family and lack the CaaX prenylation motif typical of membrane-associated Ras proteins. However, a putative CaaX motif has been identified in the alignment of the C-terminal residues of this CD.бА0АкА0АаАCDDбАаА'{вА0А0АаАВ cd04149, Arf6, ADP ribosylation factor 6 (Arf6). Arf6 subfamily. Arf6 (ADP ribosylation factor 6) proteins localize to the plasma membrane, where they perform a wide variety of functions. In its active, GTP-bound form, Arf6 is involved in cell spreading, Rac-induced formation of plasma membrane ruffles, cell migration, wound healing, and Fc-mediated phagocytosis. Arf6 appears to change the actin structure at the plasma membrane by activating Rac, a Rho family protein involved in membrane ruffling. Arf6 is required for and enhances Rac formation of ruffles. Arf6 can regulate dendritic branching in hippocampal neurons, and in yeast it localizes to the growing bud, where it plays a role in polarized growth and bud site selection. In leukocytes, Arf6 is required for chemokine-stimulated migration across endothelial cells. Arf6 also plays a role in down-regulation of beta2-adrenergic receptors and luteinizing hormone receptors by facilitating the release of sequestered arrestin to allow endocytosis. Arf6 is believed to function at multiple sites on the plasma membrane through interaction with a specific set of GEFs, GAPs, and effectors. Arf6 has been implicated in breast cancer and melanoma cell invasion, and in actin remodelling at the invasion site of Chlamydia infection.бА0АкА0АаАCDDбАаА'|вА0А0АаАВ+cd04150, Arf1_5_like, ADP-ribosylation factor-1 (Arf1) and ADP-ribosylation factor-5 (Arf5). The Arf1-Arf5-like subfamily contains Arf1, Arf2, Arf3, Arf4, Arf5, and related proteins. Arfs1-5 are soluble proteins that are crucial for assembling coat proteins during vesicle formation. Each contains an N-terminal myristoylated amphipathic helix that is folded into the protein in the GDP-bound state. GDP/GTP exchange exposes the helix, which anchors to the membrane. Following GTP hydrolysis, the helix dissociates from the membrane and folds back into the protein. A general feature of Arf1-5 signaling may be the cooperation of two Arfs at the same site. Arfs1-5 are generally considered to be interchangeable in function and location, but some specific functions have been assigned. Arf1 localizes to the early/cis-Golgi, where it is activated by GBF1 and recruits the coat protein COPI. It also localizes to the trans-Golgi network (TGN), where it is activated by BIG1/BIG2 and recruits the AP1, AP3, AP4, and GGA proteins. Humans, but not rodents and other lower eukaryotes, lack Arf2. Human Arf3 shares 96% sequence identity with Arf1 and is believed to generally function interchangeably with Arf1. Human Arf4 in the activated (GTP-bound) state has been shown to interact with the cytoplasmic domain of epidermal growth factor receptor (EGFR) and mediate the EGF-dependent activation of phospholipase D2 (PLD2), leading to activation of the activator protein 1 (AP-1) transcription factor. Arf4 has also been shown to recognize the C-terminal sorting signal of rhodopsin and regulate its incorporation into specialized post-Golgi rhodopsin transport carriers (RTCs). There is some evidence that Arf5 functions at the early-Golgi and the trans-Golgi to affect Golgi-associated alpha-adaptin homology Arf-binding proteins (GGAs).бА0АкА0АаАCDDбАаА'}вА0А0АаАВ╨cd04151, Arl1, ADP ribosylation factor 1 (Arf1). Arl1 subfamily. Arl1 (Arf-like 1) localizes to the Golgi complex, where it is believed to recruit effector proteins to the trans-Golgi network. Like most members of the Arf family, Arl1 is myristoylated at its N-terminal helix and mutation of the myristoylation site disrupts Golgi targeting. In humans, the Golgi-localized proteins golgin-97 and golgin-245 have been identified as Arl1 effectors. Golgins are large coiled-coil proteins found in the Golgi, and these golgins contain a C-terminal GRIP domain, which is the site of Arl1 binding. Additional Arl1 effectors include the GARP (Golgi-associated retrograde protein)/VFT (Vps53) vesicle-tethering complex and Arfaptin 2. Arl1 is not required for exocytosis, but appears necessary for trafficking from the endosomes to the Golgi. In Drosophila zygotes, mutation of Arl1 is lethal, and in the host-bloodstream form of Trypanosoma brucei, Arl1 is essential for viability.бА0АкА0АаАCDDбАаА'~вА0А0АаАВ;cd04152, Arl4_Arl7, Arf-like 4 (Arl4) and 7 (Arl7) GTPases. Arl4 (Arf-like 4) is highly expressed in testicular germ cells, and is found in the nucleus and nucleolus. In mice, Arl4 is developmentally expressed during embryogenesis, and a role in somite formation and central nervous system differentiation has been proposed. Arl7 has been identified as the only Arf/Arl protein to be induced by agonists of liver X-receptor and retinoid X-receptor and by cholesterol loading in human macrophages. Arl7 is proposed to play a role in transport between a perinuclear compartment and the plasma membrane, apparently linked to the ABCA1-mediated cholesterol secretion pathway. Older literature suggests that Arl6 is a part of the Arl4/Arl7 subfamily, but analyses based on more recent sequence data place Arl6 in its own subfamily.бА0АкА0АаАCDDбАаА'вА0А0АаАВгcd04153, Arl5_Arl8, Arf-like 5 (Arl5) and 8 (Arl8) GTPases. Arl5/Arl8 subfamily. Arl5 (Arf-like 5) and Arl8, like Arl4 and Arl7, are localized to the nucleus and nucleolus. Arl5 is developmentally regulated during embryogenesis in mice. Human Arl5 interacts with the heterochromatin protein 1-alpha (HP1alpha), a nonhistone chromosomal protein that is associated with heterochromatin and telomeres, and prevents telomere fusion. Arl5 may also play a role in embryonic nuclear dynamics and/or signaling cascades. Arl8 was identified from a fetal cartilage cDNA library. It is found in brain, heart, lung, cartilage, and kidney. No function has been assigned for Arl8 to date.бА0АкА0АаАCDDбАаАщвА0А0АаАВвcd04154, Arl2, Arf-like 2 (Arl2) GTPase. Arl2 (Arf-like 2) GTPases are members of the Arf family that bind GDP and GTP with very low affinity. Unlike most Arf family proteins, Arl2 is not myristoylated at its N-terminal helix. The protein PDE-delta, first identified in photoreceptor rod cells, binds specifically to Arl2 and is structurally very similar to RhoGDI. Despite the high structural similarity between Arl2 and Rho proteins and between PDE-delta and RhoGDI, the interactions between the GTPases and their effectors are very different. In its GTP bound form, Arl2 interacts with the protein Binder of Arl2 (BART), and the complex is believed to play a role in mitochondrial adenine nucleotide transport. In its GDP bound form, Arl2 interacts with tubulin- folding Cofactor D; this interaction is believed to play a role in regulation of microtubule dynamics that impact the cytoskeleton, cell division, and cytokinesis.бА0АкА0АаАCDDбАаА'АвА0А0АаАВЯcd04155, Arl3, Arf-like 3 (Arl3) GTPase. Arl3 (Arf-like 3) is an Arf family protein that differs from most Arf family members in the N-terminal extension. In is inactive, GDP-bound form, the N-terminal extension forms an elongated loop that is hydrophobically anchored into the membrane surface; however, it has been proposed that this region might form a helix in the GTP-bound form. The delta subunit of the rod-specific cyclic GMP phosphodiesterase type 6 (PDEdelta) is an Arl3 effector. Arl3 binds microtubules in a regulated manner to alter specific aspects of cytokinesis via interactions with retinitis pigmentosa 2 (RP2). It has been proposed that RP2 functions in concert with Arl3 to link the cell membrane and the cytoskeleton in photoreceptors as part of the cell signaling or vesicular transport machinery. In mice, the absence of Arl3 is associated with abnormal epithelial cell proliferation and cyst formation.бА0АкА0АаАCDDбАаА'БвА0А0АаАВ&cd04156, ARLTS1, Arf-like tumor suppressor gene 1 (ARLTS1 or Arl11). ARLTS1 (Arf-like tumor suppressor gene 1), also known as Arl11, is a member of the Arf family of small GTPases that is believed to play a major role in apoptotic signaling. ARLTS1 is widely expressed and functions as a tumor suppressor gene in several human cancers. ARLTS1 is a low-penetrance suppressor that accounts for a small percentage of familial melanoma or familial chronic lymphocytic leukemia (CLL). ARLTS1 inactivation seems to occur most frequently through biallelic down-regulation by hypermethylation of the promoter. In breast cancer, ARLTS1 alterations were typically a combination of a hypomorphic polymorphism plus loss of heterozygosity. In a case of thyroid adenoma, ARLTS1 alterations were polymorphism plus promoter hypermethylation. The nonsense polymorphism Trp149Stop occurs with significantly greater frequency in familial cancer cases than in sporadic cancer cases, and the Cys148Arg polymorphism is associated with an increase in high-risk familial breast cancer.бА0АкА0АаАCDDбАаАьвА0А0АаАВhcd04157, Arl6, Arf-like 6 (Arl6) GTPase. Arl6 (Arf-like 6) forms a subfamily of the Arf family of small GTPases. Arl6 expression is limited to the brain and kidney in adult mice, but it is expressed in the neural plate and somites during embryogenesis, suggesting a possible role for Arl6 in early development. Arl6 is also believed to have a role in cilia or flagella function. Several proteins have been identified that bind Arl6, including Arl6 interacting protein (Arl6ip), and SEC61beta, a subunit of the heterotrimeric conducting channel SEC61p. Based on Arl6 binding to these effectors, Arl6 is also proposed to play a role in protein transport, membrane trafficking, or cell signaling during hematopoietic maturation. At least three specific homozygous Arl6 mutations in humans have been found to cause Bardet-Biedl syndrome, a disorder characterized by obesity, retinopathy, polydactyly, renal and cardiac malformations, learning disabilities, and hypogenitalism. Older literature suggests that Arl6 is a part of the Arl4/Arl7 subfamily, but analyses based on more recent sequence data place Arl6 in its own subfamily.бА0АкА0АаАCDDбАаА'ВвА0А0АаАВНcd04158, ARD1, (ADP-ribosylation factor domain protein 1 (ARD1). ARD1 (ADP-ribosylation factor domain protein 1) is an unusual member of the Arf family. In addition to the C-terminal Arf domain, ARD1 has an additional 46-kDa N-terminal domain that contains a RING finger domain, two predicted B-Boxes, and a coiled-coil protein interaction motif. This domain belongs to the TRIM (tripartite motif) or RBCC (RING, B-Box, coiled-coil) family. Like most Arfs, the ARD1 Arf domain lacks detectable GTPase activity. However, unlike most Arfs, the full-length ARD1 protein has significant GTPase activity due to the GAP (GTPase-activating protein) activity exhibited by the 46-kDa N-terminal domain. The GAP domain of ARD1 is specific for its own Arf domain and does not bind other Arfs. The rate of GDP dissociation from the ARD1 Arf domain is slowed by the adjacent 15 amino acids, which act as a GDI (GDP-dissociation inhibitor) domain. ARD1 is ubiquitously expressed in cells and localizes to the Golgi and to the lysosomal membrane. Two Tyr-based motifs in the Arf domain are responsible for Golgi localization, while the GAP domain controls lysosomal localization.бА0АкА0АаАCDDбАаА'ГвА0А0АаАВ,cd04159, Arl10_like, Arf-like 9 (Arl9) and 10 (Arl10) GTPases. Arl10-like subfamily. Arl9/Arl10 was identified from a human cancer-derived EST dataset. No functional information about the subfamily is available at the current time, but crystal structures of human Arl10b and Arl10c have been solved.бА0АкА0АаАCDDбАаА'ДвА0А0АаАВkcd04160, Arfrp1, Arf-related protein 1 (Arfrp1). Arfrp1 (Arf-related protein 1), formerly known as ARP, is a membrane-associated Arf family member that lacks the N-terminal myristoylation motif. Arfrp1 is mainly associated with the trans-Golgi compartment and the trans-Golgi network, where it regulates the targeting of Arl1 and the GRIP domain-containing proteins, golgin-97 and golgin-245, onto Golgi membranes. It is also involved in the anterograde transport of the vesicular stomatitis virus G protein from the Golgi to the plasma membrane, and in the retrograde transport of TGN38 and Shiga toxin from endosomes to the trans-Golgi network. Arfrp1 also inhibits Arf/Sec7-dependent activation of phospholipase D. Deletion of Arfrp1 in mice causes embryonic lethality at the gastrulation stage and apoptosis of mesodermal cells, indicating its importance in development.бА0АкА0АаАCDDбАаА'ЕвА0А0АаАВ╥cd04161, Arl2l1_Arl13_like, Arl2-like protein 1 (Arl2l1) and Arl13. Arl2l1 (Arl2-like protein 1) and Arl13 form a subfamily of the Arf family of small GTPases. Arl2l1 was identified in human cells during a search for the gene(s) responsible for Bardet-Biedl syndrome (BBS). Like Arl6, the identified BBS gene, Arl2l1 is proposed to have cilia-specific functions. Arl13 is found on the X chromosome, but its expression has not been confirmed; it may be a pseudogene.бА0АкА0АаАCDDбАаАёвА0А0АаАВbcd04162, Arl9_Arfrp2_like, Arf-like 9 (Arl9)/Arfrp2-like GTPase. Arl9/Arfrp2-like subfamily. Arl9 (Arf-like 9) was first identified as part of the Human Cancer Genome Project. It maps to chromosome 4q12 and is sometimes referred to as Arfrp2 (Arf-related protein 2). This is a novel subfamily identified in human cancers that is uncharacterized to date.бА0АкА0АаАCDDбАаАЄвА0А0АаАВbcd04163, Era, E. coli Ras-like protein (Era) is a multifunctional GTPase. Era (E. coli Ras-like protein) is a multifunctional GTPase found in all bacteria except some eubacteria. It binds to the 16S ribosomal RNA (rRNA) of the 30S subunit and appears to play a role in the assembly of the 30S subunit, possibly by chaperoning the 16S rRNA. It also contacts several assembly elements of the 30S subunit. Era couples cell growth with cytokinesis and plays a role in cell division and energy metabolism. Homologs have also been found in eukaryotes. Era contains two domains: the N-terminal GTPase domain and a C-terminal domain KH domain that is critical for RNA binding. Both domains are important for Era function. Era is functionally able to compensate for deletion of RbfA, a cold-shock adaptation protein that is required for efficient processing of the 16S rRNA.бА0АкА0АаАCDDбАаА'ЖвА0А0АаАВ┘cd04164, trmE, trmE is a tRNA modification GTPase. TrmE (MnmE, ThdF, MSS1) is a 3-domain protein found in bacteria and eukaryotes. It controls modification of the uridine at the wobble position (U34) of tRNAs that read codons ending with A or G in the mixed codon family boxes. TrmE contains a GTPase domain that forms a canonical Ras-like fold. It functions a molecular switch GTPase, and apparently uses a conformational change associated with GTP hydrolysis to promote the tRNA modification reaction, in which the conserved cysteine in the C-terminal domain is thought to function as a catalytic residue. In bacteria that are able to survive in extremely low pH conditions, TrmE regulates glutamate-dependent acid resistance.бА0АкА0АаАCDDбАаА'ЗвА0А0АаАВVcd04165, GTPBP1_like, GTP binding protein 1 (GTPBP1)-like family includes GTPBP2. Mammalian GTP binding protein 1 (GTPBP1), GTPBP2, and nematode homologs AGP-1 and CGP-1 are GTPases whose specific functions remain unknown. In mouse, GTPBP1 is expressed in macrophages, in smooth muscle cells of various tissues and in some neurons of the cerebral cortex; GTPBP2 tissue distribution appears to overlap that of GTPBP1. In human leukemia and macrophage cell lines, expression of both GTPBP1 and GTPBP2 is enhanced by interferon-gamma (IFN-gamma). The chromosomal location of both genes has been identified in humans, with GTPBP1 located in chromosome 22q12-13.1 and GTPBP2 located in chromosome 6p21-12. Human glioblastoma multiforme (GBM), a highly-malignant astrocytic glioma and the most common cancer in the central nervous system, has been linked to chromosomal deletions and a translocation on chromosome 6. The GBM translocation results in a fusion of GTPBP2 and PTPRZ1, a protein involved in oligodendrocyte differentiation, recovery, and survival. This fusion product may contribute to the onset of GBM.бА0АкА0АаАCDDбАаА'ИвА0А0АаАВcd04166, CysN_ATPS, CysN, together with protein CysD, forms the ATP sulfurylase (ATPS) complex. CysN_ATPS subfamily. CysN, together with protein CysD, form the ATP sulfurylase (ATPS) complex in some bacteria and lower eukaryotes. ATPS catalyzes the production of ATP sulfurylase (APS) and pyrophosphate (PPi) from ATP and sulfate. CysD, which catalyzes ATP hydrolysis, is a member of the ATP pyrophosphatase (ATP PPase) family. CysN hydrolysis of GTP is required for CysD hydrolysis of ATP; however, CysN hydrolysis of GTP is not dependent on CysD hydrolysis of ATP. CysN is an example of lateral gene transfer followed by acquisition of new function. In many organisms, an ATPS exists which is not GTP-dependent and shares no sequence or structural similarity to CysN.бА0АкА0АаАCDDбАаА'ЙвА0А0АаАВ¤cd04167, Snu114p, Snu114p, a spliceosome protein, is a GTPase. Snu114p subfamily. Snu114p is one of several proteins that make up the U5 small nuclear ribonucleoprotein (snRNP) particle. U5 is a component of the spliceosome, which catalyzes the splicing of pre-mRNA to remove introns. Snu114p is homologous to EF-2, but typically contains an additional N-terminal domain not found in Ef-2. This protein is part of the GTP translation factor family and the Ras superfamily, characterized by five G-box motifs.бА0АкА0АаАCDDбАаА'КвА0А0АаАВ$cd04168, TetM_like, Tet(M)-like family includes Tet(M), Tet(O), Tet(W), and OtrA, containing tetracycline resistant proteins. Tet(M), Tet(O), Tet(W), and OtrA are tetracycline resistance genes found in Gram-positive and Gram-negative bacteria. Tetracyclines inhibit protein synthesis by preventing aminoacyl-tRNA from binding to the ribosomal acceptor site. This subfamily contains tetracycline resistance proteins that function through ribosomal protection and are typically found on mobile genetic elements, such as transposons or plasmids, and are often conjugative. Ribosomal protection proteins are homologous to the elongation factors EF-Tu and EF-G. EF-G and Tet(M) compete for binding on the ribosomes. Tet(M) has a higher affinity than EF-G, suggesting these two proteins may have overlapping binding sites and that Tet(M) must be released before EF-G can bind. Tet(M) and Tet(O) have been shown to have ribosome-dependent GTPase activity. These proteins are part of the GTP translation factor family, which includes EF-G, EF-Tu, EF2, LepA, and SelB.бА0АкА0АаАCDDбАаА'ЛвА0А0АаАВ3cd04169, RF3, Release Factor 3 (RF3) protein involved in the terminal step of translocation in bacteria. Peptide chain release factor 3 (RF3) is a protein involved in the termination step of translation in bacteria. Termination occurs when class I release factors (RF1 or RF2) recognize the stop codon at the A-site of the ribosome and activate the release of the nascent polypeptide. The class II release factor RF3 then initiates the release of the class I RF from the ribosome. RF3 binds to the RF/ribosome complex in the inactive (GDP-bound) state. GDP/GTP exchange occurs, followed by the release of the class I RF. Subsequent hydrolysis of GTP to GDP triggers the release of RF3 from the ribosome. RF3 also enhances the efficiency of class I RFs at less preferred stop codons and at stop codons in weak contexts.бА0АкА0АаАCDDбАаА'МвА0А0АаАВ cd04170, EF-G_bact, Elongation factor G (EF-G) family. Translocation is mediated by EF-G (also called translocase). The structure of EF-G closely resembles that of the complex between EF-Tu and tRNA. This is an example of molecular mimicry; a protein domain evolved so that it mimics the shape of a tRNA molecule. EF-G in the GTP form binds to the ribosome, primarily through the interaction of its EF-Tu-like domain with the 50S subunit. The binding of EF-G to the ribosome in this manner stimulates the GTPase activity of EF-G. On GTP hydrolysis, EF-G undergoes a conformational change that forces its arm deeper into the A site on the 30S subunit. To accommodate this domain, the peptidyl-tRNA in the A site moves to the P site, carrying the mRNA and the deacylated tRNA with it. The ribosome may be prepared for these rearrangements by the initial binding of EF-G as well. The dissociation of EF-G leaves the ribosome ready to accept the next aminoacyl-tRNA into the A site. This group contains only bacterial members.бА0АкА0АаАCDDбАаА'НвА0А0АаАВ┌cd04171, SelB, SelB, the dedicated elongation factor for delivery of selenocysteinyl-tRNA to the ribosome. SelB is an elongation factor needed for the co-translational incorporation of selenocysteine. Selenocysteine is coded by a UGA stop codon in combination with a specific downstream mRNA hairpin. In bacteria, the C-terminal part of SelB recognizes this hairpin, while the N-terminal part binds GTP and tRNA in analogy with elongation factor Tu (EF-Tu). It specifically recognizes the selenocysteine charged tRNAsec, which has a UCA anticodon, in an EF-Tu like manner. This allows insertion of selenocysteine at in-frame UGA stop codons. In E. coli SelB binds GTP, selenocysteyl-tRNAsec, and a stem-loop structure immediately downstream of the UGA codon (the SECIS sequence). The absence of active SelB prevents the participation of selenocysteyl-tRNAsec in translation. Archaeal and animal mechanisms of selenocysteine incorporation are more complex. Although the SECIS elements have different secondary structures and conserved elements between archaea and eukaryotes, they do share a common feature. Unlike in E. coli, these SECIS elements are located in the 3' UTRs. This group contains bacterial SelBs, as well as, one from archaea.бА0АкА0АаАCDDбАаА'ОвА0А0АаАВZcd04172, Rnd3_RhoE_Rho8, Rnd3/RhoE/Rho8 GTPases. Rnd3/RhoE/Rho8 subfamily. Rnd3/RhoE/Rho8 is a member of the novel Rho subfamily Rnd, together with Rnd1/Rho6 and Rnd2/Rho7. Rnd3/RhoE is known to bind the serine-threonine kinase ROCK I. Unphosphorylated Rnd3/RhoE associates primarily with membranes, but ROCK I-phosphorylated Rnd3/RhoE localizes in the cytosol. Phosphorylation of Rnd3/RhoE correlates with its activity in disrupting RhoA-induced stress fibers and inhibiting Ras-induced fibroblast transformation. In cells that lack stress fibers, such as macrophages and monocytes, Rnd3/RhoE induces a redistribution of actin, causing morphological changes in the cell. In addition, Rnd3/RhoE has been shown to inhibit cell cycle progression in G1 phase at a point upstream of the pRb family pocket protein checkpoint. Rnd3/RhoE has also been shown to inhibit Ras- and Raf-induced fibroblast transformation. In mammary epithelial tumor cells, Rnd3/RhoE regulates the assembly of the apical junction complex and tight junction formation. Rnd3/RhoE is underexpressed in prostate cancer cells both in vitro and in vivo; re-expression of Rnd3/RhoE suppresses cell cycle progression and increases apoptosis, suggesting it may play a role in tumor suppression. Most Rho proteins contain a lipid modification site at the C-terminus, with a typical sequence motif CaaX, where a = an aliphatic amino acid and X = any amino acid. Lipid binding is essential for membrane attachment, a key feature of most Rho proteins. Due to the presence of truncated sequences in this CD, the lipid modification site is not available for annotation.бА0АкА0АаАCDDбАаА'ПвА0А0АаАВzcd04173, Rnd2_Rho7, Rnd2/Rho7 GTPases. Rnd2/Rho7 is a member of the novel Rho subfamily Rnd, together with Rnd1/Rho6 and Rnd3/RhoE/Rho8. Rnd2/Rho7 is transiently expressed in radially migrating cells in the brain while they are within the subventricular zone of the hippocampus and cerebral cortex. These migrating cells typically develop into pyramidal neurons. Cells that exogenously expressed Rnd2/Rho7 failed to migrate to upper layers of the brain, suggesting that Rnd2/Rho7 plays a role in the radial migration and morphological changes of developing pyramidal neurons, and that Rnd2/Rho7 degradation is necessary for proper cellular migration. The Rnd2/Rho7 GEF Rapostlin is found primarily in the brain and together with Rnd2/Rho7 induces dendrite branching. Unlike Rnd1/Rho6 and Rnd3/RhoE/Rho8, which are RhoA antagonists, Rnd2/Rho7 binds the GEF Pragmin and significantly stimulates RhoA activity and Rho-A mediated cell contraction. Rnd2/Rho7 is also found to be expressed in spermatocytes and early spermatids, with male-germ-cell Rac GTPase-activating protein (MgcRacGAP), where it localizes to the Golgi-derived pro-acrosomal vesicle. Most Rho proteins contain a lipid modification site at the C-terminus, with a typical sequence motif CaaX, where a = an aliphatic amino acid and X = any amino acid. Lipid binding is essential for membrane attachment, a key feature of most Rho proteins.бА0АкА0АаАCDDбАаА'РвА0А0АаАВ╛cd04174, Rnd1_Rho6, Rnd1/Rho6 GTPases. Rnd1/Rho6 is a member of the novel Rho subfamily Rnd, together with Rnd2/Rho7 and Rnd3/RhoE/Rho8. Rnd1/Rho6 binds GTP but does not hydrolyze it to GDP, indicating that it is constitutively active. In rat, Rnd1/Rho6 is highly expressed in the cerebral cortex and hippocampus during synapse formation, and plays a role in spine formation. Rnd1/Rho6 is also expressed in the liver and in endothelial cells, and is upregulated in uterine myometrial cells during pregnancy. Like Rnd3/RhoE/Rho8, Rnd1/Rho6 is believed to function as an antagonist to RhoA. Most Rho proteins contain a lipid modification site at the C-terminus, with a typical sequence motif CaaX, where a = an aliphatic amino acid and X = any amino acid. Lipid binding is essential for membrane attachment, a key feature of most Rho proteins. Due to the presence of truncated sequences in this CD, the lipid modification site is not available for annotation.бА0АкА0АаАCDDбАаА'СвА0А0АаАВ (cd04175, Rap1, Rap1 family GTPase consists of Rap1a and Rap1b isoforms. The Rap1 subgroup is part of the Rap subfamily of the Ras family. It can be further divided into the Rap1a and Rap1b isoforms. In humans, Rap1a and Rap1b share 95% sequence homology, but are products of two different genes located on chromosomes 1 and 12, respectively. Rap1a is sometimes called smg p21 or Krev1 in the older literature. Rap1 proteins are believed to perform different cellular functions, depending on the isoform, its subcellular localization, and the effector proteins it binds. For example, in rat salivary gland, neutrophils, and platelets, Rap1 localizes to secretory granules and is believed to regulate exocytosis or the formation of secretory granules. Rap1 has also been shown to localize in the Golgi of rat fibroblasts, zymogen granules, plasma membrane, and the microsomal membrane of pancreatic acini, as well as in the endocytic compartment of skeletal muscle cells and fibroblasts. High expression of Rap1 has been observed in the nucleus of human oropharyngeal squamous cell carcinomas (SCCs) and cell lines; interestingly, in the SCCs, the active GTP-bound form localized to the nucleus, while the inactive GDP-bound form localized to the cytoplasm. Rap1 plays a role in phagocytosis by controlling the binding of adhesion receptors (typically integrins) to their ligands. In yeast, Rap1 has been implicated in multiple functions, including activation and silencing of transcription and maintenance of telomeres. Rap1a, which is stimulated by T-cell receptor (TCR) activation, is a positive regulator of T cells by directing integrin activation and augmenting lymphocyte responses. In murine hippocampal neurons, Rap1b determines which neurite will become the axon and directs the recruitment of Cdc42, which is required for formation of dendrites and axons. In murine platelets, Rap1b is required for normal homeostasis in vivo and is involved in integrin activation. Most Ras proteins contain a lipid modification site at the C-terminus, with a typical sequence motif CaaX, where a = an aliphatic amino acid and X = any amino acid. Lipid binding is essential for membrane attachment, a key feature of most Ras proteins. Due to the presence of truncated sequences in this CD, the lipid modification site is not available for annotation.бА0АкА0АаАCDDбАаА вА0А0АаАВ╦cd04176, Rap2, Rap2 family GTPase consists of Rap2a, Rap2b, and Rap2c. The Rap2 subgroup is part of the Rap subfamily of the Ras family. It consists of Rap2a, Rap2b, and Rap2c. Both isoform 3 of the human mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) and Traf2- and Nck-interacting kinase (TNIK) are putative effectors of Rap2 in mediating the activation of c-Jun N-terminal kinase (JNK) to regulate the actin cytoskeleton. In human platelets, Rap2 was shown to interact with the cytoskeleton by binding the actin filaments. In embryonic Xenopus development, Rap2 is necessary for the Wnt/beta-catenin signaling pathway. The Rap2 interacting protein 9 (RPIP9) is highly expressed in human breast carcinomas and correlates with a poor prognosis, suggesting a role for Rap2 in breast cancer oncogenesis. Rap2b, but not Rap2a, Rap2c, Rap1a, or Rap1b, is expressed in human red blood cells, where it is believed to be involved in vesiculation. A number of additional effector proteins for Rap2 have been identified, including the RalGEFs RalGDS, RGL, and Rlf, which also interact with Rap1 and Ras. Most Ras proteins contain a lipid modification site at the C-terminus, with a typical sequence motif CaaX, where a = an aliphatic amino acid and X = any amino acid. Lipid binding is essential for membrane attachment, a key feature of most Ras proteins. Due to the presence of truncated sequences in this CD, the lipid modification site is not available for annotation.бА0АкА0АаАCDDбАаА вА0А0АаАВcd04177, RSR1, RSR1/Bud1p family GTPase. RSR1/Bud1p is a member of the Rap subfamily of the Ras family that is found in fungi. In budding yeasts, RSR1 is involved in selecting a site for bud growth on the cell cortex, which directs the establishment of cell polarization. The Rho family GTPase cdc42 and its GEF, cdc24, then establish an axis of polarized growth by organizing the actin cytoskeleton and secretory apparatus at the bud site. It is believed that cdc42 interacts directly with RSR1 in vivo. In filamentous fungi, polar growth occurs at the tips of hypha and at novel growth sites along the extending hypha. In Ashbya gossypii, RSR1 is a key regulator of hyphal growth, localizing at the tip region and regulating in apical polarization of the actin cytoskeleton. Most Ras proteins contain a lipid modification site at the C-terminus, with a typical sequence motif CaaX, where a = an aliphatic amino acid and X = any amino acid. Lipid binding is essential for membrane attachment, a key feature of most Ras proteins.бА0АкА0АаАCDDбАаА вА0А0АаАВcd04178, Nucleostemin_like, A circularly permuted subfamily of the Ras GTPases. Nucleostemin (NS) is a nucleolar protein that functions as a regulator of cell growth and proliferation in stem cells and in several types of cancer cells, but is not expressed in the differentiated cells of most mammalian adult tissues. NS shuttles between the nucleolus and nucleoplasm bidirectionally at a rate that is fast and independent of cell type. Lowering GTP levels decreases the nucleolar retention of NS, and expression of NS is abruptly down-regulated during differentiation prior to terminal cell division. Found only in eukaryotes, NS consists of an N-terminal basic domain, a coiled-coil domain, a GTP-binding domain, an intermediate domain, and a C-terminal acidic domain. Experimental evidence indicates that NS uses its GTP-binding property as a molecular switch to control the transition between the nucleolus and nucleoplasm, and this process involves interaction between the basic, GTP-binding, and intermediate domains of the protein.бА0АкА0АаАCDDбАаА'бвА0А0АаАВ∙cd04179, DPM_DPG-synthase_like, DPM_DPG-synthase_like is a member of the Glycosyltransferase 2 superfamily. DPM1 is the catalytic subunit of eukaryotic dolichol-phosphate mannose (DPM) synthase. DPM synthase is required for synthesis of the glycosylphosphatidylinositol (GPI) anchor, N-glycan precursor, protein O-mannose, and C-mannose. In higher eukaryotes,the enzyme has three subunits, DPM1, DPM2 and DPM3. DPM is synthesized from dolichol phosphate and GDP-Man on the cytosolic surface of the ER membrane by DPM synthase and then is flipped onto the luminal side and used as a donor substrate. In lower eukaryotes, such as Saccharomyces cerevisiae and Trypanosoma brucei, DPM synthase consists of a single component (Dpm1p and TbDpm1, respectively) that possesses one predicted transmembrane region near the C terminus for anchoring to the ER membrane. In contrast, the Dpm1 homologues of higher eukaryotes, namely fission yeast, fungi, and animals, have no transmembrane region, suggesting the existence of adapter molecules for membrane anchoring. This family also includes bacteria and archaea DPM1_like enzymes. However, the enzyme structure and mechanism of function are not well understood. The UDP-glucose:dolichyl-phosphate glucosyltransferase (DPG_synthase) is a transmembrane-bound enzyme of the endoplasmic reticulum involved in protein N-linked glycosylation. This enzyme catalyzes the transfer of glucose from UDP-glucose to dolichyl phosphate. This protein family belongs to Glycosyltransferase 2 superfamily.бА0АкА0АаАCDDбАаАЮвА0А0АаАВПcd04180, UGPase_euk_like, Eukaryotic UGPase-like includes UDPase and UDPGlcNAc pyrophosphorylase enzymes. This family includes UDP-Glucose Pyrophosphorylase (UDPase) and UDPGlcNAc pyrophosphorylase enzymes. The two enzymes share significant sequence and structure similarity. UDP-Glucose Pyrophosphorylase catalyzes a reversible production of UDP-Glucose and pyrophosphate (PPi) from Glucose-1-phosphate and UTP. UDP-glucose plays pivotal roles in galactose utilization, in glycogen synthesis, and in the synthesis of the carbohydrate moieties of glycolipids , glycoproteins , and proteoglycans . UDP-N-acetylglucosamine (UDPGlcNAc) pyrophosphorylase (UAP) (also named GlcNAc1P uridyltransferase), catalyzes the reversible conversion of UTP and GlcNAc1P from PPi and UDPGlcNAc, which is a key precursor of N- and O-linked glycosylations and is essential for the synthesis of chitin (a major component of the fungal cell wall) and of the glycosylphosphatidylinositol (GPI) linker anchoring a variety of cell surface proteins to the plasma membrane. In bacteria, UDPGlcNAc represents an essential precursor for both peptidoglycan and lipopolysaccharide biosynthesis.бА0АкА0АаАCDDбАаАЯвА0А0АаАВ┼cd04181, NTP_transferase, NTP_transferases catalyze the transfer of nucleotides onto phosphosugars. Nucleotidyltransferases transfer nucleotides onto phosphosugars. The enzyme family includes Alpha-D-Glucose-1-Phosphate Cytidylyltransferase, Mannose-1-phosphate guanyltransferase, and Glucose-1-phosphate thymidylyltransferase. The products are activated sugars that are precursors for synthesis of lipopolysaccharide, glycolipids and polysaccharides.бА0АкА0АаАCDDбАаАавА0А0АаАВOcd04182, GT_2_like_f, GT_2_like_f is a subfamily of the glycosyltransferase family 2 (GT-2) with unknown function. GT-2 includes diverse families of glycosyltransferases with a common GT-A type structural fold, which has two tightly associated beta/alpha/beta domains that tend to form a continuous central sheet of at least eight beta-strands. These are enzymes that catalyze the transfer of sugar moieties from activated donor molecules to specific acceptor molecules, forming glycosidic bonds. Glycosyltransferases have been classified into more than 90 distinct sequence based families.бА0АкА0АаАCDDбАаАбвА0А0АаАВcd04183, GT2_BcE_like, GT2_BcbE_like is likely involved in the biosynthesis of the polysaccharide capsule. GT2_BcbE_like: The bcbE gene is one of the genes in the capsule biosynthetic locus of Pasteurella multocida. Its deducted product is likely involved in the biosynthesis of the polysaccharide capsule, which is found on surface of a wide range of bacteria. It is a subfamily of Glycosyltransferase Family GT2, which includes diverse families of glycosyltransferases with a common GT-A type structural fold, which has two tightly associated beta/alpha/beta domains that tend to form a continuous central sheet of at least eight beta-strands. These are enzymes that catalyze the transfer of sugar moieties from activated donor molecules to specific acceptor molecules, forming glycosidic bonds.бА0АкА0АаАCDDбАаАввА0А0АаАВгcd04184, GT2_RfbC_Mx_like, Myxococcus xanthus RfbC like proteins are required for O-antigen biosynthesis. The rfbC gene encodes a predicted protein of 1,276 amino acids, which is required for O-antigen biosynthesis in Myxococcus xanthus. It is a subfamily of Glycosyltransferase Family GT2, which includes diverse families of glycosyl transferases with a common GT-A type structural fold, which has two tightly associated beta/alpha/beta domains that tend to form a continuous central sheet of at least eight beta-strands. These are enzymes that catalyze the transfer of sugar moieties from activated donor molecules to specific acceptor molecules, forming glycosidic bonds.бА0АкА0АаАCDDбАаАгвА0А0АаАВ3cd04185, GT_2_like_b, Subfamily of Glycosyltransferase Family GT2 of unknown function. GT-2 includes diverse families of glycosyltransferases with a common GT-A type structural fold, which has two tightly associated beta/alpha/beta domains that tend to form a continuous central sheet of at least eight beta-strands. These are enzymes that catalyze the transfer of sugar moieties from activated donor molecules to specific acceptor molecules, forming glycosidic bonds. Glycosyltransferases have been classified into more than 90 distinct sequence based families.бА0АкА0АаАCDDбАаАдвА0А0АаАВ3cd04186, GT_2_like_c, Subfamily of Glycosyltransferase Family GT2 of unknown function. GT-2 includes diverse families of glycosyltransferases with a common GT-A type structural fold, which has two tightly associated beta/alpha/beta domains that tend to form a continuous central sheet of at least eight beta-strands. These are enzymes that catalyze the transfer of sugar moieties from activated donor molecules to specific acceptor molecules, forming glycosidic bonds. Glycosyltransferases have been classified into more than 90 distinct sequence based families.бА0АкА0АаАCDDбАаАевА0А0АаАВ3cd04187, DPM1_like_bac, Bacterial DPM1_like enzymes are related to eukaryotic DPM1. A family of bacterial enzymes related to eukaryotic DPM1; Although the mechanism of eukaryotic enzyme is well studied, the mechanism of the bacterial enzymes is not well understood. The eukaryotic DPM1 is the catalytic subunit of eukaryotic Dolichol-phosphate mannose (DPM) synthase. DPM synthase is required for synthesis of the glycosylphosphatidylinositol (GPI) anchor, N-glycan precursor, protein O-mannose, and C-mannose. The enzyme has three subunits, DPM1, DPM2 and DPM3. DPM is synthesized from dolichol phosphate and GDP-Man on the cytosolic surface of the ER membrane by DPM synthase and then is flipped onto the luminal side and used as a donor substrate. This protein family belongs to Glycosyltransferase 2 superfamily.бА0АкА0АаАCDDбАаАжвА0А0АаАВTcd04188, DPG_synthase, DPG_synthase is involved in protein N-linked glycosylation. UDP-glucose:dolichyl-phosphate glucosyltransferase (DPG_synthase) is a transmembrane-bound enzyme of the endoplasmic reticulum involved in protein N-linked glycosylation. This enzyme catalyzes the transfer of glucose from UDP-glucose to dolichyl phosphate.бА0АкА0АаАCDDбАаАзвА0А0АаАВ#cd04189, G1P_TT_long, G1P_TT_long represents the long form of glucose-1-phosphate thymidylyltransferase. This family is the long form of Glucose-1-phosphate thymidylyltransferase. Glucose-1-phosphate thymidylyltransferase catalyses the formation of dTDP-glucose, from dTTP and glucose 1-phosphate. It is the first enzyme in the biosynthesis of dTDP-L-rhamnose, a cell wall constituent and a feedback inhibitor of the enzyme.There are two forms of Glucose-1-phosphate thymidylyltransferase in bacteria and archeae; short form and long form. The long form, which has an extra 50 amino acids c-terminal, is found in many species for which it serves as a sugar-activating enzyme for antibiotic biosynthesis and or other, unknown pathways, and in which dTDP-L-rhamnose is not necessarily produced.The long from enzymes also have a left-handed parallel helix domain at the c-terminus, whereas, th eshort form enzymes do not have this domain. The homotetrameric, feedback inhibited short form is found in numerous bacterial species that produce dTDP-L-rhamnose.бА0АкА0АаАCDDбАаАивА0А0АаАВыcd04190, Chitin_synth_C, C-terminal domain of Chitin Synthase catalyzes the incorporation of GlcNAc from substrate UDP-GlcNAc into chitin. Chitin synthase, also called UDP-N-acetyl-D-glucosamine:chitin 4-beta-N-acetylglucosaminyltransferase, catalyzes the incorporation of GlcNAc from substrate UDP-GlcNAc into chitin, which is a linear homopolymer of GlcNAc residues formed by covalent beta-1,4 linkages. Chitin is an important component of the cell wall of fungi and bacteria and it is synthesized on the cytoplasmic surface of the cell membrane by membrane bound chitin synthases. Studies with fungi have revealed that most of them contain more than one chitin synthase gene. At least five subclasses of chitin synthases have been identified.бА0АкА0АаАCDDбАаАйвА0А0АаАВ¤cd04191, Glucan_BSP_ModH, Glucan_BSP_ModH catalyzes the elongation of beta-1,2 polyglucose chains of glucan. Periplasmic Glucan Biosynthesis protein ModH is a glucosyltransferase that catalyzes the elongation of beta-1,2 polyglucose chains of glucan, requiring a beta-glucoside as a primer and UDP-glucose as a substrate. Glucans are composed of 5 to 10 units of glucose forming a highly branched structure, where beta-1,2-linked glucose constitutes a linear backbone to which branches are attached by beta-1,6 linkages. In Escherichia coli, glucans are located in the periplasmic space, functioning as regulator of osmolarity. It is synthesized at a maximum when cells are grown in a medium with low osmolarity. It has been shown to span the cytoplasmic membrane.бА0АкА0АаАCDDбАаАквА0А0АаАВ3cd04192, GT_2_like_e, Subfamily of Glycosyltransferase Family GT2 of unknown function. GT-2 includes diverse families of glycosyltransferases with a common GT-A type structural fold, which has two tightly associated beta/alpha/beta domains that tend to form a continuous central sheet of at least eight beta-strands. These are enzymes that catalyze the transfer of sugar moieties from activated donor molecules to specific acceptor molecules, forming glycosidic bonds. Glycosyltransferases have been classified into more than 90 distinct sequence based families.бА0АкА0АаАCDDбАаАлвА0А0АаАВ╫cd04193, UDPGlcNAc_PPase, UDPGlcNAc pyrophosphorylase catalayzes the synthesis of UDPGlcNAc. UDP-N-acetylglucosamine (UDPGlcNAc) pyrophosphorylase (UAP) (also named GlcNAc1P uridyltransferase), catalyzes the reversible conversion of UTP and GlcNAc1 to PPi and UDPGlcNAc. UDP-N-acetylglucosamine (UDPGlcNAc), the activated form of GlcNAc, is a key precursor of N- and O-linked glycosylations. It is essential for the synthesis of chitin (a major component of the fungal cell wall) and of the glycosylphosphatidylinositol (GPI) linker which anchors a variety of cell surface proteins to the plasma membrane. In bacteria, UDPGlcNAc represents an essential precursor for both peptidoglycan and lipopolysaccharide biosynthesis. Human UAP has two isoforms, resulting from alternative splicing of a single gene and differing by the presence or absence of 17 amino acids. UDPGlcNAc pyrophosphorylase shares significant sequence and structure conservation with UDPglucose pyrophosphorylase.бА0АкА0АаАCDDбАаАмвА0А0АаАВ6cd04194, GT8_A4GalT_like, A4GalT_like proteins catalyze the addition of galactose or glucose residues to the lipooligosaccharide (LOS) or lipopolysaccharide (LPS) of the bacterial cell surface. The members of this family of glycosyltransferases catalyze the addition of galactose or glucose residues to the lipooligosaccharide (LOS) or lipopolysaccharide (LPS) of the bacterial cell surface. The enzymes exhibit broad substrate specificities. The known functions found in this family include: Alpha-1,4-galactosyltransferase, LOS-alpha-1,3-D-galactosyltransferase, UDP-glucose:(galactosyl) LPS alpha1,2-glucosyltransferase, UDP-galactose: (glucosyl) LPS alpha1,2-galactosyltransferase, and UDP-glucose:(glucosyl) LPS alpha1,2-glucosyltransferase. Alpha-1,4-galactosyltransferase from N. meningitidis adds an alpha-galactose from UDP-Gal (the donor) to a terminal lactose (the acceptor) of the LOS structure of outer membrane. LOSs are virulence factors that enable the organism to evade the immune system of host cells. In E. coli, the three alpha-1,2-glycosyltransferases, that are involved in the synthesis of the outer core region of the LPS, are all members of this family. The three enzymes share 40 % of sequence identity, but have different sugar donor or acceptor specificities, representing the structural diversity of LPS.бА0АкА0АаАCDDбАаАнвА0А0АаАВЎcd04195, GT2_AmsE_like, GT2_AmsE_like is involved in exopolysaccharide amylovora biosynthesis. AmsE is a glycosyltransferase involved in exopolysaccharide amylovora biosynthesis in Erwinia amylovora. Amylovara is one of the three exopolysaccharide produced by E. amylovora. Amylovara-deficient mutants are non-pathogenic. It is a subfamily of Glycosyltransferase Family GT2, which includes diverse families of glycosyltransferases with a common GT-A type structural fold, which has two tightly associated beta/alpha/beta domains that tend to form a continuous central sheet of at least eight beta-strands. These are enzymes that catalyze the transfer of sugar moieties from activated donor molecules to specific acceptor molecules, forming glycosidic bonds.бА0АкА0АаАCDDбАаАовА0А0АаАВ3cd04196, GT_2_like_d, Subfamily of Glycosyltransferase Family GT2 of unknown function. GT-2 includes diverse families of glycosyltransferases with a common GT-A type structural fold, which has two tightly associated beta/alpha/beta domains that tend to form a continuous central sheet of at least eight beta-strands. These are enzymes that catalyze the transfer of sugar moieties from activated donor molecules to specific acceptor molecules, forming glycosidic bonds. Glycosyltransferases have been classified into more than 90 distinct sequence based families.бА0АкА0АаАCDDбАаАпвА0А0АаАВccd04197, eIF-2B_epsilon_N, The N-terminal domain of epsilon subunit of the eIF-2B is a subfamily of glycosyltransferase 2. N-terminal domain of epsilon subunit of the eukaryotic translation initiation factor 2B (eIF-2B): eIF-2B is a guanine nucleotide-exchange factor which mediates the exchange of GDP (bound to initiation factor eIF2) for GTP, generating active eIF2.GTP complex. EIF2B is a complex multimeric protein consisting of five subunits named alpha, beta, gamma, delta and epsilon. Subunit epsilon shares sequence similarity with gamma subunit, and with a family of bifunctional nucleotide-binding enzymes such as ADP-glucose pyrophosphorylase, suggesting that epsilon subunit may play roles in nucleotide binding activity. In yeast, eIF2B gamma enhances the activity of eIF2B-epsilon leading to the idea that these subunits form the catalytic subcomplex.бА0АкА0АаАCDDбАаА░вА0А0АаАВ]cd04198, eIF-2B_gamma_N, The N-terminal domain of gamma subunit of the eIF-2B is a subfamily of glycosyltransferase 2. N-terminal domain of gamma subunit of the eukaryotic translation initiation factor 2B (eIF-2B): eIF-2B is a guanine nucleotide-exchange factor which mediates the exchange of GDP (bound to initiation factor eIF2) for GTP, generating active eIF2.GTP complex. EIF2B is a complex multimeric protein consisting of five subunits named alpha, beta, gamma, delta and epsilon. Subunit gamma shares sequence similarity with epsilon subunit, and with a family of bifunctional nucleotide-binding enzymes such as ADP-glucose pyrophosphorylase, suggesting that epsilon subunit may play roles in nucleotide binding activity. In yeast, eIF2B gamma enhances the activity of eIF2B-epsilon leading to the idea that these subunits form the catalytic subcomplex.бА0АкА0АаАCDDбАаА▒вА0А0АаАВФcd04199, CuRO_1_ceruloplasmin_like, Cupredoxin domains 1, 3, and 5 of ceruloplasmin and similar proteins. This family includes the first, third, and fifth cupredoxin domains of ceruloplasmin and similar proteins including the first, third and fifth cupredoxin domains of unprocessed coagulation factors V and VIII. Ceruloplasmin (ferroxidase) is a multicopper oxidase essential for normal iron homeostasis. It functions in copper transport, amine oxidation and as an antioxidant preventing free radicals in serum. The protein has 6 cupredoxin domains and exhibits internal sequence homology that appears to have evolved from the triplication of a sequence unit composed of two tandem cupredoxin domains. Human Factor VIII facilitates blood clotting by acting as a cofactor for factor IXa. Factor VIII and IXa forms a complex in the presence of Ca+2 and phospholipids that converts factor X to the activated form Xa.бА0АкА0АаАCDDбАаАўвА0А0АаАВйcd04200, CuRO_2_ceruloplasmin_like, Cupredoxin domains 2, 4, and 6 of ceruloplasmin and similar proteins. This family includes the second, fourth and sixth cupredoxin domains of ceruloplasmin and similar proteins, including the second, fourth, and sixth cupredoxin domains of unprocessed coagulation factors V and VIII. Ceruloplasmin (ferroxidase) is a multicopper oxidase essential for normal iron homeostasis. Ceruloplasmin also functions in copper transport, amine oxidase and as an antioxidant preventing free radicals in serum. The protein has 6 cupredoxin domains and exhibits internal sequence homology that appears to have evolved from the triplication of a sequence unit composed of two tandem cupredoxin domains. Human Factor VIII facilitates blood clotting by acting as a cofactor for factor IXa Factor VIII and IXa forms a complex in the presence of Ca+2 and phospholipids that converts factor X to the activated form Xa.бА0АкА0АаАCDDбАаАўвА0А0АаАВccd04201, CuRO_1_CuNIR_like, Cupredoxin domain 1 of Copper-containing nitrite reductase and two-domain laccase. Copper-containing nitrite reductase (CuNIR), which catalyzes the reduction of NO2- to NO, is the key enzyme in the denitrification process in denitrifying bacteria. CuNIR contains at least one type 1 copper center and a type 2 copper center, which serves as the active site of the enzyme. A histidine, bound to the Type 2 Cu center, is responsible for binding and reducing nitrite. A Cys-His bridge plays an important role in facilitating rapid electron transfer from the type 1 center to the type 2 center. A reduced type I blue copper protein (pseudoazurin) was found to be a specific electron transfer donor for the copper-containing NIR in bacteria Alcaligenes faecalis. The two-domain laccase (small laccase) in this family differs significantly from all laccases. It resembles two domain nitrite reductase in both sequence homology and structure similarity. It consists of two domains and forms trimers and hence resembles the quaternary structure of nitrite reductases more than that of larger laccases.бА0АкА0АаАCDDбАаАўвА0А0АаАВcd04202, CuRO_D2_2dMcoN_like, The second cupredoxin domain of bacterial two domain multicopper oxidase McoN and similar proteins. This family includes bacterial two domain multicopper oxidases (2dMCOs) represented by the McoN from Nitrosomonas europaea. McoN is a trimeric type C blue copper oxidase. Each subunit houses a type 1 copper site in domain 1 and a type 2/type 3 trinuclear copper cluster at the subunit-subunit interface. The 2dMCO is proposed to be a key intermediate in the evolution of three domain MCOs. The biological function of McoN has not been characterized. Multicopper oxidases couple oxidation of substrates with reduction of dioxygen to water. These MCOs are capable of oxidizing a vast range of substrates, varying from aromatic to inorganic compounds such as metals.бА0АкА0АаАCDDбАаАўвА0А0АаАВ+cd04203, Cupredoxin_like_3, Uncharacterized subfamiy of Cupredoxin. Cupredoxins contain type I copper centers and are involved in inter-molecular electron transfer reactions. Cupredoxins are blue copper proteins, having an intense blue color due to the presence of a mononuclear type 1 (T1) copper site. Structurally, the cupredoxin-like fold consists of a beta-sandwich with 7 strands in 2 beta-sheets, which is arranged in a Greek-key beta-barrel. Some of these proteins have lost the ability to bind copper. Majority of family members contain multiple cupredoxin domain repeats: ceruloplamin and coagulation factors V/VIII have six repeats; laccase, ascorbate oxidase, and spore coat protein A, and multicopper oxidase CueO contain three repeats; and nitrite reductase has two repeats. Others are mono-domain cupredoxins, such as plastocyanin, pseudoazurin, plantacyanin, azurin, rusticyanin, stellacyanin, quinol oxidase and the periplasmic domain of cytochrome c oxidase subunit II. Proteins of this uncharacterized subfamily contain a single cupredoxin domain.бА0АкА0АаАCDDбАаАўвА0А0АаАВ cd04204, Pseudoazurin_like, Small blue copper proteins including pseudocyanin, plastocyanin, halocyanin and amicyanin. The Pseudocyanin-like family of copper-binding proteins (or blue (type 1) copper domain) is a family of small proteins that bind a single copper atom and are characterized by an intense electronic absorption band near 600 nm. Pseudoazurin (PAz) has been identified as a electron donor in the denitrification pathway. For example, PAz acts as an electron donor to cytochrome c peroxidase and N2OR from Paracoccus pantotrophus (Pp), and to the copper containing nitrite reductase (NiR) that catalyzes the second step of denitrification. Plastocyanin is found in cyanobacteria, higher plants, and some algae where it plays a role in photosynthesis. Plastocyanin is responsible for transporting electrons from PSII to PSI. This family also includes halocyanins found in halophilic archaea such as Natronomonas pharaonis (Natronobacterium pharaonis) and amicyanin found in bacteria Paracoccus denitrificans.бА0АкА0АаАCDDбАаАўвА0А0АаАВМcd04205, CuRO_2_LCC_like, Cupredoxin domain 2 of laccase-like multicopper oxidases; including laccase, CueO, spore coat protein A, ascorbate oxidase and similar proteins. Laccase-like multicopper oxidases (MCOs) are able to couple oxidation of substrates with reduction of dioxygen to water. MCOs are capable of oxidizing a vast range of substrates, varying from aromatic compounds to inorganic compounds such as metals. Although the members of this family have diverse functions, majority of them have three cupredoxin domain repeats. The copper ions are bound in several sites: Type 1, Type 2, and/or Type 3. The ensemble of types 2 and 3 copper is called a trinuclear cluster. MCOs oxidize their substrate by accepting electrons at a mononuclear copper center and transferring them to the active site trinuclear copper center. The cupredoxin domain 2 of 3-domain MCOs has lost the ability to bind copper.бА0АкА0АаАCDDбАаАўвА0А0АаАВscd04206, CuRO_1_LCC_like, Cupredoxin domain 1 of laccase-like multicopper oxidases; including laccase, CueO, spore coat protein A, ascorbate oxidase and similar proteins. Laccase-like multicopper oxidases (MCOs) in this family contain three cupredoxin domains. They are able to couple oxidation of substrates with reduction of dioxygen to water. MCOs are capable of oxidizing a vast range of substrates, varying from aromatic to inorganic compounds such as metals. Although the members of this family have diverse functions, majority of them have three cupredoxin domain repeats. The copper ions are bound in several sites; Type 1, Type 2, and/or Type 3. The ensemble of types 2 and 3 copper is called a trinuclear cluster. MCOs oxidize their substrate by accepting electrons at a mononuclear copper center and transferring them to the active site trinuclear copper center. The cupredoxin domain 1 of 3-domain MCOs contains part the trinuclear copper binding site, which is located at the interface of domains 1 and 3. Also included in this family are cupredoxin domains 1, 3, and 5 of the 6-domain MCO ceruloplasmin and similar proteins.бА0АкА0АаАCDDбАаАўвА0А0АаАВЫcd04207, CuRO_3_LCC_like, Cupredoxin domain 3 of laccase-like multicopper oxidases; including laccase, CueO, spore coat protein A, ascorbate oxidase and similar proteins. Laccase-like multicopper oxidases (MCOs) in this family contain three cupredoxin domains. They are able to couple oxidation of substrates with reduction of dioxygen to water. MCOs are capable of oxidizing a vast range of substrates, varying from aromatic to inorganic compounds such as metals. Although the members of this family have diverse functions, majority of them have three cupredoxin domain repeats. The copper ions are bound in several sites; Type 1, Type 2, and/or Type 3. The ensemble of types 2 and 3 copper is called a trinuclear cluster. MCOs oxidize their substrate by accepting electrons at a mononuclear copper center and transferring them to the active site trinuclear copper center. The cupredoxin domain 3 of 3-domain MCOs contains the Type 1 (T1) copper binding site and part the trinuclear copper binding site, which is located at the interface of domains 1 and 3. Also included in this family are cupredoxin domains 2, 4, and 6 of the 6-domain MCO ceruloplasmin and similar proteins.бА0АкА0АаАCDDбАаАўвА0А0АаАВ0cd04208, CuRO_2_CuNIR, Cupredoxin domain 2 of Copper-containing nitrite reductase. Copper-containing nitrite reductase (CuNIR), which catalyzes the reduction of NO2- to NO, is the key enzyme in the denitrification process in denitrifying bacteria. CuNIR contains at least one type 1 copper center and a type 2 copper center in the protein. The type 2 copper center of a copper nitrite reductase is the active site of the enzyme. A histidine, bound to the Type 2 Cu center, is responsible for binding and reducing nitrite. A Cys-His bridge plays an important role in facilitating rapid electron transfer from the type 1 center to the type 2 center. A reduced type I blue copper protein (pseudoazurin) was found to be a specific electron transfer donor for the copper-containing NIR in bacteria Alcaligenes faecalis.бА0АкА0АаАCDDбАаАўвА0А0АаАВъcd04210, Cupredoxin_like_1, Uncharacterized Cupredoxin-like subfamily. Cupredoxins contain type I copper centers and are involved in inter-molecular electron transfer reactions. Cupredoxins are blue copper proteins because they have an intense blue color due to the presence of a mononuclear type 1 (T1) copper site. Structurally, the cupredoxin-like fold consists of a beta-sandwich with 7 strands in 2 beta-sheets, which is arranged in a Greek-key beta-barrel. Some of these proteins have lost the ability to bind copper. Majority of family members contain multiple cupredoxin domain repeats; ceruloplasmin and coagulation factors V/VIII have six repeats; Laccase, ascorbate oxidase, and spore coat protein A, and multicopper oxidase CueO contain three repeats; and nitrite reductase has two repeats. Others are mono-domain cupredoxins, such as plastocyanin, pseudoazurin, plantacyanin, azurin, rusticyanin, stellacyanin, quinol oxidase and the periplasmic domain of cytochrome c oxidase subunit II.бА0АкА0АаАCDDбАаАў вА0А0АаАВъcd04211, Cupredoxin_like_2, Uncharacterized Cupredoxin-like subfamily. Cupredoxins contain type I copper centers and are involved in inter-molecular electron transfer reactions. Cupredoxins are blue copper proteins because they have an intense blue color due to the presence of a mononuclear type 1 (T1) copper site. Structurally, the cupredoxin-like fold consists of a beta-sandwich with 7 strands in 2 beta-sheets, which is arranged in a Greek-key beta-barrel. Some of these proteins have lost the ability to bind copper. Majority of family members contain multiple cupredoxin domain repeats; ceruloplasmin and coagulation factors V/VIII have six repeats; Laccase, ascorbate oxidase, and spore coat protein A, and multicopper oxidase CueO contain three repeats; and nitrite reductase has two repeats. Others are mono-domain cupredoxins, such as plastocyanin, pseudoazurin, plantacyanin, azurin, rusticyanin, stellacyanin, quinol oxidase and the periplasmic domain of cytochrome c oxidase subunit II.бА0АкА0АаАCDDбАаАў!вА0А0АаАВcd04212, CuRO_UO_II, The cupredoxin domain of Ubiquinol oxidase subunit II. Ubiquinol oxidase, the terminal oxidase in the respiratory chains of aerobic bacteria, is a multi-chain transmembrane protein located in the cell membrane. It catalyzes the reduction of O2 and simultaneously pumps protons across the membrane. The number of subunits in ubiquinol oxidase varies from two to five. Although subunit II of ubiquinol oxidase lacks the binuclear CuA site found in cytochrome c oxidases, the structure is conserved.бА0АкА0АаАCDDбАаАў"вА0А0АаАВMcd04213, CuRO_CcO_Caa3_II, The cupredoxin domain of Caa3 type Cytochrome c oxidase subunit II. Cytochrome c oxidase (CcO), the terminal oxidase in the respiratory chains of most bacteria, is a multi-chain transmembrane protein located in the inner membrane the cell membrane of prokaryotes. It catalyzes the reduction of O2 and simultaneously pumps protons across the membrane. Caa3 type of CcO Subunit II contains a copper-copper binuclear site called CuA, which is believed to be involved in electron transfer from cytochrome c to the cytochromes a, a3 and CuB active site in subunit I.бА0АкА0АаАCDDбАаАў#вА0А0АаАВёcd04214, PAD_N, N-terminal non-catalytic domain of protein-arginine deiminase. The N-terminal non-catalytic domain of protein-arginine deiminase has a cupredoxin-like fold, but lacks the Cu binding site. PAD (protein-arginine deiminase) and protein L-arginine iminohydrolase catalyze the conversion of protein arginine residues to citrulline residues post-translationally in a process called citrullination. The modification plays crucial regulatory roles in development and cell differentiation.бА0АкА0АаАCDDбАаАў$вА0А0АаАВcd04215, Nitrosocyanin, Nitrosocyanin (NC) is a mononuclear red copper protein. Nitrosocyanin (NC) is isolated from the ammonia oxidizing bacterium Nitrosomonas europaea. Nitrosocyanin exhibits remote sequence homology to classic blue copper proteins; its spectroscopic and electrochemical properties are different. The structure of NC is a trimer of single domain cupredoxins. Nitroscocyanin may mediate electron transfer. It could have a novel role as a nitric oxide dehydrogenase or a nitric oxide reductase in the oxidation of ammonia.бА0АкА0АаАCDDбАаАў%вА0А0АаАВLcd04216, Phytocyanin, Phytocyanins are plant blue or type I copper proteins. Phytocyanins are plant blue or type I copper proteins. They are involved in electron transfer reactions with the Cu center transitioning between the oxidized Cu(II) form and the reduced Cu(I) form. Phytocyanins are classified into four groups: stellacyanin, plantacyanin, uclacyanin and early nodulin groups. Stellacyanin appears to be associated with the plant cell wall; it may be involved in oxidative reactions to build polymeric material making up the cell wall. Plantacyanin is shown to play a role in reproduction in Arabidopsis. Plantacyanins may also be stress-related proteins and may be involved in plant defense responses. The early nodulin-like protein (OsENODL1) from Oryza sativa is expressed specifically at the late developmental stage of the seeds.бА0АкА0АаАCDDбАаАў&вА0А0АаАВTcd04217, Cupredoxin_Fibrocystin-L_like, Cupredoxin domain of PKHDL1, a homolog of the autosomal recessive polycystic kidney disease protein. One member of this family is Fibrocystin-L, a homolog of the autosomal recessive polycystic kidney disease protein PKHD1. Human fibrocystin-L is predicted to be a large receptor protein (466 kDa) with a signal peptide, a single transmembrane domain and a short cytoplasmic tail. Fibrocystin-L is widely expressed at a low level in most tissues but is up-regulated specifically in T lymphocytes following activation signals. It may play roles in immunity.бА0АкА0АаАCDDбАаАў'вА0А0АаАВcd04218, Pseudoazurin, Pseudoazurin (Paz) is a type I blue copper electron-transfer protein. Pseudoazurin (PAz) has been identified as an electron donor to the denitrification pathway. For example, PAz acts as an electron donor to cytochrome c peroxidase and N2OR from Paracoccus pantotrophus (Pp), and to the copper containing nitrite reductase (NiR) that catalyzes the second step of denitrification. It has been shown that pseudoazurin dramatically enhances the reaction profile of nitrite reduction by Paracoccus pantotrophus cytochrome cd1 and facilitates release of the product nitric oxide. The ability of this small redox protein to interact with a multitude of structurally different partners has been attributed to the hydrophobic character of the binding surface.бА0АкА0АаАCDDбАаАў(вА0А0АаАВcd04219, Plastocyanin, Plastocyanin is a type I copper protein and functions in the electron transfer from PSII to PSI. Plastocyanin is a small copper-containing protein found in cyanobacteria, higher plants, and some algae, where it plays a role in photosynthesis. The two photosystems that are primarily responsible for photosynthesis are photosystem I (PSI) and photosystem II (PSII). The flow of electrons begins in PSII, which acts as a proton pump. Plastocyanin is responsible for transporting electrons from PSII to PSI.бА0АкА0АаАCDDбАаАў)вА0А0АаАВУcd04220, Halocyanin, Halocyanin is an archaea blue (type I) copper redox protein. Halocyanins are blue (type I) copper redox proteins found in halophilic archaea such as Natronomonas pharaonis (Natronobacterium pharaonis). Halocyanin may serve as a mobile electron carrier at a peripheral membrane protein. The copper-binding domain is present only once in some halocyanins and is duplicated in others.бА0АкА0АаАCDDбАаАў*вА0А0АаАВчcd04221, MauL, Methylamine utilization protein MauL. MauL is one of the products from the methylamine utilization gene cluster in Methylobacterium extorquens AM1. Mutants generated by insertions in mauL were not able to grow on methylamine or any other primary amine as carbon sources. MauL belongs to the blue or type I copper protein family. They are involved in electron transfer reactions with the Cu center transitioning between the oxidized Cu(II) form and the reduced Cu(I) form.бА0АкА0АаАCDDбАаАў+вА0А0АаАВ╗cd04222, CuRO_1_ceruloplasmin, The first cupredoxin domain of Ceruloplasmin. Ceruloplasmin is a multicopper oxidase essential for normal iron homeostasis and copper transport in blood. It also functions in amine oxidation and as an antioxidant preventing free radicals in serum. The protein has 6 cupredoxin domains with six copper centers; three mononuclear sites in domain 2, 4 and 6 and three in the form of trinuclear clusters at the interface of domains 1 and 6. Ceruloplasmin exhibits internal sequence homology that appears to have evolved from the triplication of a sequence unit composed of two tandem cupredoxin domains. This model represents the first cupredoxin domain of ceruloplasmin.бА0АкА0АаАCDDбАаАў,вА0А0АаАВ╨cd04223, N2OR_C, The C-terminal cupredoxin domain of Nitrous-oxide reductase. Nitrous-oxide reductase participates in nitrogen metabolism and catalyzes the last step in dissimilatory nitrate reduction, the two-electron reduction of N2O to N2. It contains copper ions as cofactors in the form of a binuclear CuA center at the site of electron entry and a tetranuclear CuZ centre at the active site. The C-terminus of Nitrous-oxide reductase is a cupredoxin domain.бА0АкА0АаАCDDбАаАў-вА0А0АаАВ╗cd04224, CuRO_3_ceruloplasmin, The third cupredoxin domain of Ceruloplasmin. Ceruloplasmin is a multicopper oxidase essential for normal iron homeostasis and copper transport in blood. It also functions in amine oxidation and as an antioxidant preventing free radicals in serum. The protein has 6 cupredoxin domains with six copper centers; three mononuclear sites in domain 2, 4 and 6 and three in the form of trinuclear clusters at the interface of domains 1 and 6. Ceruloplasmin exhibits internal sequence homology that appears to have evolved from the triplication of a sequence unit composed of two tandem cupredoxin domains. This model represents the third cupredoxin domain of ceruloplasmin.бА0АкА0АаАCDDбАаАў.вА0А0АаАВ╗cd04225, CuRO_5_ceruloplasmin, The fifth cupredoxin domain of Ceruloplasmin. Ceruloplasmin is a multicopper oxidase essential for normal iron homeostasis and copper transport in blood. It also functions in amine oxidation and as an antioxidant preventing free radicals in serum. The protein has 6 cupredoxin domains with six copper centers; three mononuclear sites in domain 2, 4 and 6 and three in the form of trinuclear clusters at the interface of domains 1 and 6. Ceruloplasmin exhibits internal sequence homology that appears to have evolved from the triplication of a sequence unit composed of two tandem cupredoxin domains. This model represents the fifth cupredoxin domain of ceruloplasmin.бА0АкА0АаАCDDбАаАў/вА0А0АаАВ╔cd04226, CuRO_1_FV_like, The first cupredoxin domain of coagulation factor VIII and similar proteins. Factor V is an essential coagulation protein with both pro- and anti-coagulant functions. Aberrant expression of human factor V can lead to bleeding or thromboembolic disease, which may be life-threatening. Bovine factor Va serves as the cofactor in the prothrombinase complex that results in a 300,000-fold increase in the rate of thrombin generation. Factor V is synthesized as a single polypeptide with six cupredoxin domains and a domain structure of 1-2-3-4-B-5-6-C1-C2, where 1-6 are cupredoxin domains, B is a domain with no known structural homologs and is dispensible for coagulant activity, and C are domains distantly related to discoidin protein-fold family members. Factor V has little activity prior to proteolytic cleavage by thrombin or FXa upon secretion. The resulting Factor Va is a heterodimer consisting of a heavy chain (1-2-3-4) and a light chain (5-6-C1-C2). This model represents the cupredoxin domain 1 of unprocessed Factor V or the heavy chain of Factor Va, and similar proteins including pseutarin C non-catalytic subunit. Pseutarin C is a prothrombin activator from Pseudonaja textilis venom.бА0АкА0АаАCDDбАаАў0вА0А0АаАВ]cd04227, CuRO_3_FVIII_like, The third cupredoxin domain of coagulation factor VIII and similar proteins. Factor VIII functions in the factor X-activating complex of the intrinsic coagulation pathway. It facilitates blood clotting by acting as a cofactor for factor IXa. In the presence of Ca2+ and phospholipids, Factor VIII and IXa form a complex that converts factor X to the activated form Xa. A variety of mutations in the Factor VIII gene can cause hemophilia A, which typically requires replacement therapy with purified protein. Factor VIII is synthesized as a single polypeptide with six cupredoxin domains and a domain structure of 1-2-3-4-B-5-6-C1-C2, where 1-6 are cupredoxin domains, B is a domain with no known structural homologs and is dispensible for coagulant activity, and C are domains distantly related to discoidin protein-fold family members. Factor VIII is initially processed through proteolysis to generate a heterodimer consisting of a heavy chain (1-2-3-4) and a light chain (5-6-C1-C2), which circulates in a tight complex with von Willebrand factor (VWF). Further processing of the heavy chain produces activated factor VIIIa, a heterotrimer composed of polypeptides (1-2), (3-4), and the light chain. This model represents the cupredoxin domain 3 of unprocessed Factor VIII or the heavy chain of circulating Factor VIII, and similar proteins.бА0АкА0АаАCDDбАаАў1вА0А0АаАВ|cd04228, CuRO_5_FVIII_like, The fifth cupredoxin domain of coagulation factor VIII and similar proteins. Factor VIII functions in the factor X-activating complex of the intrinsic coagulation pathway. It facilitates blood clotting by acting as a cofactor for factor IXa. In the presence of Ca2+ and phospholipids, Factor VIII and IXa form a complex that converts factor X to the activated form Xa. A variety of mutations in the Factor VIII gene can cause hemophilia A, which typically requires replacement therapy with purified protein. Factor VIII is synthesized as a single polypeptide with six cupredoxin domains and a domain structure of 1-2-3-4-B-5-6-C1-C2, where 1-6 are cupredoxin domains, B is a domain with no known structural homologs and is dispensible for coagulant activity, and C are domains distantly related to discoidin protein-fold family members. Factor VIII is initially processed through proteolysis to generate a heterodimer consisting of a heavy chain (1-2-3-4) and a light chain (5-6-C1-C2), which circulates in a tight complex with von Willebrand factor (VWF). Further processing of the heavy chain produces activated factor VIIIa, a heterotrimer composed of polypeptides (1-2), (3-4), and the light chain. This model represents the cupredoxin domain 5 of unprocessed Factor VIII or the first cupredoxin domain of the light chain of circulating Factor VIII, and similar proteins.бА0АкА0АаАCDDбАаАў2вА0А0АаАВicd04229, CuRO_1_Ceruloplasmin_like_1, cupredoxin domain of ceruloplasmin homologs. Uncharacterized subfamily of ceruloplasmin homologous proteins. Ceruloplasmin (ferroxidase) is a multicopper oxidase essential for normal iron homeostasis. Ceruloplasmin also functions in copper transport, amine oxidase and as an antioxidant preventing free radicals in serum. The protein has 6 cupredoxin domains and exhibits internal sequence homology that appears to have evolved from the triplication of a sequence unit composed of two tandem cupredoxin domains. This model represents the first domain of the triplicated units.бА0АкА0АаАCDDбАаАў3вА0А0АаАВ$cd04230, Sulfocyanin, Sulfocyanin is a blue copper protein in archaebacterium Sulfolobus acidocaldarius. Sulfocyanin is a blue copper protein with a putative membrane anchoring hydrophobic motif at the N-terminus. It may substitute for cytochrome C in electron transfer reactions in archaea.бА0АкА0АаАCDDбАаАў4вА0А0АаАВГcd04231, Rusticyanin, Rusticyanin is a cupredoxin in archaea and proteobacteria. Rusticyanin is a copper-containing protein which is involved in electron-transfer. The members of this family are found in archaea and proteobacteria. It is a cupredoxin, or blue-copper protein due to its color. Rusticyanin, extracted from the bacteria Thiobacillus ferrooxidans is redox active down to PH 2.0 and the acid-stable cytochrome c is the primary acceptor of the electron. This organism can grow on Fe2+ as its sole energy source. Rusticyanin is thought to be a principal component in the iron respiratory electron transport chain of T. ferrooxidans.бА0АкА0АаАCDDбАаАў5вА0А0АаАВыcd04232, CuRO_1_CueO_FtsP, The first Cupredoxin domain of the multicopper oxidase CueO, the cell division protein FtsP, and similar proteins. CueO is a multicopper oxidase (MCO) that is part of the copper-regulatory cue operon, which employs a cytosolic metalloregulatory protein CueR that induces expression of CopA and CueO under copper stress conditions. CueO is a periplasmic multicopper oxidase that is stimulated by exogenous copper(II). FtsP (also named SufI) is a component of the cell division apparatus. It is involved in protecting or stabilizing the assembly of divisomes under stress conditions. FtsP belongs to the multicopper oxidase superfamily but lacks metal cofactors. The protein is localized at septal rings and may serve as a scaffolding function. Members of this subfamily contain three cupredoxin domains and this model represents the first domain. Although MCOs have diverse functions, majority of them have three cupredoxin domain repeats that include one mononuclear and one trinuclear copper center. The copper ions are bound in several sites: Type 1, Type 2, and/or Type 3. The ensemble of types 2 and 3 copper is called a trinuclear cluster. MCOs oxidize their substrate by accepting electrons at a mononuclear copper center and transferring them to the active site trinuclear copper center. The cupredoxin domain 1 of 3-domain MCOs contains part the trinuclear copper binding site, which is located at the interface of domains 1 and 3. FtsP does not contain any copper binding sites.бА0АкА0АаАCDDбАаАў6вА0А0АаАВjcd04233, Auracyanin, Auracyanins A and B and similar proteins. This subfamily includes both auracyanins A and B from the photosynthetic bacterium Chloroflexus aurantiacus and similar proteins. Auracyanins A and B are very similar blue copper proteins with 38% sequence identity and are homologous to the bacterial redox protein Azurin. However, auracyanin A is expressed only when C. aurantiacus cells are grown in light, whereas auracyanin B is expressed in both dark and light conditions. Thus, auracyanin A may function as a redox partner in photosynthesis, while auracyanin B may function in aerobic respiration.бА0АкА0АаАCDDбАаАў7вА0А0АаАВ Jcd04234, AAK_AK, AAK_AK: Amino Acid Kinase Superfamily (AAK), Aspartokinase (AK); this CD includes the N-terminal catalytic domain of aspartokinase (4-L-aspartate-4-phosphotransferase;). AK is the first enzyme in the biosynthetic pathway of the aspartate family of amino acids (lysine, threonine, methionine, and isoleucine) and the bacterial cell wall component, meso-diaminopimelate. It also catalyzes the conversion of aspartate and ATP to aspartylphosphate and ADP. One mechanism for the regulation of this pathway is by the production of several isoenzymes of aspartokinase with different repressors and allosteric inhibitors. Pairs of ACT domains are proposed to specifically bind amino acids leading to allosteric regulation of the enzyme. In Escherichia coli, three different aspartokinase isoenzymes are regulated specifically by lysine, methionine, and threonine. AK-HSDHI (ThrA) and AK-HSDHII (MetL) are bifunctional enzymes that consist of an N-terminal AK and a C-terminal homoserine dehydrogenase (HSDH). ThrA and MetL are involved in threonine and methionine biosynthesis, respectively. The third isoenzyme, AKIII (LysC), is monofunctional and is involved in lysine synthesis. The three Bacillus subtilis isoenzymes, AKI (DapG), AKII (LysC), and AKIII (YclM), are feedback-inhibited by meso-diaminopimelate, lysine, and lysine plus threonine, respectively. The E. coli lysine-sensitive AK is described as a homodimer, whereas, the B. subtilis lysine-sensitive AK is described as a heterodimeric complex of alpha- and beta- subunits that are formed from two in-frame overlapping genes. A single AK enzyme type has been described in Pseudomonas, Amycolatopsis, and Corynebacterium. The fungal aspartate pathway is regulated at the AK step, with L-Thr being an allosteric inhibitor of the Saccharomyces cerevisiae AK (Hom3). At least two distinct AK isoenzymes can occur in higher plants, one is a monofunctional lysine-sensitive isoenzyme, which is involved in the overall regulation of the pathway and can be synergistically inhibited by S-adenosylmethionine. The other isoenzyme is a bifunctional, threonine-sensitive AK-HSDH protein. Also included in this CD is the catalytic domain of the Methylomicrobium alcaliphilum ectoine AK, the first enzyme of the ectoine biosynthetic pathway, found in this bacterium, and several other halophilic/halotolerant bacteria.бА0АкА0АаАCDDбАаАиЧвА0А0АаАВ╒cd04235, AAK_CK, AAK_CK: Carbamate kinase (CK) catalyzes both the ATP-phosphorylation of carbamate and carbamoyl phosphate (CP) utilization with the production of ATP from ADP and CP. Both CK (this CD) and nonhomologous CP synthetase synthesize carbamoyl phosphate, an essential precursor of arginine and pyrimidine bases, in the presence of ATP, bicarbonate, and ammonia. CK is a homodimer of 33 kDa subunits and is a member of the Amino Acid Kinase Superfamily (AAK).бА0АкА0АаАCDDбАаАиШвА0А0АаАВ╨cd04236, AAK_NAGS-Urea, AAK_NAGS-Urea: N-acetylglutamate (NAG) kinase-like domain of the NAG Synthase (NAGS) of the urea cycle found in animals. Ureogenic NAGS is a mitochondrial enzyme catalyzing the formation of NAG from acetylcoenzyme A and L-glutamate; NAG is an essential allosteric activator of carbamylphosphate synthase I, the first and rate limiting enzyme of the urea cycle. Ureogenic NAGS activity is dependent on the concentration of glutamate (substrate) and arginine (activator). Domain architecture of ureogenic NAGS consists of an N-terminal NAG kinase-like (ArgB) domain (this CD) and a C-terminal DUF619 domain. Members of this CD belong to the protein superfamily, the Amino Acid Kinase Family (AAKF).бА0АкА0АаАCDDбАаАиЩвА0А0АаАВ,cd04237, AAK_NAGS-ABP, AAK_NAGS-ABP: N-acetylglutamate (NAG) kinase-like domain of the NAG Synthase (NAGS) of the arginine-biosynthesis pathway (ABP) found in gamma- and beta-proteobacteria and higher plant chloroplasts. Domain architecture of these NAGS consisted of an N-terminal NAG kinase-like (ArgB) domain (this CD) and a C-terminal NAG synthase, acetyltransferase (ArgA) domain. Both bacterial and plant sequences in this CD have a conserved N-terminal extension; a similar sequence in the NAG kinases of the cyclic arginine-biosynthesis pathway has been implicated in feedback inhibition sensing. Plant sequences also have an N-terminal chloroplast transit peptide and an insert (approx. 70 residues) in the C-terminal region of ArgB. Members of this CD belong to the Amino Acid Kinase Superfamily (AAK).бА0АкА0АаАCDDбАаАиЪвА0А0АаАВZcd04238, AAK_NAGK-like, AAK_NAGK-like: N-Acetyl-L-glutamate kinase (NAGK)-like . Included in this CD are the Escherichia coli and Pseudomonas aeruginosa type NAGKs which catalyze the phosphorylation of N-acetyl-L-glutamate (NAG) by ATP in the second step of arginine biosynthesis found in bacteria and photosynthetic organisms using either the acetylated, noncyclic (NC), or non-acetylated, cyclic (C) route of ornithine biosynthesis. Also included in this CD is a distinct group of uncharacterized (UC) bacterial and archeal NAGKs. Members of this CD belong to the Amino Acid Kinase Superfamily (AAK).бА0АкА0АаАCDDбАаАиЫвА0А0АаАВcd04239, AAK_UMPK-like, AAK_UMPK-like: UMP kinase (UMPK)-like, the microbial/chloroplast uridine monophosphate kinase (uridylate kinase) enzyme that catalyzes UMP phosphorylation and plays a key role in pyrimidine nucleotide biosynthesis. Regulation of this process is via feed-back control and via gene repression of carbamoyl phosphate synthetase (the first enzyme of the pyrimidine biosynthesis pathway). The UMP kinases of E. coli (Ec) and Pyrococcus furiosus (Pf) are known to function as homohexamers, with GTP and UTP being allosteric effectors. Like other related enzymes (carbamate kinase, aspartokinase, and N-acetylglutamate kinase) the E. coli and most bacterial UMPKs have a conserved, N-terminal, lysine residue proposed to function in the catalysis of the phosphoryl group transfer, whereas most archaeal UMPKs appear to lack this residue and the Pyrococcus furiosus structure has an additional Mg ion bound to the ATP molecule which is proposed to function as the catalysis instead. Also included in this CD are the alpha and beta subunits of the Mo storage protein (MosA and MosB) characterized as an alpha4-beta4 octamer containing an ATP-dependent, polynuclear molybdenum-oxide cluster. These and related sequences in this CD are members of the Amino Acid Kinase Superfamily (AAK).бА0АкА0АаАCDDбАаАиЬвА0А0АаАБ╞cd04240, AAK_UC, AAK_UC: Uncharacterized (UC) amino acid kinase-like proteins found mainly in archaea and a few bacteria. Sequences in this CD are members of the Amino Acid Kinase (AAK) superfamily.бА0АкА0АаАCDDбАаАиЭвА0А0АаАВТcd04241, AAK_FomA-like, AAK_FomA-like: This CD includes a fosfomycin biosynthetic gene product, FomA, and similar proteins found in a wide range of organisms. Together, the fomA and fomB genes in the fosfomycin biosynthetic gene cluster of Streptomyces wedmorensis confer high-level fosfomycin resistance. FomA and FomB proteins converted fosfomycin to fosfomycin monophosphate and fosfomycin diphosphate in the presence of ATP and a magnesium ion, indicating that FomA and FomB catalyzed phosphorylations of fosfomycin and fosfomycin monophosphate, respectively. FomA and related sequences in this CD are members of the Amino Acid Kinase Superfamily (AAK).бА0АкА0АаАCDDбАаАиЮвА0А0АаАВюcd04242, AAK_G5K_ProB, AAK_G5K_ProB: Glutamate-5-kinase (G5K) catalyzes glutamate-dependent ATP cleavage; G5K transfers the terminal phosphoryl group of ATP to the gamma-carboxyl group of glutamate, in the first and controlling step of proline (and, in mammals, ornithine) biosynthesis. G5K is subject to feedback allosteric inhibition by proline or ornithine. In microorganisms and plants, proline plays an important role as an osmoprotectant and, in mammals, ornithine biosynthesis is crucial for proper ammonia detoxification, since a G5K mutation has been shown to cause human hyperammonaemia. Microbial G5K generally consists of two domains: a catalytic G5K domain and one PUA (pseudo uridine synthases and archaeosine-specific transglycosylases) domain, and some lack the PUA domain. G5K requires free Mg for activity, it is tetrameric, and it aggregates to higher forms in a proline-dependent way. G5K lacking the PUA domain remains tetrameric, active, and proline-inhibitable, but the Mg requirement and the proline-triggered aggregation are greatly diminished and abolished, respectively, and more proline is needed for inhibition. Although plant and animal G5Ks are part of a bifunctional polypeptide, delta 1-pyrroline-5-carboxylate synthetase (P5CS), composed of an N-terminal G5K (ProB) and a C-terminal glutamyl 5- phosphate reductase (G5PR; ProA); bacterial and yeast G5Ks are monofunctional single-polypeptide enzymes. In this CD, all three domain architectures are present: G5K, G5K+PUA, and G5K+G5PR.бА0АкА0АаАCDDбАаАиЯвА0А0АаАВЪcd04243, AAK_AK-HSDH-like, AAK_AK-HSDH-like: Amino Acid Kinase Superfamily (AAK), AK-HSDH-like; this family includes the N-terminal catalytic domain of aspartokinase (AK) of the bifunctional enzyme AK- homoserine dehydrogenase (HSDH). These aspartokinases are found in such bacteria as E. coli (AKI-HSDHI, ThrA and AKII-HSDHII, MetL) and in higher plants (Z. mays AK-HSDH). AK and HSDH are the first and third enzymes in the biosynthetic pathway of the aspartate family of amino acids. AK catalyzes the phosphorylation of Asp to P-aspartyl phosphate. HSDH catalyzes the NADPH-dependent conversion of Asp 3-semialdehyde to homoserine. ThrA and MetL are involved in threonine and methionine biosynthesis, respectively. In E. coli, ThrA is subject to allosteric regulation by the end product L-threonine and the native enzyme is reported to be tetrameric. As with bacteria, plant AK and HSDH are feedback inhibited by pathway end products. Maize AK-HSDH is a Thr-sensitive 180-kD enzyme. Arabidopsis AK-HSDH is an alanine-activated, threonine-sensitive enzyme whose ACT domains, located C-terminal to the AK catalytic domain, were shown to be involved in allosteric activation. Also included in this CD is the catalytic domain of the aspartokinase (AK) of the lysine-sensitive aspartokinase isoenzyme AKIII, a monofunctional class enzyme (LysC) found in some bacteria such as E. coli. In E. coli, LysC is reported to be a homodimer of 50 kD subunits. Also included in this CD is the catalytic domain of aspartokinase (AK) of the bifunctional enzyme AK - DAP decarboxylase (DapDC) found in some bacteria. DapDC, which is the lysA gene product, catalyzes the decarboxylation of DAP to lysine.бА0АкА0АаАCDDбАаАиавА0А0АаАВTcd04244, AAK_AK-LysC-like, AAK_AK-LysC-like: Amino Acid Kinase Superfamily (AAK), AK-LysC-like; this CD includes the N-terminal catalytic aspartokinase (AK) domain of the lysine-sensitive AK isoenzyme found in higher plants. The lysine-sensitive AK isoenzyme is a monofunctional protein. It is involved in the overall regulation of the aspartate pathway and can be synergistically inhibited by S-adenosylmethionine. Also included in this CD is an uncharacterized LysC-like AK found in Euryarchaeota and some bacteria. AK catalyzes the conversion of aspartate and ATP to aspartylphosphate and ADP.бА0АкА0АаАCDDбАаАибвА0А0АаАВ└cd04245, AAK_AKiii-YclM-BS, AAK_AKiii-YclM-BS: Amino Acid Kinase Superfamily (AAK), AKiii-YclM-BS; this CD includes the N-terminal catalytic aspartokinase (AK) domain of the lysine plus threonine-sensitive aspartokinase isoenzyme AKIII, a monofunctional class enzyme found in Bacilli (Bacillus subtilis YclM) and Clostridia species. Aspartokinase is the first enzyme in the aspartate metabolic pathway and catalyzes the conversion of aspartate and ATP to aspartylphosphate and ADP. In Bacillus subtilis (BS), YclM is reported to be a single polypeptide of 50 kD. The Bacillus subtilis 168 AKIII is induced by lysine and repressed by threonine, and it is synergistically inhibited by lysine and threonine.бА0АкА0АаАCDDбАаАиввА0А0АаАВыcd04246, AAK_AK-DapG-like, AAK_AK-DapG-like: Amino Acid Kinase Superfamily (AAK), AK-DapG-like; this CD includes the N-terminal catalytic aspartokinase (AK) domain of the diaminopimelate-sensitive aspartokinase isoenzyme AKI (DapG), a monofunctional enzymes found in Bacilli (Bacillus subtilis 168), Clostridia, and Actinobacteria bacterial species, as well as, the catalytic AK domain of the lysine-sensitive aspartokinase isoenzyme AKII of Bacillus subtilis 168, the lysine plus threonine-sensitive aspartokinase of Corynebacterium glutamicum, and related isoenzymes. In Bacillus subtilis, the regulation of the diaminopimelate-lysine biosynthetic pathway involves dual control by diaminopimelate and lysine, effected through separate diaminopimelate- and lysine-sensitive aspartokinase isoenzymes. The role of the AKI isoenzyme is most likely to provide a constant level of aspartyl-beta-phosphate for the biosynthesis of diaminopimelate for peptidoglycan synthesis and dipicolinate during sporulation. The B. subtilis 168 AKII is induced by methionine, and repressed and inhibited by lysine. In Corynebacterium glutamicum and other various Gram-positive bacteria, the DAP-lysine pathway is feedback regulated by the concerted action of lysine and threonine. Also included in this CD are the aspartokinases of the extreme thermophile, Thermus thermophilus HB27, the Gram-negative obligate methylotroph, Methylophilus methylotrophus AS1, and those single aspartokinase isoenzyme types found in Pseudomonas, C. glutamicum, and Amycolatopsis lactamdurans. The B. subtilis AKI is tetrameric consisting of two alpha and two beta subunits; the alpha (43 kD) and beta (17 kD) subunit formed by two in-phase overlapping genes. The alpha subunit contains the AK catalytic domain and two ACT domains. The beta subunit contains two ACT domains. The B. subtilis 168 AKII aspartokinase is also described as tetrameric consisting of two alpha and two beta subunits. Some archeal aspartokinases in this group lack recognizable ACT domains.бА0АкА0АаАCDDбАаАигвА0А0АаАВmcd04247, AAK_AK-Hom3, AAK_AK-Hom3: Amino Acid Kinase Superfamily (AAK), AK-Hom3; this CD includes the N-terminal catalytic domain of the aspartokinase HOM3, a monofunctional class enzyme found in Saccharomyces cerevisiae and other related AK domains. Aspartokinase, the first enzyme in the aspartate metabolic pathway, catalyzes the conversion of aspartate and ATP to aspartylphosphate and ADP, and in fungi, is responsible for the production of threonine, isoleucine and methionine. S. cerevisiae has a single aspartokinase isoenzyme type, which is regulated by feedback, allosteric inhibition by L-threonine. Recent studies show that the allosteric transition triggered by binding of threonine to AK involves a large change in the conformation of the native hexameric enzyme that is converted to an inactive one of different shape and substantially smaller hydrodynamic size.бА0АкА0АаАCDDбАаАидвА0А0АаАВсcd04248, AAK_AK-Ectoine, AAK_AK-Ectoine: Amino Acid Kinase Superfamily (AAK), AK-Ectoine; this CD includes the N-terminal catalytic domain of the aspartokinase of the ectoine (1,4,5,6-tetrahydro-2-methyl pyrimidine-4-carboxylate) biosynthetic pathway found in Methylomicrobium alcaliphilum, Vibrio cholerae, and other various halotolerant or halophilic bacteria. Bacteria exposed to hyperosmotic stress accumulate organic solutes called 'compatible solutes' of which ectoine, a heterocyclic amino acid, is one. Apart from its osmotic function, ectoine also exhibits a protective effect on proteins, nucleic acids and membranes against a variety of stress factors. de novo synthesis of ectoine starts with the phosphorylation of L-aspartate and shares its first two enzymatic steps with the biosynthesis of amino acids of the aspartate family: aspartokinase and L-aspartate-semialdehyde dehydrogenase. The M. alcaliphilum and the V. cholerae aspartokinases are encoded on the ectABCask operon.бА0АкА0АаАCDDбАаАиевА0А0АаАВ╢cd04249, AAK_NAGK-NC, AAK_NAGK-NC: N-Acetyl-L-glutamate kinase - noncyclic (NAGK-NC) catalyzes the phosphorylation of the gamma-COOH group of N-acetyl-L-glutamate (NAG) by ATP in the second step of microbial arginine biosynthesis using the acetylated, noncyclic route of ornithine biosynthesis. There are two variants of this pathway. In one, typified by the pathway in Escherichia coli, glutamate is acetylated by acetyl-CoA and acetylornithine is deacylated hydrolytically. In this pathway, feedback inhibition by arginine occurs at the initial acetylation of glutamate and not at the phosphorylation of NAG by NAGK. Homodimeric NAGK-NC are members of the Amino Acid Kinase Superfamily (AAK).бА0АкА0АаАCDDбАаАижвА0А0АаАВcd04250, AAK_NAGK-C, AAK_NAGK-C: N-Acetyl-L-glutamate kinase - cyclic (NAGK-C) catalyzes the phosphorylation of the gamma-COOH group of N-acetyl-L-glutamate (NAG) by ATP in the second step of arginine biosynthesis found in some bacteria and photosynthetic organisms using the non-acetylated, cyclic route of ornithine biosynthesis. In this pathway, glutamate is first N-acetylated and then phosphorylated by NAGK to give phosphoryl NAG, which is converted to NAG-ornithine. There are two variants of this pathway. In one, typified by the pathway in Thermotoga maritima and Pseudomonas aeruginosa, the acetyl group is recycled by reversible transacetylation from acetylornithine to glutamate. The phosphorylation of NAG by NAGK is feedback inhibited by arginine. In photosynthetic organisms, NAGK is the target of the nitrogen-signaling protein PII. Hexameric formation of NAGK domains appears to be essential to both arginine inhibition and NAGK-PII complex formation. NAGK-C are members of the Amino Acid Kinase Superfamily (AAK).бА0АкА0АаАCDDбАаАизвА0А0АаАВ▀cd04251, AAK_NAGK-UC, AAK_NAGK-UC: N-Acetyl-L-glutamate kinase - uncharacterized (NAGK-UC). This domain is similar to Escherichia coli and Pseudomonas aeruginosa NAGKs which catalyze the phosphorylation of the gamma-COOH group of N-acetyl-L-glutamate (NAG) by ATP in the second step of microbial arginine biosynthesis. These uncharacterized domain sequences are found in some bacteria (Deinococci and Chloroflexi) and archea and belong to the Amino Acid Kinase Superfamily (AAK).бА0АкА0АаАCDDбАаАиивА0А0АаАВcd04252, AAK_NAGK-fArgBP, AAK_NAGK-fArgBP: N-Acetyl-L-glutamate kinase (NAGK) of the fungal arginine-biosynthetic pathway (fArgBP). The nuclear-encoded, mitochondrial polyprotein precursor with an N-terminal NAGK (ArgB) domain (this CD), a central DUF619 domain, and a C-terminal reductase domain (ArgC, N-Acetylglutamate Phosphate Reductase, NAGPR). The precursor is cleaved in the mitochondria into two distinct enzymes (NAGK-DUF619 and NAGPR). Native molecular weights of these proteins indicate that the kinase is an octamer whereas the reductase is a dimer. This CD also includes some gamma-proteobacteria (Xanthomonas and Xylella) NAG kinases with an N-terminal NAGK (ArgB) domain (this CD) and a C-terminal DUF619 domain. The DUF619 domain is described as a putative distant homolog of the acetyltransferase, ArgA, predicted to function in NAG synthase association in fungi. Eukaryotic sequences have an N-terminal mitochondrial transit peptide. Members of this NAG kinase domain CD belong to the Amino Acid Kinase Superfamily (AAK).бА0АкА0АаАCDDбАаАийвА0А0АаАВ!cd04253, AAK_UMPK-PyrH-Pf, AAK_UMPK-PyrH-Pf: UMP kinase (UMPK)-Pf, the mostly archaeal uridine monophosphate kinase (uridylate kinase) enzymes that catalyze UMP phosphorylation and play a key role in pyrimidine nucleotide biosynthesis; regulation of this process is via feed-back control and via gene repression of carbamoyl phosphate synthetase (the first enzyme of the pyrimidine biosynthesis pathway). The UMP kinase of Pyrococcus furiosus (Pf) is known to function as a homohexamer, with GTP and UTP being allosteric effectors. Like other related enzymes (carbamate kinase, aspartokinase, and N-acetylglutamate kinase) the E. coli and most bacterial UMPKs have a conserved, N-terminal, lysine residue proposed to function in the catalysis of the phosphoryl group transfer, whereas most archaeal UMPKs (this CD) appear to lack this residue and the Pyrococcus furiosus structure has an additional Mg ion bound to the ATP molecule which is proposed to function as the catalysis instead. Members of this CD belong to the Amino Acid Kinase Superfamily (AAK).бА0АкА0АаАCDDбАаАиквА0А0АаАВcd04254, AAK_UMPK-PyrH-Ec, UMP kinase (UMPK)-Ec, the microbial/chloroplast uridine monophosphate kinase (uridylate kinase) enzyme that catalyzes UMP phosphorylation and plays a key role in pyrimidine nucleotide biosynthesis; regulation of this process is via feed-back control and via gene repression of carbamoyl phosphate synthetase (the first enzyme of the pyrimidine biosynthesis pathway). The UMP kinase of E. coli (Ec) is known to function as a homohexamer, with GTP and UTP being allosteric effectors. Like other related enzymes (carbamate kinase, aspartokinase, and N-acetylglutamate kinase) the E. coli and most bacterial and chloroplast UMPKs (this CD) have a conserved, N-terminal, lysine residue proposed to function in the catalysis of the phosphoryl group transfer, whereas most archaeal UMPKs appear to lack this residue and the Pyrococcus furiosus structure has an additional Mg ion bound to the ATP molecule which is proposed to function as the catalysis instead. Members of this CD belong to the Amino Acid Kinase Superfamily (AAK).бА0АкА0АаАCDDбАаАилвА0А0АаАВЩcd04255, AAK_UMPK-MosAB, AAK_UMPK-MosAB: This CD includes the alpha and beta subunits of the Mo storage protein (MosA and MosB) which are related to uridine monophosphate kinase (UMPK) enzymes that catalyze the phosphorylation of UMP by ATP, yielding UDP, and playing a key role in pyrimidine nucleotide biosynthesis. The Mo storage protein from the nitrogen-fixing bacterium, Azotobacter vinelandii, is characterized as an alpha4-beta4 octamer containing a polynuclear molybdenum-oxide cluster which is ATP-dependent to bind Mo and pH-dependent to release Mo. These and related bacterial sequences in this CD are members of the Amino Acid Kinase Superfamily (AAK).бА0АкА0АаАCDDбАаАимвА0А0АаАВ╬cd04256, AAK_P5CS_ProBA, AAK_P5CS_ProBA: Glutamate-5-kinase (G5K) domain of the bifunctional delta 1-pyrroline-5-carboxylate synthetase (P5CS), composed of an N-terminal G5K (ProB) and a C-terminal glutamyl 5- phosphate reductase (G5PR, ProA), the first and second enzyme catalyzing proline (and, in mammals, ornithine) biosynthesis. G5K transfers the terminal phosphoryl group of ATP to the gamma-carboxyl group of glutamate, and is subject to feedback allosteric inhibition by proline or ornithine. In plants, proline plays an important role as an osmoprotectant and, in mammals, ornithine biosynthesis is crucial for proper ammonia detoxification, since a G5K mutation has been shown to cause human hyperammonaemia.бА0АкА0АаАCDDбАаАинвА0А0АаАВВcd04257, AAK_AK-HSDH, AAK_AK-HSDH: Amino Acid Kinase Superfamily (AAK), AK-HSDH; this CD includes the N-terminal catalytic domain of aspartokinase (AK) of the bifunctional enzyme AK - homoserine dehydrogenase (HSDH). These aspartokinases are found in bacteria (E. coli AKI-HSDHI, ThrA and E. coli AKII-HSDHII, MetL) and higher plants (Z. mays AK-HSDH). AK and HSDH are the first and third enzymes in the biosynthetic pathway of the aspartate family of amino acids. AK catalyzes the phosphorylation of Asp to P-aspartyl phosphate. HSDH catalyzes the NADPH-dependent conversion of Asp 3-semialdehyde to homoserine. ThrA and MetL are involved in threonine and methionine biosynthesis, respectively. In E. coli, ThrA is subject to allosteric regulation by the end product L-threonine and the native enzyme is reported to be tetrameric. As with bacteria, plant AK and HSDH are feedback inhibited by pathway end products. Maize AK-HSDH is a Thr-sensitive 180-kD enzyme. Arabidopsis AK-HSDH is an alanine-activated, threonine-sensitive enzyme whose ACT domains, located C-terminal to the AK catalytic domain, were shown to be involved in allosteric activation.бА0АкА0АаАCDDбАаАиовА0А0АаАВ cd04258, AAK_AKiii-LysC-EC, AAK_AKiii-LysC-EC: Amino Acid Kinase Superfamily (AAK), AKiii-LysC-EC: this CD includes the N-terminal catalytic aspartokinase (AK) domain of the lysine-sensitive aspartokinase isoenzyme AKIII. AKIII is a monofunctional class enzyme (LysC) found in some bacteria such as E. coli. Aspartokinase is the first enzyme in the aspartate metabolic pathway and catalyzes the conversion of aspartate and ATP to aspartylphosphate and ADP. In E. coli, LysC is reported to be a homodimer of 50 kD subunits.бА0АкА0АаАCDDбАаАипвА0А0АаАВ╥cd04259, AAK_AK-DapDC, AAK_AK-DapDC: Amino Acid Kinase Superfamily (AAK), AK-DapDC; this CD includes the N-terminal catalytic aspartokinase (AK) domain of the bifunctional enzyme AK - DAP decarboxylase (DapDC) found in some bacteria. Aspartokinase is the first enzyme in the aspartate metabolic pathway, catalyzes the conversion of aspartate and ATP to aspartylphosphate and ADP. DapDC, which is the lysA gene product, catalyzes the decarboxylation of DAP to lysine.бА0АкА0АаАCDDбАаАи░вА0А0АаАВ╜cd04260, AAK_AKi-DapG-BS, AAK_AKi-DapG-BS: Amino Acid Kinase Superfamily (AAK), AKi-DapG; this CD includes the N-terminal catalytic aspartokinase (AK) domain of the diaminopimelate-sensitive aspartokinase isoenzyme AKI (DapG), a monofunctional class enzyme found in Bacilli (Bacillus subtilis 168), Clostridia, and Actinobacteria bacterial species. In Bacillus subtilis, the regulation of the diaminopimelate-lysine biosynthetic pathway involves dual control by diaminopimelate and lysine, effected through separate diaminopimelate- and lysine-sensitive aspartokinase isoenzymes. AKI activity is invariant during the exponential and stationary phases of growth and is not altered by addition of amino acids to the growth medium. The role of this isoenzyme is most likely to provide a constant level of aspartyl-beta-phosphate for the biosynthesis of diaminopimelate for peptidoglycan synthesis and dipicolinate during sporulation. The B. subtilis AKI is tetrameric consisting of two alpha and two beta subunits; the alpha (43 kD) and beta (17 kD) subunit formed by two in-phase overlapping genes. The alpha subunit contains the AK catalytic domain and two ACT domains. The beta subunit contains two ACT domains.бА0АкА0АаАCDDбАаАи▒вА0А0АаАВcd04261, AAK_AKii-LysC-BS, AAK_AKii-LysC-BS: Amino Acid Kinase Superfamily (AAK), AKii; this CD includes the N-terminal catalytic aspartokinase (AK) domain of the lysine-sensitive aspartokinase isoenzyme AKII of Bacillus subtilis 168, and the lysine plus threonine-sensitive aspartokinase of Corynebacterium glutamicum, and related sequences. In B. subtilis 168, the regulation of the diaminopimelate (Dap)-lysine biosynthetic pathway involves dual control by Dap and lysine, effected through separate Dap- and lysine-sensitive aspartokinase isoenzymes. The B. subtilis 168 AKII is induced by methionine, and repressed and inhibited by lysine. Although Corynebacterium glutamicum is known to contain a single aspartokinase isoenzyme type, both the succinylase and dehydrogenase variant pathways of DAP-lysine synthesis operate simultaneously in this organism. In this organism and other various Gram-positive bacteria, the DAP-lysine pathway is feedback regulated by the concerted action of lysine and theronine. Also included in this CD are the aspartokinases of the extreme thermophile, Thermus thermophilus HB27, the Gram-negative obligate methylotroph, Methylophilus methylotrophus AS1, and those single aspartokinases found in Pseudomons, C. glutamicum, and Amycolatopsis lactamdurans. B. subtilis 168 AKII, and the C. glutamicum, Streptomyces clavuligerus and A. lactamdurans aspartokinases are described as tetramers consisting of two alpha and two beta subunits; the alpha (44 kD) and beta (18 kD) subunits formed by two in-phase overlapping polypeptides.бА0АкА0АаАCDDбАаАи▓вА0А0АаАВBcd04263, DUF619-NAGK-FABP, DUF619 domain of N-acetylglutamate kinase (NAGK) of the fungal arginine-biosynthetic pathway. DUF619-NAGK-FABP: DUF619 domain of N-acetylglutamate kinase (NAGK) of the fungal arginine-biosynthetic pathway (FABP). The nuclear-encoded, mitochondrial polyprotein precursor (ARG5,6) consists of an N-terminal NAGK (ArgB) domain, a central DUF619 domain, and a C-terminal reductase domain (ArgC, N-Acetylglutamate Phosphate Reductase, NAGPR). The precursor is cleaved into two distinct enzymes (NAGK-DUF619 and NAGPR) in the mitochondria. Native molecular weights of these proteins indicate that the kinase is an octamer whereas the reductase is a dimer. Arg5,6 catalyzes the second reaction of arginine biosynthesis; the phosphorylation of the gamma-carboxyl group of NAG to produce N-acetylglutamylphosphate (NAGP) which is subsequently converted to ornithine in two more steps. It also binds and regulates the promoters of nuclear and mitochondrial genes, and may possibly regulate precursor mRNA metabolism. The DUF619 domain function has yet to be characterized.бА0АкА0АаАCDDбАаА░ЙвА0А0АаАВ╞cd04264, DUF619-NAGS, DUF619 domain of various N-acetylglutamate Synthases of the fungal arginine-biosynthetic pathway and urea cycle found in humans and fish. DUF619-NAGS: This family includes the DUF619 domain of various N-acetylglutamate synthases (NAGS) of the urea cycle found in humans and fish, the DUF619 domain of the NAGS of the fungal arginine-biosynthetic pathway (FABP), as well as the DUF619 domain present in C-terminal of a NAG kinase-like domain in a limited number of predicted NAGSs found in bacteria and Dictyostelium. Ureogenic NAGS is a mitochondrial enzyme catalyzing the formation of NAG from acetylcoenzyme A and L-glutamate. NAGS is an essential allosteric activator of carbamylphosphate synthase I, the first and rate limiting enzyme of the urea cycle. Domain architecture of ureogenic and fungal NAGS consists of an N-terminal NAG kinase-like domain and a C-terminal DUF619 domain. The DUF619 domain function has yet to be characterized.бА0АкА0АаАCDDбАаА░КвА0А0АаАВЧcd04265, DUF619-NAGS-U, DUF619 domain of various N-acetylglutamate Synthases (NAGS) of the urea (U) cycle of humans and fish. This family includes the DUF619 domain of various N-acetylglutamate synthases (NAGS) of the urea cycle found in humans and fish, the DUF619 domain of the NAGS of the fungal arginine-biosynthetic pathway (FABP), as well as the DUF619 domain present in C-terminal of a NAG kinase-like domain in a limited number of predicted NAGSs found in bacteria and Dictyostelium. Ureogenic NAGS is a mitochondrial enzyme catalyzing the formation of NAG from acetylcoenzyme A and L-glutamate. NAGS is an essential allosteric activator of carbamylphosphate synthase I, the first and rate limiting enzyme of the urea cycle. Domain architecture of ureogenic and fungal NAGS consists of an N-terminal NAG kinase-like domain and a C-terminal DUF619 domain. The DUF619 domain function has yet to be characterized.бА0АкА0АаАCDDбАаА░ЛвА0А0АаАВDcd04266, DUF619-NAGS-FABP, DUF619 domain of N-acetylglutamate Synthase of the fungal arginine-biosynthetic pathway. DUF619-NAGS-FABP: This family includes the DUF619 domain of N-acetylglutamate synthase (NAGS) of the fungal arginine-biosynthetic pathway (FABP). This NAGS (also known as arginine-requiring protein 2 or ARG2) consists of an N-terminal NAG kinase-like domain and a C-terminal DUF619 domain. NAGS catalyzes the formation of NAG from acetylcoenzyme A and L-glutamate. The DUF619 domain, yet to be characterized, is predicted to function in NAGS association in fungi.бА0АкА0АаАCDDбАаА░МвА0А0АаАВ╖cd04267, ZnMc_ADAM_like, Zinc-dependent metalloprotease, ADAM_like or reprolysin_like subgroup. The adamalysin_like or ADAM family of metalloproteases contains proteolytic domains from snake venoms, proteases from the mammalian reproductive tract, and the tumor necrosis factor alpha convertase, TACE. ADAMs (A Disintegrin And Metalloprotease) are glycoproteins, which play roles in cell signaling, cell fusion, and cell-cell interactions.бА0АкА0АаАCDDбАаАи│вА0А0АаАБ╕cd04268, ZnMc_MMP_like, Zinc-dependent metalloprotease, MMP_like subfamily. This group contains matrix metalloproteinases (MMPs), serralysins, and the astacin_like family of proteases.бА0АкА0АаАCDDбАаАи┤вА0А0АаАВжcd04269, ZnMc_adamalysin_II_like, Zinc-dependent metalloprotease; adamalysin_II_like subfamily. Adamalysin II is a snake venom zinc endopeptidase. This subfamily contains other snake venom metalloproteinases, as well as membrane-anchored metalloproteases belonging to the ADAM family. ADAMs (A Disintegrin And Metalloprotease) are glycoproteins, which play roles in cell signaling, cell fusion, and cell-cell interactions.бА0АкА0АаАCDDбАаАи╡вА0А0АаАБ─cd04270, ZnMc_TACE_like, Zinc-dependent metalloprotease; TACE_like subfamily. TACE, the tumor-necrosis factor-alpha converting enzyme, releases soluble TNF-alpha from transmembrane pro-TNF-alpha.бА0АкА0АаАCDDбАаАи╢вА0А0АаАВвcd04271, ZnMc_ADAM_fungal, Zinc-dependent metalloprotease, ADAM_fungal subgroup. The adamalysin_like or ADAM (A Disintegrin And Metalloprotease) family of metalloproteases are integral membrane proteases acting on a variety of extracellular targets. They are involved in shedding soluble peptides or proteins from the cell surface. This subfamily contains fungal ADAMs, whose precise function has yet to be determined.бА0АкА0АаАCDDбАаАи╖вА0А0АаАБХcd04272, ZnMc_salivary_gland_MPs, Zinc-dependent metalloprotease, salivary_gland_MPs. Metalloproteases secreted by the salivary glands of arthropods.бА0АкА0АаАCDDбАаАи╕вА0А0АаАВ╗cd04273, ZnMc_ADAMTS_like, Zinc-dependent metalloprotease, ADAMTS_like subgroup. ADAMs (A Disintegrin And Metalloprotease) are glycoproteins, which play roles in cell signaling, cell fusion, and cell-cell interactions. This particular subfamily represents domain architectures that combine ADAM-like metalloproteinases with thrombospondin type-1 repeats. ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) proteinases are inhibited by TIMPs (tissue inhibitors of metalloproteinases), and they play roles in coagulation, angiogenesis, development and progression of arthritis. They hydrolyze the von Willebrand factor precursor and various components of the extracellular matrix.бА0АкА0АаАCDDбАаАи╣вА0А0АаАВ╪cd04275, ZnMc_pappalysin_like, Zinc-dependent metalloprotease, pappalysin_like subfamily. The pregnancy-associated plasma protein A (PAPP-A or pappalysin-1) cleaves insulin-like growth factor-binding proteins 4 and 5, thereby promoting cell growth by releasing bound growth factor. This model includes pappalysins and related metalloprotease domains from all three kingdoms of life. The three-dimensional structure of an archaeal representative, ulilysin, has been solved.бА0АкА0АаАCDDбАаАи║вА0А0АаАБ▒cd04276, ZnMc_MMP_like_2, Zinc-dependent metalloprotease; MMP_like sub-family 2. A group of bacterial metalloproteinase domains similar to matrix metalloproteinases and astacin.бА0АкА0АаАCDDбАаАи╗вА0А0АаАВIcd04277, ZnMc_serralysin_like, Zinc-dependent metalloprotease, serralysin_like subfamily. Serralysins and related proteases are important virulence factors in pathogenic bacteria. They may be secreted into the medium via a mechanism found in gram-negative bacteria, that does not require n-terminal signal sequences which are cleaved after the transmembrane translocation. A calcium-binding domain c-terminal to the metalloprotease domain, which contains multiple tandem repeats of a nine-residue motif including the pattern GGxGxD, and which forms a parallel beta roll may be involved in the translocation mechanism and/or substrate binding. Serralysin family members may have a broad spectrum of substrates each, including host immunoglobulins, complement proteins, cell matrix and cytoskeletal proteins, as well as antimicrobial peptides.бА0АкА0АаАCDDбАаАи╝вА0А0АаАВ%cd04278, ZnMc_MMP, Zinc-dependent metalloprotease, matrix metalloproteinase (MMP) sub-family. MMPs are responsible for a great deal of pericellular proteolysis of extracellular matrix and cell surface molecules, playing crucial roles in morphogenesis, cell fate specification, cell migration, tissue repair, tumorigenesis, gain or loss of tissue-specific functions, and apoptosis. In many instances, they are anchored to cell membranes via trans-membrane domains, and their activity is controlled via TIMPs (tissue inhibitors of metalloproteinases).бА0АкА0АаАCDDбАаАи╜вА0А0АаАБ╟cd04279, ZnMc_MMP_like_1, Zinc-dependent metalloprotease; MMP_like sub-family 1. A group of bacterial, archaeal, and fungal metalloproteinase domains similar to matrix metalloproteinases and astacin.бА0АкА0АаАCDDбАаАи╛вА0А0АаАВ╚cd04280, ZnMc_astacin_like, Zinc-dependent metalloprotease, astacin_like subfamily or peptidase family M12A, a group of zinc-dependent proteolytic enzymes with a HExxH zinc-binding site/active site. Members of this family may have an amino terminal propeptide, which is cleaved to yield the active protease domain, which is consequently always found at the N-terminus in multi-domain architectures. This family includes: astacin, a digestive enzyme from Crayfish; meprin, a multiple domain membrane component that is constructed from a homologous alpha and beta chain, proteins involved in (bone) morphogenesis, tolloid from drosophila, and the sea urchin SPAN protein, which may also play a role in development.бА0АкА0АаАCDDбАаАи┐вА0А0АаАВ\cd04281, ZnMc_BMP1_TLD, Zinc-dependent metalloprotease; BMP1/TLD-like subfamily. BMP1 (Bone morphogenetic protein 1) and TLD (tolloid)-like metalloproteases play vital roles in extracellular matrix formation, by cleaving precursor proteins such as enzymes, structural proteins, and proteins involved in the mineralization of the extracellular matrix. The drosophila protein tolloid and its Xenopus homologue xolloid cleave and inactivate Sog and chordin, respectively, which are inhibitors of Dpp (the Drosophila decapentaplegic gene product) and its homologue BMP4, involved in dorso-ventral patterning.бА0АкА0АаАCDDбАаАи└вА0А0АаАВqcd04282, ZnMc_meprin, Zinc-dependent metalloprotease, meprin_like subfamily. Meprins are membrane-bound or secreted extracellular proteases, which cleave a variety of targets, including peptides such as parathyroid hormone, gastrin, and cholecystokinin, cytokines such as osteopontin, and proteins such as collagen IV, fibronectin, casein and gelatin. Meprins may also be able to release proteins from the cell surface. Closely related meprin alpha- and beta-subunits form homo- and hetero-oligomers; these complexes are found on epithelial cells of the intestine, for example, and are also expressed in certain cancer cells.бА0АкА0АаАCDDбАаАи┴вА0А0АаАВ└cd04283, ZnMc_hatching_enzyme, Zinc-dependent metalloprotease, hatching enzyme-like subfamily. Hatching enzymes are secreted by teleost embryos to digest the egg envelope or chorion. In some teleosts, the hatching enzyme may be a system consisting of two evolutionary related metalloproteases, high choriolytic enzyme and low choriolytic enzyme (HCE and LCE), which may have different substrate specificities and cooperatively digest the chorion.бА0АкА0АаАCDDбАаАи┬вА0А0АаАВМcd04299, GT1_Glycogen_Phosphorylase_like, This family is most closely related to the oligosaccharide phosphorylase domain family and other unidentified sequences. Oligosaccharide phosphorylase catalyzes the breakdown of oligosaccharides into glucose-1-phosphate units. They are important allosteric enzymes in carbohydrate metabolism. The members of this family are found in bacteria and Archaea.бА0АкА0АаАCDDбАаАЖЫвА0А0АаАВЦcd04300, GT1_Glycogen_Phosphorylase, This is a family of oligosaccharide phosphorylases. It includes yeast and mammalian glycogen phosphorylases, plant starch/glucan phosphorylase, as well as the maltodextrin phosphorylases of bacteria. The members of this family catalyze the breakdown of oligosaccharides into glucose-1-phosphate units. They are important allosteric enzymes in carbohydrate metabolism. The allosteric control mechanisms of yeast and mammalian members of this family are different from that of bacterial members. The members of this family belong to the GT-B structural superfamily of glycoslytransferases, which have characteristic N- and C-terminal domains each containing a typical Rossmann fold. The two domains have high structural homology despite minimal sequence homology. The large cleft that separates the two domains includes the catalytic center and permits a high degree of flexibility.бА0АкА0АаАCDDбАаАЖЬвА0А0АаАВвА0А0АаАВAcd04489, ExoVII_LU_OBF, ExoVII_LU_OBF: A subfamily of OB folds corresponding to the N-terminal OB-fold domain of Escherichia coli exodeoxyribonuclease VII (ExoVII) large subunit. E. coli ExoVII is composed of two non-identical subunits. E. coli ExoVII is a single-strand-specific exonuclease which degrades ssDNA from both 3-prime and 5-prime ends. ExoVII plays a role in methyl-directed mismatch repair in vivo. ExoVII may also guard the genome from mutagenesis by removing excess ssDNA, since the build up of ssDNA would lead to SOS induction and PolIV-dependent mutagenesis.бА0АкА0АаАCDDбАаАй?вА0А0АаАВуcd04490, PolII_SU_OBF, PolII_SU_OBF: A subfamily of OB folds corresponding to the OB fold found in Pyrococcus abyssi DNA polymerase II (PolII) small subunit. PolII is a family D DNA polymerase, having a 3-prime to 5-prime exonuclease activity. P. abyssi PolII is heterodimeric. The large subunit appears to be the polymerase, and the small subunit may be the exonuclease. The small subunit contains a calcineurin-like phosphatase superfamily domain C-terminal to this OB-fold domain.бА0АкА0АаАCDDбАаАй@вА0А0АаАВcd04491, SoSSB_OBF, SoSSB_OBF: A subfamily of OB folds similar to the OB fold of the crenarchaeote Sulfolobus solfataricus single-stranded (ss) DNA-binding protein (SSoSSB). SSoSSB has a single OB fold, and it physically and functionally interacts with RNA polymerase. In vitro, SSoSSB can substitute for the basal transcription factor TBP, stimulating transcription from promoters under conditions in which TBP is limiting, and supporting transcription when TBP is absent. SSoSSB selectively melts the duplex DNA of promoter sequences. It also relieves transcriptional repression by the chromatin Alba. In addition, SSoSSB activates reverse gyrase activity, which involves DNA binding, DNA cleavage, strand passage and ligation. SSoSSB stimulates all these steps in the presence of the chromatin protein, Sul7d. SSoSSB antagonizes the inhibitory effect of Sul7d on reverse gyrase supercoiling activity. It also physically and functionally interacts with Mini-chromosome Maintenance (MCM), stimulating the DNA helicase activity of MCM.бА0АкА0АаАCDDбАаАйAвА0А0АаАВЧcd04492, YhaM_OBF_like, YhaM_OBF_like: A subfamily of OB folds similar to that found in Bacillus subtilis YhaM and Staphylococcus aureus cmp-binding factor-1 (SaCBF1). Both these proteins are 3'-to-5'exoribonucleases. YhaM requires Mn2+ or Co2+ for activity and is inactive in the presence of Mg2+. YhaM also has a Mn2+ dependent 3'-to-5'single-stranded DNA exonuclease activity. SaCBF is also a double-stranded DNA binding protein, binding specifically to cmp, the replication enhancer found in S. aureus plasmid pT181. Proteins in this group combine an N-terminal OB fold with a C-terminal HD domain. The HD domain is found in metal-dependent phosphohydrolases.бА0АкА0АаАCDDбАаАйBвА0А0АаАВъcd04493, BRCA2DBD_OB1, BRCA2DBD_OB1: A subfamily of OB folds corresponding to the first OB fold (OB1) of the 800-amino acid C-terminal ssDNA binding domain (DBD) of BRCA2 (breast cancer susceptibility gene 2) protein, called BRCA2DBD. BRCA2 participates in homologous recombination-mediated repair of double-strand DNA breaks. It stimulates the displacement of Replication protein A (RPA), the most abundant eukaryotic ssDNA binding protein. It also facilitates filament formation. Mutations that map throughout the BRCA2 protein are associated with breast cancer susceptibility. BRCA2 is a large nuclear protein and its most conserved region is the C-terminal BRCA2DBD. BRCA2DBD binds ssDNA in vitro, and is composed of five structural domains, three of which are OB folds (OB1, OB2, and OB3). BRCA2DBD OB2 and OB3 are arranged in tandem, and their mode of binding can be considered qualitatively similar to two OB folds of RPA1, DBD-A and DBD-B (the major DBDs of RPA). BRCA2DBD OB1 binds DNA weakly.бА0АкА0АаАCDDбАаАйCвА0А0АаАВ╠cd04494, BRCA2DBD_OB2, BRCA2DBD_OB2: A subfamily of OB folds corresponding to the second OB fold (OB2) of the 800-amino acid C-terminal ssDNA binding domain (DBD) of BRCA2 (breast cancer susceptibility gene 2) protein, called BRCA2DBD. BRCA2 participates in homologous recombination-mediated repair of double-strand DNA breaks. It stimulates the displacement of Replication protein A (RPA), the most abundant eukaryotic ssDNA binding protein. It also facilitates filament formation. Mutations that map throughout the BRCA2 protein are associated with breast cancer susceptibility. BRCA2 is a large nuclear protein and its most conserved region is the C-terminal BRCA2DBD. BRCA2DBD binds ssDNA in vitro, and is composed of five structural domains, three of which are OB folds (OB1, OB2, and OB3). BRCA2DBD OB2 and OB3 are arranged in tandem, and their mode of binding can be considered qualitatively similar to two OB folds of RPA1, DBD-A and DBD-B (the major DBDs of RPA).бА0АкА0АаАCDDбАаАйDвА0А0АаАВ╦cd04495, BRCA2DBD_OB3, BRCA2DBD_OB3: A subfamily of OB folds corresponding to the third OB fold (OB3) of the 800-amino acid C-terminal ssDNA binding domain (DBD) of BRCA2 (breast cancer susceptibility gene 2) protein, called BRCA2DBD. BRCA2 participates in homologous recombination-mediated repair of double-strand DNA breaks. It stimulates the displacement of Replication protein A (RPA), the most abundant eukaryotic ssDNA binding protein. It also facilitates filament formation. Mutations that map throughout the BRCA2 protein are associated with breast cancer susceptibility. BRCA2 is a large nuclear protein and its most conserved region is the C-terminal BRCA2DBD. BRCA2DBD binds ssDNA in vitro, and is composed of five structural domains, three of which are OB folds (OB1, OB2, and OB3). BRCA2DBD OB2 and OB3 are arranged in tandem, and their mode of binding can be considered qualitatively similar to two OB folds of RPA1, DBD-A and DBD-B (the major DBDs of RPA).бА0АкА0АаАCDDбАаАйEвА0А0АаАВ┘cd04496, SSB_OBF, SSB_OBF: A subfamily of OB folds similar to the OB fold of ssDNA-binding protein (SSB). SSBs bind with high affinity to ssDNA. They bind to and protect ssDNA intermediates during DNA metabolic pathways. All bacterial and eukaryotic SSBs studied to date oligomerize to bring together four OB folds in their active state. The majority (e.g. Escherichia coli SSB) have a single OB fold per monomer, which oligomerize to form a homotetramer. However, Deinococcus and Thermus SSB proteins have two OB folds per monomer, which oligomerize to form a homodimer. Mycobacterium tuberculosis SSB varies in quaternary structure from E. coli SSB. It forms a dimer of dimers having a unique dimer interface, which lends the protein greater stability. Included in this group are OB folds similar to Escherichia coli PriB. E.coli PriB is homodimeric with each monomer having a single OB fold. It does not appear to form higher order oligomers. PriB is an essential protein for the replication restart at forks that have stalled at sites of DNA damage. It also plays a role in the assembly of primosome during replication initiation at the bacteriophage phiX174 origin. PriB physically interacts with SSB and binds ssDNA with high affinity.бА0АкА0АаАCDDбАаАйFвА0А0АаАВ/cd04497, hPOT1_OB1_like, hPOT1_OB1_like: A subfamily of OB folds similar to the first OB fold (OB1) of human protection of telomeres 1 protein (hPOT1), the single OB fold of the N-terminal domain of Schizosaccharomyces pombe POT1 (SpPOT1), and the first OB fold of the N-terminal domain of the alpha subunit (OB1Nalpha) of Oxytricha nova telomere end binding protein (OnTEBP). POT1 proteins recognize single-stranded (ss) 3-prime ends of the telomere. A 3-prime ss overhang is conserved in ciliated protozoa, yeast, and mammals. SpPOT1 is essential for telomere maintenance. It binds specifically to the ss G-rich telomeric sequence (GGTTAC) of S. pombe. hPOT1 binds specifically to ss telomeric DNA repeats ending with the sequence GGTTAG. Deletion of the S. pombe pot1+ gene results in a rapid loss of telomere sequences, chromosome mis-segregation and chromosome circularization. hPOT1 is implicated in telomere length regulation. The hPOT1 monomer consists of two closely connected OB folds (OB1-OB2) which cooperate to bind telomeric ssDNA. OB1 makes more extensive contact with the ssDNA than OB2. OB2 protects the 3' end of the ssDNA. A second OB fold has not been predicted in S. pombe POT1. OnTEBP binds the extreme 3-prime end of telomeric DNA. It is heterodimeric and contains four OB folds - three in the alpha subunit (two in the N-terminal domain and one in the C-terminal domain) and one in the beta subunit. OB1Nalpha, together with the second OB fold of the N-terminal domain of OnTEBP alpha subunit and the beta subunit OB fold, forms a deep cleft that binds ssDNA.бА0АкА0АаАCDDбАаАйGвА0А0АаАВ4cd04498, hPOT1_OB2, hPOT1_OB2: A subfamily of OB folds similar to the second OB fold (OB2) of human protection of telomeres 1 protein (hPOT1). POT1 proteins bind to the single-stranded (ss) 3-prime ends of the telomere. hPOT1 binds specifically to ss telomeric DNA repeats ending with the sequence GGTTAG. The hPOT1 monomer consists of two closely connected OB folds (OB1-OB2) which cooperate to bind telomeric ssDNA. OB1 makes more extensive contact with the ssDNA than OB2. OB2 protects the 3' end of the ssDNA. hPOT1 is implicated in telomere length regulation.бА0АкА0АаАCDDбАаАйHвА0А0АаАВАcd04501, SGNH_hydrolase_like_4, Members of the SGNH-hydrolase superfamily, a diverse family of lipases and esterases. The tertiary fold of the enzyme is substantially different from that of the alpha/beta hydrolase family and unique among all known hydrolases; its active site closely resembles the Ser-His-Asp(Glu) triad from other serine hydrolases, but may lack the carboxlic acid.бА0АкА0АаАCDDбАаАйIвА0А0АаАВАcd04502, SGNH_hydrolase_like_7, Members of the SGNH-hydrolase superfamily, a diverse family of lipases and esterases. The tertiary fold of the enzyme is substantially different from that of the alpha/beta hydrolase family and unique among all known hydrolases; its active site closely resembles the Ser-His-Asp(Glu) triad from other serine hydrolases, but may lack the carboxlic acid.бА0АкА0АаАCDDбАаАйJвА0А0АаАВ┐cd04506, SGNH_hydrolase_YpmR_like, Members of the SGNH-hydrolase superfamily, a diverse family of lipases and esterases. The tertiary fold of the enzyme is substantially different from that of the alpha/beta hydrolase family and unique among all known hydrolases; its active site closely resembles the Ser-His-Asp(Glu) triad from other serine hydrolases, but may lack the carboxlic acid. This subfamily contains sequences similar to Bacillus YpmR.бА0АкА0АаАCDDбАаАйKвА0А0АаАВscd04508, TUDOR, Tudor domains are found in many eukaryotic organisms and have been implicated in protein-protein interactions in which methylated protein substrates bind to these domains. For example, the Tudor domain of Survival of Motor Neuron (SMN) binds to symmetrically dimethylated arginines of arginine-glycine (RG) rich sequences found in the C-terminal tails of Sm proteins. The SMN protein is linked to spinal muscular atrophy. Another example is the tandem tudor domains of 53BP1, which bind to histone H4 specifically dimethylated at Lys20 (H4-K20me2). 53BP1 is a key transducer of the DNA damage checkpoint signal.бА0АкА0АаАCDDбАаА╥_вА0А0АаАВсcd04509, PBP1_ABC_transporter_GCPR_C_like, Family C of G-protein coupled receptors and their close homologs, the type I periplasmic-binding proteins of ATP-binding cassette transporter-like systems. This CD includes members of the family C of G-protein coupled receptors and their close homologs, the type I periplasmic-binding proteins of ATP-binding cassette transporter-like systems. The family C GPCR includes glutamate/glycine-gated ion channels such as the NMDA receptor, G-protein-coupled receptors, metabotropic glutamate, GABA-B, calcium sensing, phermone receptors, and atrial natriuretic peptide-guanylate cyclase receptors. The glutamate receptors that form cation-selective ion channels, iGluR, can be classified into three different subgroups according to their binding-affinity for the agonists NMDA (N-methyl-D-asparate), AMPA (alpha-amino-3-dihydro-5-methyl-3-oxo-4-isoxazolepropionic acid), and kainate. L-glutamate is a major neurotransmitter in the brain of vertebrates and acts through either mGluRs or iGluRs. mGluRs subunits possess seven transmembrane segments and a large N-terminal extracellular domain. ABC-type leucine-isoleucine-valine-binding protein (LIVBP) is a bacterial periplasmic binding protein that has homology with the amino-terminal domain of the glutamate-receptor ion channels (iGluRs). The extracellular regions of iGluRs are made of two PBP-like domains in tandem, a LIVBP-like domain that constitutes the N terminus - which is included in this CD - followed by a domain related to lysine-arginine-ornithine-binding protein (LAOBP) that belongs to the type II periplasmic binding fold protein superfamily. The uncharacterized periplasmic components of various ABC-type transport systems are included in this group.бА0АкА0АаАCDDбАаАв¤вА0А0АаАВ▄cd04511, Nudix_Hydrolase_4, Members of the Nudix hydrolase superfamily catalyze the hydrolysis of NUcleoside DIphosphates linked to other moieties, X. Enzymes belonging to this superfamily require a divalent cation, such as Mg2+ or Mn2+, for their activity and contain a highly conserved 23-residue nudix motif (GX5EX7REUXEEXGU, U=I, L or V), which functions as a metal binding and catalytic site. Substrates of nudix hydrolases include intact and oxidatively damaged nucleoside triphosphates, dinucleoside polyphosphates, nucleotide-sugars and dinucleotide enzymes. These substrates are metabolites or cell signaling molecules that require regulation during different stages of the cell cycle or during periods of stress. In general, the role of the nudix hydrolase is to sanitize the nucleotide pools and to maintain cell viability, thereby serving as surveillance & "house-cleaning" enzymes. Substrate specificity is used to define families within the superfamily. Differences in substrate specificity are determined by the N-terminal extension or by residues in variable loop regions. Mechanistically, substrate hydrolysis occurs by a nucleophilic substitution reaction, with variation in the numbers and roles of divalent cations required.бА0АкА0АаАCDDбАаАйLвА0А0АаАВ cd04512, Ntn_Asparaginase_2_like, L-Asparaginase type 2-like enzymes of the NTN-hydrolase superfamily. This family includes Glycosylasparaginase, Taspase 1, and L-Asparaginase type 2 enzymes. Glycosylasparaginase catalyzes the hydrolysis of the glycosylamide bond of asparagine-linked glycoprotein. Taspase1 catalyzes the cleavage of the Mix Lineage Leukemia (MLL) nuclear protein and transcription factor TFIIA. L-Asparaginase type 2 hydrolyzes L-asparagine to L-aspartate and ammonia. The proenzymes of this family undergo autoproteolytic cleavage before a threonine to generate alpha and beta subunits. The threonine becomes the N-terminal residue of the beta subunit and is the catalytic residue. The family is circularly permuted relative to other NTN-hydrolase families.бА0АкА0АаАCDDбАаА#цвА0А0АаАВrcd04513, Glycosylasparaginase, Glycosylasparaginase and similar proteins. Glycosylasparaginase catalyzes the hydrolysis of the glycosylamide bond of asparagine-linked glycoproteins. This enzyme is an amidase located inside lysosomes. Mutation of this gene in humans causes a genetic disorder known as aspartylglycosaminuria (AGU). The glycosylasparaginase precursor undergoes autoproteolysis through an N-O or N-S acyl rearrangement of the peptide bond, which leads to the cleavage of a peptide bond between an Asp and a Thr. This proteolysis step generates an exposed N-terminal catalytic threonine and activates the enzyme.бА0АкА0АаАCDDбАаА#чвА0А0АаАВоcd04514, Taspase1_like, Taspase 1 (threonine aspartase 1) and similar proteins. Taspase1 catalyzes the cleavage of the mix lineage leukemia (MLL) nuclear protein and transcription factor TFIIA. Taspase1 is a threonine aspartase, a member of the Ntn hydrolase superfamily and the type 2 asparaginase family. A threonine residue acts as the active site nucleophile in both endopeptidease and protease activities to cleave polypeptide substrates after an aspartate residue. The Taspase1 proenzyme undergoes autoproteolysis into alpha and beta subunits. The N-terminal residue of the beta subunit is a threonine which is the active catalytic residue. The active enzyme is a heterotetramer.бА0АкА0АаАCDDбАаА#швА0А0АаАВ)cd04516, TBP_eukaryotes, eukaryotic TATA box binding protein (TBP): Present in archaea and eukaryotes, TBPs are transcription factors that recognize promoters and initiate transcription. TBP has been shown to be an essential component of three different transcription initiation complexes: SL1, TFIID and TFIIIB, directing transcription by RNA polymerases I, II and III, respectively. TBP binds directly to the TATA box promoter element, where it nucleates polymerase assembly, thus defining the transcription start site. TBP's binding in the minor groove induces a dramatic DNA bending while its own structure barely changes. The conserved core domain of TBP, which binds to the TATA box, has a bipartite structure, with intramolecular symmetry generating a saddle-shaped structure that sits astride the DNA.бА0АкА0АаАCDDбАаАйPвА0А0АаАВcd04517, TLF, TBP-like factors (TLF; also called TLP, TRF, TRP), which are found in most metazoans. TLFs and TBPs have well-conserved core domains; however, they only share about 60% similarity. TLFs, like TBPs, interact with TFIIA and TFIIB, which are part of the basal transcription machinery. Yet, in contrast to TBPs, TLFs seem not to interact with the TATA-box and even have a negative effect on the transcription of TATA-containing promoters. Recent results indicate that TLFs are involved in the transcription via TATA-less promoters.бА0АкА0АаАCDDбАаАйQвА0А0АаАВ$cd04518, TBP_archaea, archaeal TATA box binding protein (TBP): TBPs are transcription factors present in archaea and eukaryotes, that recognize promoters and initiate transcription. TBP has been shown to be an essential component of three different transcription initiation complexes: SL1, TFIID and TFIIIB, directing transcription by RNA polymerases I, II and III, respectively. TBP binds directly to the TATA box promoter element, where it nucleates polymerase assembly, thus defining the transcription start site. TBP's binding in the minor groove induces a dramatic DNA bending while its own structure barely changes. The conserved core domain of TBP, which binds to the TATA box, has a bipartite structure, with intramolecular symmetry generating a saddle-shaped structure that sits astride the DNA.бА0АкА0АаАCDDбАаАйRвА0А0АаАВ▓cd04519, RasGAP, Ras GTPase Activating Domain. RasGAP functions as an enhancer of the hydrolysis of GTP that is bound to Ras-GTPases. Proteins having a RasGAP domain include p120GAP, IQGAP, Rab5-activating protein 6, and Neurofibromin, among others. Although the Rho (Ras homolog) GTPases are most closely related to members of the Ras family, RhoGAP and RasGAP exhibit no similarity at their amino acid sequence level. RasGTPases function as molecular switches in a large number of signaling pathways. They are in the on state when bound to GTP, and in the off state when bound to GDP. The RasGAP domain speeds up the hydrolysis of GTP in Ras-like proteins acting as a negative regulator.бА0АкА0АаАCDDбАаАAPвА0А0АаАВcd04582, CBS_pair_ABC_OpuCA_assoc, This cd contains two tandem repeats of the cystathionine beta-synthase (CBS pair) domains in association with the ABC transporter OpuCA. OpuCA is the ATP binding component of a bacterial solute transporter that serves a protective role to cells growing in a hyperosmolar environment but the function of the CBS domains in OpuCA remains unknown. In the related ABC transporter, OpuA, the tandem CBS domains have been shown to function as sensors for ionic strength, whereby they control the transport activity through an electronic switching mechanism. ABC transporters are a large family of proteins involved in the transport of a wide variety of different compounds, like sugars, ions, peptides, and more complex organic molecules. They are a subset of nucleotide hydrolases that contain a signature motif, Q-loop, and H-loop/switch region, in addition to the Walker A motif/P-loop and Walker B motif commonly found in a number of ATP- and GTP-binding and hydrolyzing proteins. CBS is a small domain originally identified in cystathionine beta-synthase and subsequently found in a wide range of different proteins. CBS domains usually come in tandem repeats, which associate to form a so-called Bateman domain or a CBS pair which is reflected in this model. The interface between the two CBS domains forms a cleft that is a potential ligand binding site. The CBS pair coexists with a variety of other functional domains. It has been proposed that the CBS domain may play a regulatory role, although its exact function is unknown.бА0АкА0АаАCDDбАаАйSвА0А0АаАВ cd04583, CBS_pair_ABC_OpuCA_assoc2, This cd contains two tandem repeats of the cystathionine beta-synthase (CBS pair) domains in association with the ABC transporter OpuCA. OpuCA is the ATP binding component of a bacterial solute transporter that serves a protective role to cells growing in a hyperosmolar environment but the function of the CBS domains in OpuCA remains unknown. In the related ABC transporter, OpuA, the tandem CBS domains have been shown to function as sensors for ionic strength, whereby they control the transport activity through an electronic switching mechanism. ABC transporters are a large family of proteins involved in the transport of a wide variety of different compounds, like sugars, ions, peptides, and more complex organic molecules. They are a subset of nucleotide hydrolases that contain a signature motif, Q-loop, and H-loop/switch region, in addition to the Walker A motif/P-loop and Walker B motif commonly found in a number of ATP- and GTP-binding and hydrolyzing proteins. CBS is a small domain originally identified in cystathionine beta-synthase and subsequently found in a wide range of different proteins. CBS domains usually come in tandem repeats, which associate to form a so-called Bateman domain or a CBS pair which is reflected in this model. The interface between the two CBS domains forms a cleft that is a potential ligand binding site. The CBS pair coexists with a variety of other functional domains. It has been proposed that the CBS domain may play a regulatory role, although its exact function is unknown.бА0АкА0АаАCDDбАаАйTвА0А0АаАВЇcd04584, CBS_pair_ACT_assoc, This cd contains two tandem repeats of the cystathionine beta-synthase (CBS pair) domains in the acetoin utilization proteins in bacteria. Acetoin is a product of fermentative metabolism in many prokaryotic and eukaryotic microorganisms. They produce acetoin as an external carbon storage compound and then later reuse it as a carbon and energy source during their stationary phase and sporulation. In addition these CBS domains are associated with a downstream ACT domain, which is linked to a wide range of metabolic enzymes that are regulated by amino acid concentration. Pairs of ACT domains bind specifically to a particular amino acid leading to regulation of the linked enzyme. CBS is a small domain originally identified in cystathionine beta-synthase and subsequently found in a wide range of different proteins. CBS domains usually come in tandem repeats, which associate to form a so-called Bateman domain or a CBS pair which is reflected in this model. The interface between the two CBS domains forms a cleft that is a potential ligand binding site. The CBS pair coexists with a variety of other functional domains. It has been proposed that the CBS domain may play a regulatory role, although its exact function is unknown.бА0АкА0АаАCDDбАаАйUвА0А0АаАВїcd04585, CBS_pair_ACT_assoc2, This cd contains two tandem repeats of the cystathionine beta-synthase (CBS pair) domains in the acetoin utilization proteins in bacteria. Acetoin is a product of fermentative metabolism in many prokaryotic and eukaryotic microorganisms. They produce acetoin as an external carbon storage compound and then later reuse it as a carbon and energy source during their stationary phase and sporulation. In addition these CBS domains are associated with a downstream ACT domain, which is linked to a wide range of metabolic enzymes that are regulated by amino acid concentration. Pairs of ACT domains bind specifically to a particular amino acid leading to regulation of the linked enzyme. CBS is a small domain originally identified in cystathionine beta-synthase and subsequently found in a wide range of different proteins. CBS domains usually come in tandem repeats, which associate to form a so-called Bateman domain or a CBS pair which is reflected in this model. The interface between the two CBS domains forms a cleft that is a potential ligand binding site. The CBS pair coexists with a variety of other functional domains. It has been proposed that the CBS domain may play a regulatory role, although its exact function is unknown.бА0АкА0АаАCDDбАаАйVвА0А0АаАВ╤cd04586, CBS_pair_BON_assoc, This cd contains two tandem repeats of the cystathionine beta-synthase (CBS pair) domains associated with the BON (bacterial OsmY and nodulation domain) domain. BON is a putative phospholipid-binding domain found in a family of osmotic shock protection proteins. It is also found in some secretins and a group of potential haemolysins. Its likely function is attachment to phospholipid membranes. CBS is a small domain originally identified in cystathionine beta-synthase and subsequently found in a wide range of different proteins. CBS domains usually come in tandem repeats, which associate to form a so-called Bateman domain or a CBS pair which is reflected in this model. The interface between the two CBS domains forms a cleft that is a potential ligand binding site. The CBS pair coexists with a variety of other functional domains. It has been proposed that the CBS domain may play a regulatory role, although its exact function is unknown.бА0АкА0АаАCDDбАаАйWвА0А0АаАВcd04587, CBS_pair_CAP-ED_DUF294_PBI_assoc, This cd contains two tandem repeats of the cystathionine beta-synthase (CBS pair) domains associated with either the CAP_ED (cAMP receptor protein effector domain) family of transcription factors and the DUF294 domain or the PB1 (Phox and Bem1p) domain. Members of CAP_ED, include CAP which binds cAMP, FNR (fumarate and nitrate reductase) which uses an iron-sulfur cluster to sense oxygen, and CooA a heme containing CO sensor. In all cases binding of the effector leads to conformational changes and the ability to activate transcription. DUF294 is a putative nucleotidyltransferase with a conserved DxD motif. The PB1 domain adopts a beta-grasp fold, similar to that found in ubiquitin and Ras-binding domains. A motif, variously termed OPR, PC and AID, represents the most conserved region of the majority of PB1 domains, and is necessary for PB1 domain function. This function is the formation of PB1 domain heterodimers, although not all PB1 domain pairs associate. CBS is a small domain originally identified in cystathionine beta-synthase and subsequently found in a wide range of different proteins. CBS domains usually come in tandem repeats, which associate to form a so-called Bateman domain or a CBS pair which is reflected in this model. The interface between the two CBS domains forms a cleft that is a potential ligand binding site. The CBS pair coexists with a variety of other functional domains. It has been proposed that the CBS domain may play a regulatory role, although its exact function is unknown.бА0АкА0АаАCDDбАаАйXвА0А0АаАВЩcd04588, CBS_pair_CAP-ED_DUF294_assoc_arch, This cd contains two tandem repeats of the cystathionine beta-synthase (CBS pair) domains associated with the archaeal CAP_ED (cAMP receptor protein effector domain) family of transcription factors and the DUF294 domain. Members of CAP_ED, include CAP which binds cAMP, FNR (fumarate and nitrate reductase) which uses an iron-sulfur cluster to sense oxygen, and CooA a heme containing CO sensor. In all cases binding of the effector leads to conformational changes and the ability to activate transcription. DUF294 is a putative nucleotidyltransferase with a conserved DxD motif. CBS is a small domain originally identified in cystathionine beta-synthase and subsequently found in a wide range of different proteins. CBS domains usually come in tandem repeats, which associate to form a so-called Bateman domain or a CBS pair which is reflected in this model. The interface between the two CBS domains forms a cleft that is a potential ligand binding site. The CBS pair coexists with a variety of other functional domains. It has been proposed that the CBS domain may play a regulatory role, although its exact function is unknown.бА0АкА0АаАCDDбАаАйYвА0А0АаАВ(cd04589, CBS_pair_CAP-ED_DUF294_assoc_bac, This cd contains two tandem repeats of the cystathionine beta-synthase (CBS pair) domains associated with the bacterial CAP_ED (cAMP receptor protein effector domain) family of transcription factors and the DUF294 domain. Members of CAP_ED, include CAP which binds cAMP, FNR (fumarate and nitrate reductase) which uses an iron-sulfur cluster to sense oxygen, and CooA a heme containing CO sensor. In all cases binding of the effector leads to conformational changes and the ability to activate transcription. DUF294 is a putative nucleotidyltransferase with a conserved DxD motif. CBS is a small domain originally identified in cystathionine beta-synthase and subsequently found in a wide range of different proteins. CBS domains usually come in tandem repeats, which associate to form a so-called Bateman domain or a CBS pair which is reflected in this model. CBS domains usually come in tandem repeats, which associate to form a so-called Bateman domain or a CBS pair which is reflected in this model. The interface between the two CBS domains forms a cleft that is a potential ligand binding site. The CBS pair coexists with a variety of other functional domains. It has been proposed that the CBS domain may play a regulatory role, although its exact function is unknown.бА0АкА0АаАCDDбАаАйZвА0А0АаАВBcd04590, CBS_pair_CorC_HlyC_assoc, This cd contains two tandem repeats of the cystathionine beta-synthase (CBS pair) domains associated with the CorC_HlyC domain. CorC_HlyC is a transporter associated domain. This small domain is found in Na+/H+ antiporters, in proteins involved in magnesium and cobalt efflux, and in association with some proteins of unknown function. The function of the CorC_HlyC domain is uncertain but it might be involved in modulating transport of ion substrates. CBS is a small domain originally identified in cystathionine beta-synthase and subsequently found in a wide range of different proteins. CBS domains usually come in tandem repeats, which associate to form a so-called Bateman domain or a CBS pair which is reflected in this model. The interface between the two CBS domains forms a cleft that is a potential ligand binding site. The CBS pair coexists with a variety of other functional domains. It has been proposed that the CBS domain may play a regulatory role, although its exact function is unknown. The second CBS domain in this CD is degenerate.бА0АкА0АаАCDDбАаАй[вА0А0АаАВacd04591, CBS_pair_EriC_assoc_euk_bac, This cd contains two tandem repeats of the cystathionine beta-synthase (CBS pair) domains in the EriC CIC-type chloride channels in eukaryotes and bacteria. These ion channels are proteins with a seemingly simple task of allowing the passive flow of chloride ions across biological membranes. CIC-type chloride channels come from all kingdoms of life, have several gene families, and can be gated by voltage. The members of the CIC-type chloride channel are double-barreled: two proteins forming homodimers at a broad interface formed by four helices from each protein. The two pores are not found at this interface, but are completely contained within each subunit, as deduced from the mutational analyses, unlike many other channels, in which four or five identical or structurally related subunits jointly form one pore. CBS is a small domain originally identified in cystathionine beta-synthase and subsequently found in a wide range of different proteins. CBS domains usually come in tandem repeats, which associate to form a so-called Bateman domain or a CBS pair which is reflected in this model. The interface between the two CBS domains forms a cleft that is a potential ligand binding site. The CBS pair coexists with a variety of other functional domains. It has been proposed that the CBS domain may play a regulatory role, although its exact function is unknown. Mutations of conserved residues within this domain in CLC chloride channel family members have been associated with classic Bartter syndrome, Osteopetrosis, Dent's disease, idiopathic generalized epilepsy, and myotonia.бА0АкА0АаАCDDбАаАй\вА0А0АаАВPcd04592, CBS_pair_EriC_assoc_euk, This cd contains two tandem repeats of the cystathionine beta-synthase (CBS pair) domains in the EriC CIC-type chloride channels in eukaryotes. These ion channels are proteins with a seemingly simple task of allowing the passive flow of chloride ions across biological membranes. CIC-type chloride channels come from all kingdoms of life, have several gene families, and can be gated by voltage. The members of the CIC-type chloride channel are double-barreled: two proteins forming homodimers at a broad interface formed by four helices from each protein. The two pores are not found at this interface, but are completely contained within each subunit, as deduced from the mutational analyses, unlike many other channels, in which four or five identical or structurally related subunits jointly form one pore. CBS is a small domain originally identified in cystathionine beta-synthase and subsequently found in a wide range of different proteins. CBS domains usually come in tandem repeats, which associate to form a so-called Bateman domain or a CBS pair which is reflected in this model. The interface between the two CBS domains forms a cleft that is a potential ligand binding site. The CBS pair coexists with a variety of other functional domains. It has been proposed that the CBS domain may play a regulatory role, although its exact function is unknown. Mutations of conserved residues within this domain in CLC chloride channel family members have been associated with classic Bartter syndrome, Osteopetrosis, Dent's disease, idiopathic generalized epilepsy, and myotonia.бА0АкА0АаАCDDбАаАй]вА0А0АаАВ_cd04593, CBS_pair_EriC_assoc_bac_arch, This cd contains two tandem repeats of the cystathionine beta-synthase (CBS pair) domains in the EriC CIC-type chloride channels in bacteria and archaea. These ion channels are proteins with a seemingly simple task of allowing the passive flow of chloride ions across biological membranes. CIC-type chloride channels come from all kingdoms of life, have several gene families, and can be gated by voltage. The members of the CIC-type chloride channel are double-barreled: two proteins forming homodimers at a broad interface formed by four helices from each protein. The two pores are not found at this interface, but are completely contained within each subunit, as deduced from the mutational analyses, unlike many other channels, in which four or five identical or structurally related subunits jointly form one pore. CBS is a small domain originally identified in cystathionine beta-synthase and subsequently found in a wide range of different proteins. CBS domains usually come in tandem repeats, which associate to form a so-called Bateman domain or a CBS pair which is reflected in this model. The interface between the two CBS domains forms a cleft that is a potential ligand binding site. The CBS pair coexists with a variety of other functional domains. It has been proposed that the CBS domain may play a regulatory role, although its exact function is unknown. Mutations of conserved residues within this domain in CLC chloride channel family members have been associated with classic Bartter syndrome, Osteopetrosis, Dent's disease, idiopathic generalized epilepsy, and myotonia.бА0АкА0АаАCDDбАаАй^вА0А0АаАВ_cd04594, CBS_pair_EriC_assoc_archaea, This cd contains two tandem repeats of the cystathionine beta-synthase (CBS pair) domains associated with the EriC CIC-type chloride channels in archaea. These ion channels are proteins with a seemingly simple task of allowing the passive flow of chloride ions across biological membranes. CIC-type chloride channels come from all kingdoms of life, have several gene families, and can be gated by voltage. The members of the CIC-type chloride channel are double-barreled: two proteins forming homodimers at a broad interface formed by four helices from each protein. The two pores are not found at this interface, but are completely contained within each subunit, as deduced from the mutational analyses, unlike many other channels, in which four or five identical or structurally related subunits jointly form one pore. CBS is a small domain originally identified in cystathionine beta-synthase and subsequently found in a wide range of different proteins. CBS domains usually come in tandem repeats, which associate to form a so-called Bateman domain or a CBS pair which is reflected in this model. The interface between the two CBS domains forms a cleft that is a potential ligand binding site. The CBS pair coexists with a variety of other functional domains. It has been proposed that the CBS domain may play a regulatory role, although its exact function is unknown. Mutations of conserved residues within this domain in CLC chloride channel family members have been associated with classic Bartter syndrome, Osteopetrosis, Dent's disease, idiopathic generalized epilepsy, and myotonia.бА0АкА0АаАCDDбАаАй_вА0А0АаАВ#cd04595, CBS_pair_DHH_polyA_Pol_assoc, This cd contains two tandem repeats of the cystathionine beta-synthase (CBS pair) domains associated with an upstream DHH domain which performs a phosphoesterase function and a downstream polyA polymerase domain. CBS is a small domain originally identified in cystathionine beta-synthase and subsequently found in a wide range of different proteins. CBS domains usually come in tandem repeats, which associate to form a so-called Bateman domain or a CBS pair which is reflected in this model. The interface between the two CBS domains forms a cleft that is a potential ligand binding site. The CBS pair coexists with a variety of other functional domains. It has been proposed that the CBS domain may play a regulatory role, although its exact function is unknown.бА0АкА0АаАCDDбАаАй`вА0А0АаАВcd04596, CBS_pair_DRTGG_assoc, This cd contains two tandem repeats of the cystathionine beta-synthase (CBS pair) domains associated with a DRTGG domain upstream. The function of the DRTGG domain, named after its conserved residues, is unknown. CBS is a small domain originally identified in cystathionine beta-synthase and subsequently found in a wide range of different proteins. CBS domains usually come in tandem repeats, which associate to form a so-called Bateman domain or a CBS pair which is reflected in this model. The interface between the two CBS domains forms a cleft that is a potential ligand binding site. The CBS pair coexists with a variety of other functional domains. It has been proposed that the CBS domain may play a regulatory role, although its exact function is unknown.бА0АкА0АаАCDDбАаАйaвА0А0АаАВcd04597, CBS_pair_DRTGG_assoc2, This cd contains two tandem repeats of the cystathionine beta-synthase (CBS pair) domains associated with a DRTGG domain upstream. The function of the DRTGG domain, named after its conserved residues, is unknown. CBS is a small domain originally identified in cystathionine beta-synthase and subsequently found in a wide range of different proteins. CBS domains usually come in tandem repeats, which associate to form a so-called Bateman domain or a CBS pair which is reflected in this model. The interface between the two CBS domains forms a cleft that is a potential ligand binding site. The CBS pair coexists with a variety of other functional domains. It has been proposed that the CBS domain may play a regulatory role, although its exact function is unknown.бА0АкА0АаАCDDбАаАйbвА0А0АаАВУcd04598, CBS_pair_GGDEF_assoc, This cd contains two tandem repeats of the cystathionine beta-synthase (CBS pair) domains in association with the GGDEF (DiGuanylate-Cyclase (DGC)) domain. The GGDEF domain has been suggested to be homologous to the adenylyl cyclase catalytic domain and is thought to be involved in regulating cell surface adhesiveness in bacteria. CBS is a small domain originally identified in cystathionine beta-synthase and subsequently found in a wide range of different proteins. CBS domains usually come in tandem repeats, which associate to form a so-called Bateman domain or a CBS pair which is reflected in this model. The interface between the two CBS domains forms a cleft that is a potential ligand binding site. The CBS pair coexists with a variety of other functional domains. It has been proposed that the CBS domain may play a regulatory role, although its exact function is unknown.бА0АкА0АаАCDDбАаАйcвА0А0АаАВФcd04599, CBS_pair_GGDEF_assoc2, This cd contains two tandem repeats of the cystathionine beta-synthase (CBS pair) domains in association with the GGDEF (DiGuanylate-Cyclase (DGC)) domain. The GGDEF domain has been suggested to be homologous to the adenylyl cyclase catalytic domain and is thought to be involved in regulating cell surface adhesiveness in bacteria. CBS is a small domain originally identified in cystathionine beta-synthase and subsequently found in a wide range of different proteins. CBS domains usually come in tandem repeats, which associate to form a so-called Bateman domain or a CBS pair which is reflected in this model. The interface between the two CBS domains forms a cleft that is a potential ligand binding site. The CBS pair coexists with a variety of other functional domains. It has been proposed that the CBS domain may play a regulatory role, although its exact function is unknown.бА0АкА0АаАCDDбАаАйdвА0А0АаАВscd04600, CBS_pair_HPP_assoc, This cd contains two tandem repeats of the cystathionine beta-synthase (CBS pair) domains associated with the HPP motif domain. These proteins are integral membrane proteins with four transmembrane spanning helices. The function of these proteins is uncertain, but they are thought to be transporters. CBS is a small domain originally identified in cystathionine beta-synthase and subsequently found in a wide range of different proteins. CBS domains usually come in tandem repeats, which associate to form a so-called Bateman domain or a CBS pair which is reflected in this model. The interface between the two CBS domains forms a cleft that is a potential ligand binding site. The CBS pair coexists with a variety of other functional domains. It has been proposed that the CBS domain may play a regulatory role, although its exact function is unknown.бА0АкА0АаАCDDбАаАйeвА0А0АаАВъcd04601, CBS_pair_IMPDH, This cd contains two tandem repeats of the cystathionine beta-synthase (CBS pair) domains in the inosine 5' monophosphate dehydrogenase (IMPDH) protein. IMPDH is an essential enzyme that catalyzes the first step unique to GTP synthesis, playing a key role in the regulation of cell proliferation and differentiation. CBS is a small domain originally identified in cystathionine beta-synthase and subsequently found in a wide range of different proteins. CBS domains usually come in tandem repeats, which associate to form a so-called Bateman domain or a CBS pair which is reflected in this model. The interface between the two CBS domains forms a cleft that is a potential ligand binding site. The CBS pair coexists with a variety of other functional domains. It has been proposed that the CBS domain may play a regulatory role, although its exact function is unknown. Mutations of conserved residues within this domain in IMPDH have been associated with retinitis pigmentosa.бА0АкА0АаАCDDбАаАйfвА0А0АаАВьcd04602, CBS_pair_IMPDH_2, This cd contains two tandem repeats of the cystathionine beta-synthase (CBS pair) domains in the inosine 5' monophosphate dehydrogenase (IMPDH) protein. IMPDH is an essential enzyme that catalyzes the first step unique to GTP synthesis, playing a key role in the regulation of cell proliferation and differentiation. CBS is a small domain originally identified in cystathionine beta-synthase and subsequently found in a wide range of different proteins. CBS domains usually come in tandem repeats, which associate to form a so-called Bateman domain or a CBS pair which is reflected in this model. The interface between the two CBS domains forms a cleft that is a potential ligand binding site. The CBS pair coexists with a variety of other functional domains. It has been proposed that the CBS domain may play a regulatory role, although its exact function is unknown. Mutations of conserved residues within this domain in IMPDH have been associated with retinitis pigmentosa.бА0АкА0АаАCDDбАаАйgвА0А0АаАВcd04603, CBS_pair_KefB_assoc, This cd contains two tandem repeats of the cystathionine beta-synthase (CBS pair) domains associated with the KefB (Kef-type K+ transport systems) domain which is involved in inorganic ion transport and metabolism. CBS is a small domain originally identified in cystathionine beta-synthase and subsequently found in a wide range of different proteins. CBS domains usually come in tandem repeats, which associate to form a so-called Bateman domain or a CBS pair which is reflected in this model. The interface between the two CBS domains forms a cleft that is a potential ligand binding site. The CBS pair coexists with a variety of other functional domains. It has been proposed that the CBS domain may play a regulatory role, although its exact function is unknown.бА0АкА0АаАCDDбАаАйhвА0А0АаАВecd04604, CBS_pair_KpsF_GutQ_assoc, This cd contains two tandem repeats of the cystathionine beta-synthase (CBS pair) domains associated with KpsF/GutQ domains in the API [A5P (D-arabinose 5-phosphate) isomerase] protein. These APIs catalyze the conversion of the pentose pathway intermediate D-ribulose 5-phosphate into A5P, a precursor of 3-deoxy-D-manno-octulosonate, which is an integral carbohydrate component of various glycolipids coating the surface of the outer membrane of Gram-negative bacteria, including lipopolysaccharide and many group 2 K-antigen capsules. CBS is a small domain originally identified in cystathionine beta-synthase and subsequently found in a wide range of different proteins. CBS domains usually come in tandem repeats, which associate to form a so-called Bateman domain or a CBS pair which is reflected in this model. The interface between the two CBS domains forms a cleft that is a potential ligand binding site. The CBS pair coexists with a variety of other functional domains. It has been proposed that the CBS domain may play a regulatory role, although its exact function is unknown.бА0АкА0АаАCDDбАаАйiвА0А0АаАВZcd04605, CBS_pair_MET2_assoc, This cd contains two tandem repeats of the cystathionine beta-synthase (CBS pair) domains associated with the MET2 domain. Met2 is a key enzyme in the biosynthesis of methionine. It encodes a homoserine transacetylase involved in converting homoserine to O-acetyl homoserine. CBS is a small domain originally identified in cystathionine beta-synthase and subsequently found in a wide range of different proteins. CBS domains usually come in tandem repeats, which associate to form a so-called Bateman domain or a CBS pair which is reflected in this model. The interface between the two CBS domains forms a cleft that is a potential ligand binding site. The CBS pair coexists with a variety of other functional domains. It has been proposed that the CBS domain may play a regulatory role, although its exact function is unknown.бА0АкА0АаАCDDбАаАйjвА0А0АаАВИcd04606, CBS_pair_Mg_transporter, This cd contains two tandem repeats of the cystathionine beta-synthase (CBS pair) domain in the magnesium transporter, MgtE. MgtE and its homologs are found in eubacteria, archaebacteria, and eukaryota. Members of this family transport Mg2+ or other divalent cations into the cell via two highly conserved aspartates. CBS is a small domain originally identified in cystathionine beta-synthase and subsequently found in a wide range of different proteins. CBS domains usually come in tandem repeats, which associate to form a so-called Bateman domain or a CBS pair which is reflected in this model. The interface between the two CBS domains forms a cleft that is a potential ligand binding site. The CBS pair coexists with a variety of other functional domains. It has been proposed that the CBS domain may play a regulatory role, although its exact function is unknown.бА0АкА0АаАCDDбАаАйkвА0А0АаАВЁcd04607, CBS_pair_NTP_transferase_assoc, This cd contains two tandem repeats of the cystathionine beta-synthase (CBS pair) domain associated with the NTP (Nucleotidyl transferase) domain downstream. CBS is a small domain originally identified in cystathionine beta-synthase and subsequently found in a wide range of different proteins. CBS domains usually come in tandem repeats, which associate to form a so-called Bateman domain or a CBS pair which is reflected in this model. The interface between the two CBS domains forms a cleft that is a potential ligand binding site. The CBS pair coexists with a variety of other functional domains. It has been proposed that the CBS domain may play a regulatory role, although its exact function is unknown.бА0АкА0АаАCDDбАаАйlвА0А0АаАВ│cd04608, CBS_pair_PALP_assoc, This cd contains two tandem repeats of the cystathionine beta-synthase (CBS pair) domains associated with the pyridoxal-phosphate (PALP) dependent enzyme domain upstream. The vitamin B6 complex comprises pyridoxine, pyridoxal, and pyridoxamine, as well as the 5'-phosphate esters of pyridoxal (PALP) and pyridoxamine, the last two being the biologically active coenzyme derivatives. The members of the PALP family are principally involved in the biosynthesis of amino acids and amino acid-derived metabolites, but they are also found in the biosynthetic pathways of amino sugars and other amine-containing compounds. CBS is a small domain originally identified in cystathionine beta-synthase and subsequently found in a wide range of different proteins. CBS domains usually come in tandem repeats, which associate to form a so-called Bateman domain or a CBS pair which is reflected in this model. The interface between the two CBS domains forms a cleft that is a potential ligand binding site. The CBS pair coexists with a variety of other functional domains. It has been proposed that the CBS domain may play a regulatory role, although its exact function is unknown.бА0АкА0АаАCDDбАаАйmвА0А0АаАВ┤cd04609, CBS_pair_PALP_assoc2, This cd contains two tandem repeats of the cystathionine beta-synthase (CBS pair) domains associated with the pyridoxal-phosphate (PALP) dependent enzyme domain upstream. The vitamin B6 complex comprises pyridoxine, pyridoxal, and pyridoxamine, as well as the 5'-phosphate esters of pyridoxal (PALP) and pyridoxamine, the last two being the biologically active coenzyme derivatives. The members of the PALP family are principally involved in the biosynthesis of amino acids and amino acid-derived metabolites, but they are also found in the biosynthetic pathways of amino sugars and other amine-containing compounds. CBS is a small domain originally identified in cystathionine beta-synthase and subsequently found in a wide range of different proteins. CBS domains usually come in tandem repeats, which associate to form a so-called Bateman domain or a CBS pair which is reflected in this model. The interface between the two CBS domains forms a cleft that is a potential ligand binding site. The CBS pair coexists with a variety of other functional domains. It has been proposed that the CBS domain may play a regulatory role, although its exact function is unknown.бА0АкА0АаАCDDбАаАйnвА0А0АаАВсcd04610, CBS_pair_ParBc_assoc, This cd contains two tandem repeats of the cystathionine beta-synthase (CBS pair) domains associated with a ParBc (ParB-like nuclease) domain downstream. CBS is a small domain originally identified in cystathionine beta-synthase and subsequently found in a wide range of different proteins. CBS domains usually come in tandem repeats, which associate to form a so-called Bateman domain or a CBS pair which is reflected in this model. The interface between the two CBS domains forms a cleft that is a potential ligand binding site. The CBS pair coexists with a variety of other functional domains. It has been proposed that the CBS domain may play a regulatory role, although its exact function is unknown.бА0АкА0АаАCDDбАаАйoвА0А0АаАВ6cd04611, CBS_pair_PAS_GGDEF_DUF1_assoc, This cd contains two tandem repeats of the cystathionine beta-synthase (CBS pair) domains in association with a PAS domain, a GGDEF (DiGuanylate-Cyclase (DGC) domain, and a DUF1 domain downstream. PAS domains have been found to bind ligands, and to act as sensors for light and oxygen in signal transduction. The GGDEF domain has been suggested to be homologous to the adenylyl cyclase catalytic domain and is thought to be involved in regulating cell surface adhesiveness in bacteria. CBS is a small domain originally identified in cystathionine beta-synthase and subsequently found in a wide range of different proteins. CBS domains usually come in tandem repeats, which associate to form a so-called Bateman domain or a CBS pair which is reflected in this model. The interface between the two CBS domains forms a cleft that is a potential ligand binding site. The CBS pair coexists with a variety of other functional domains. It has been proposed that the CBS domain may play a regulatory role, although its exact function is unknown.бА0АкА0АаАCDDбАаАйpвА0А0АаАВ┼cd04612, CBS_pair_SpoIVFB_EriC_assoc, This cd contains two tandem repeats of the cystathionine beta-synthase (CBS pair) domains in association with either the SpoIVFB domain (sporulation protein, stage IV cell wall formation, F locus, promoter-distal B) or the chloride channel protein EriC. SpoIVFB is one of 4 proteins involved in endospore formation; the others are SpoIVFA (sporulation protein, stage IV cell wall formation, F locus, promoter-proximal A), BofA (bypass-of-forespore A ), and SpoIVB (sporulation protein, stage IV cell wall formation, B locus). SpoIVFB is negatively regulated by SpoIVFA and BofA and activated by SpoIVB. It is thought that SpoIVFB, SpoIVFA, and BofA are located in the mother-cell membrane that surrounds the forespore and that SpoIVB is secreted from the forespore into the space between the two where it activates SpoIVFB. EriC is involved in inorganic ion transport and metabolism. CBS is a small domain originally identified in cystathionine beta-synthase and subsequently found in a wide range of different proteins. CBS domains usually come in tandem repeats, which associate to form a so-called Bateman domain or a CBS pair which is reflected in this model. The interface between the two CBS domains forms a cleft that is a potential ligand binding site. The CBS pair coexists with a variety of other functional domains. It has been proposed that the CBS domain may play a regulatory role, although its exact function is unknown.бА0АкА0АаАCDDбАаАйqвА0А0АаАВ╞cd04613, CBS_pair_SpoIVFB_EriC_assoc2, This cd contains two tandem repeats of the cystathionine beta-synthase (CBS pair) domains in association with either the SpoIVFB domain (sporulation protein, stage IV cell wall formation, F locus, promoter-distal B) or the chloride channel protein EriC. SpoIVFB is one of 4 proteins involved in endospore formation; the others are SpoIVFA (sporulation protein, stage IV cell wall formation, F locus, promoter-proximal A), BofA (bypass-of-forespore A ), and SpoIVB (sporulation protein, stage IV cell wall formation, B locus). SpoIVFB is negatively regulated by SpoIVFA and BofA and activated by SpoIVB. It is thought that SpoIVFB, SpoIVFA, and BofA are located in the mother-cell membrane that surrounds the forespore and that SpoIVB is secreted from the forespore into the space between the two where it activates SpoIVFB. EriC is involved in inorganic ion transport and metabolism. CBS is a small domain originally identified in cystathionine beta-synthase and subsequently found in a wide range of different proteins. CBS domains usually come in tandem repeats, which associate to form a so-called Bateman domain or a CBS pair which is reflected in this model. The interface between the two CBS domains forms a cleft that is a potential ligand binding site. The CBS pair coexists with a variety of other functional domains. It has been proposed that the CBS domain may play a regulatory role, although its exact function is unknown.бА0АкА0АаАCDDбАаАйrвА0А0АаАВ cd04614, CBS_pair_1, The CBS domain, named after human CBS, is a small domain originally identified in cystathionine beta-synthase and is subsequently found in a wide range of different proteins. CBS domains usually occur in tandem repeats. They associate to form a so-called Bateman domain or a CBS pair based on crystallographic studies in bacteria. The CBS pair was used as a basis for this cd hierarchy since the human CBS proteins can adopt the typical core structure and form an intramolecular CBS pair. The interface between the two CBS domains forms a cleft that is a potential ligand binding site. The CBS pair coexists with a variety of other functional domains and this has been used to help in its classification here. It has been proposed that the CBS domain may play a regulatory role, although its exact function is unknown. Mutations of conserved residues within this domain are associated with a variety of human hereditary diseases, including congenital myotonia, idiopathic generalized epilepsy, hypercalciuric nephrolithiasis, and classic Bartter syndrome (CLC chloride channel family members), Wolff-Parkinson-White syndrome (gamma 2 subunit of AMP-activated protein kinase), retinitis pigmentosa (IMP dehydrogenase-1), and homocystinuria (cystathionine beta-synthase).бА0АкА0АаАCDDбАаАйsвА0А0АаАВ cd04615, CBS_pair_2, The CBS domain, named after human CBS, is a small domain originally identified in cystathionine beta-synthase and is subsequently found in a wide range of different proteins. CBS domains usually occur in tandem repeats. They associate to form a so-called Bateman domain or a CBS pair based on crystallographic studies in bacteria. The CBS pair was used as a basis for this cd hierarchy since the human CBS proteins can adopt the typical core structure and form an intramolecular CBS pair. The interface between the two CBS domains forms a cleft that is a potential ligand binding site. The CBS pair coexists with a variety of other functional domains and this has been used to help in its classification here. It has been proposed that the CBS domain may play a regulatory role, although its exact function is unknown. Mutations of conserved residues within this domain are associated with a variety of human hereditary diseases, including congenital myotonia, idiopathic generalized epilepsy, hypercalciuric nephrolithiasis, and classic Bartter syndrome (CLC chloride channel family members), Wolff-Parkinson-White syndrome (gamma 2 subunit of AMP-activated protein kinase), retinitis pigmentosa (IMP dehydrogenase-1), and homocystinuria (cystathionine beta-synthase).бА0АкА0АаАCDDбАаАйtвА0А0АаАВ cd04617, CBS_pair_4, The CBS domain, named after human CBS, is a small domain originally identified in cystathionine beta-synthase and is subsequently found in a wide range of different proteins. CBS domains usually occur in tandem repeats. They associate to form a so-called Bateman domain or a CBS pair based on crystallographic studies in bacteria. The CBS pair was used as a basis for this cd hierarchy since the human CBS proteins can adopt the typical core structure and form an intramolecular CBS pair. The interface between the two CBS domains forms a cleft that is a potential ligand binding site. The CBS pair coexists with a variety of other functional domains and this has been used to help in its classification here. It has been proposed that the CBS domain may play a regulatory role, although its exact function is unknown. Mutations of conserved residues within this domain are associated with a variety of human hereditary diseases, including congenital myotonia, idiopathic generalized epilepsy, hypercalciuric nephrolithiasis, and classic Bartter syndrome (CLC chloride channel family members), Wolff-Parkinson-White syndrome (gamma 2 subunit of AMP-activated protein kinase), retinitis pigmentosa (IMP dehydrogenase-1), and homocystinuria (cystathionine beta-synthase).бА0АкА0АаАCDDбАаАйuвА0А0АаАВ cd04618, CBS_pair_5, The CBS domain, named after human CBS, is a small domain originally identified in cystathionine beta-synthase and is subsequently found in a wide range of different proteins. CBS domains usually occur in tandem repeats. They associate to form a so-called Bateman domain or a CBS pair based on crystallographic studies in bacteria. The CBS pair was used as a basis for this cd hierarchy since the human CBS proteins can adopt the typical core structure and form an intramolecular CBS pair. The interface between the two CBS domains forms a cleft that is a potential ligand binding site. The CBS pair coexists with a variety of other functional domains and this has been used to help in its classification here. It has been proposed that the CBS domain may play a regulatory role, although its exact function is unknown. Mutations of conserved residues within this domain are associated with a variety of human hereditary diseases, including congenital myotonia, idiopathic generalized epilepsy, hypercalciuric nephrolithiasis, and classic Bartter syndrome (CLC chloride channel family members), Wolff-Parkinson-White syndrome (gamma 2 subunit of AMP-activated protein kinase), retinitis pigmentosa (IMP dehydrogenase-1), and homocystinuria (cystathionine beta-synthase).бА0АкА0АаАCDDбАаАйvвА0А0АаАВ cd04619, CBS_pair_6, The CBS domain, named after human CBS, is a small domain originally identified in cystathionine beta-synthase and is subsequently found in a wide range of different proteins. CBS domains usually occur in tandem repeats. They associate to form a so-called Bateman domain or a CBS pair based on crystallographic studies in bacteria. The CBS pair was used as a basis for this cd hierarchy since the human CBS proteins can adopt the typical core structure and form an intramolecular CBS pair. The interface between the two CBS domains forms a cleft that is a potential ligand binding site. The CBS pair coexists with a variety of other functional domains and this has been used to help in its classification here. It has been proposed that the CBS domain may play a regulatory role, although its exact function is unknown. Mutations of conserved residues within this domain are associated with a variety of human hereditary diseases, including congenital myotonia, idiopathic generalized epilepsy, hypercalciuric nephrolithiasis, and classic Bartter syndrome (CLC chloride channel family members), Wolff-Parkinson-White syndrome (gamma 2 subunit of AMP-activated protein kinase), retinitis pigmentosa (IMP dehydrogenase-1), and homocystinuria (cystathionine beta-synthase).бА0АкА0АаАCDDбАаАйwвА0А0АаАВ cd04620, CBS_pair_7, The CBS domain, named after human CBS, is a small domain originally identified in cystathionine beta-synthase and is subsequently found in a wide range of different proteins. CBS domains usually occur in tandem repeats. They associate to form a so-called Bateman domain or a CBS pair based on crystallographic studies in bacteria. The CBS pair was used as a basis for this cd hierarchy since the human CBS proteins can adopt the typical core structure and form an intramolecular CBS pair. The interface between the two CBS domains forms a cleft that is a potential ligand binding site. The CBS pair coexists with a variety of other functional domains and this has been used to help in its classification here. It has been proposed that the CBS domain may play a regulatory role, although its exact function is unknown. Mutations of conserved residues within this domain are associated with a variety of human hereditary diseases, including congenital myotonia, idiopathic generalized epilepsy, hypercalciuric nephrolithiasis, and classic Bartter syndrome (CLC chloride channel family members), Wolff-Parkinson-White syndrome (gamma 2 subunit of AMP-activated protein kinase), retinitis pigmentosa (IMP dehydrogenase-1), and homocystinuria (cystathionine beta-synthase).бА0АкА0АаАCDDбАаАйxвА0А0АаАВ cd04621, CBS_pair_8, The CBS domain, named after human CBS, is a small domain originally identified in cystathionine beta-synthase and is subsequently found in a wide range of different proteins. CBS domains usually occur in tandem repeats. They associate to form a so-called Bateman domain or a CBS pair based on crystallographic studies in bacteria. The CBS pair was used as a basis for this cd hierarchy since the human CBS proteins can adopt the typical core structure and form an intramolecular CBS pair. The interface between the two CBS domains forms a cleft that is a potential ligand binding site. The CBS pair coexists with a variety of other functional domains and this has been used to help in its classification here. It has been proposed that the CBS domain may play a regulatory role, although its exact function is unknown. Mutations of conserved residues within this domain are associated with a variety of human hereditary diseases, including congenital myotonia, idiopathic generalized epilepsy, hypercalciuric nephrolithiasis, and classic Bartter syndrome (CLC chloride channel family members), Wolff-Parkinson-White syndrome (gamma 2 subunit of AMP-activated protein kinase), retinitis pigmentosa (IMP dehydrogenase-1), and homocystinuria (cystathionine beta-synthase).бА0АкА0АаАCDDбАаАйyвА0А0АаАВ cd04622, CBS_pair_9, The CBS domain, named after human CBS, is a small domain originally identified in cystathionine beta-synthase and is subsequently found in a wide range of different proteins. CBS domains usually occur in tandem repeats. They associate to form a so-called Bateman domain or a CBS pair based on crystallographic studies in bacteria. The CBS pair was used as a basis for this cd hierarchy since the human CBS proteins can adopt the typical core structure and form an intramolecular CBS pair. The interface between the two CBS domains forms a cleft that is a potential ligand binding site. The CBS pair coexists with a variety of other functional domains and this has been used to help in its classification here. It has been proposed that the CBS domain may play a regulatory role, although its exact function is unknown. Mutations of conserved residues within this domain are associated with a variety of human hereditary diseases, including congenital myotonia, idiopathic generalized epilepsy, hypercalciuric nephrolithiasis, and classic Bartter syndrome (CLC chloride channel family members), Wolff-Parkinson-White syndrome (gamma 2 subunit of AMP-activated protein kinase), retinitis pigmentosa (IMP dehydrogenase-1), and homocystinuria (cystathionine beta-synthase).бА0АкА0АаАCDDбАаАйzвА0А0АаАВcd04623, CBS_pair_10, The CBS domain, named after human CBS, is a small domain originally identified in cystathionine beta-synthase and is subsequently found in a wide range of different proteins. CBS domains usually occur in tandem repeats. They associate to form a so-called Bateman domain or a CBS pair based on crystallographic studies in bacteria. The CBS pair was used as a basis for this cd hierarchy since the human CBS proteins can adopt the typical core structure and form an intramolecular CBS pair. The interface between the two CBS domains forms a cleft that is a potential ligand binding site. The CBS pair coexists with a variety of other functional domains and this has been used to help in its classification here. It has been proposed that the CBS domain may play a regulatory role, although its exact function is unknown. Mutations of conserved residues within this domain are associated with a variety of human hereditary diseases, including congenital myotonia, idiopathic generalized epilepsy, hypercalciuric nephrolithiasis, and classic Bartter syndrome (CLC chloride channel family members), Wolff-Parkinson-White syndrome (gamma 2 subunit of AMP-activated protein kinase), retinitis pigmentosa (IMP dehydrogenase-1), and homocystinuria (cystathionine beta-synthase).бА0АкА0АаАCDDбАаАй{вА0А0АаАВcd04624, CBS_pair_11, The CBS domain, named after human CBS, is a small domain originally identified in cystathionine beta-synthase and is subsequently found in a wide range of different proteins. CBS domains usually occur in tandem repeats. They associate to form a so-called Bateman domain or a CBS pair based on crystallographic studies in bacteria. The CBS pair was used as a basis for this cd hierarchy since the human CBS proteins can adopt the typical core structure and form an intramolecular CBS pair. The interface between the two CBS domains forms a cleft that is a potential ligand binding site. The CBS pair coexists with a variety of other functional domains and this has been used to help in its classification here. It has been proposed that the CBS domain may play a regulatory role, although its exact function is unknown. Mutations of conserved residues within this domain are associated with a variety of human hereditary diseases, including congenital myotonia, idiopathic generalized epilepsy, hypercalciuric nephrolithiasis, and classic Bartter syndrome (CLC chloride channel family members), Wolff-Parkinson-White syndrome (gamma 2 subunit of AMP-activated protein kinase), retinitis pigmentosa (IMP dehydrogenase-1), and homocystinuria (cystathionine beta-synthase).бА0АкА0АаАCDDбАаАй|вА0А0АаАВcd04625, CBS_pair_12, The CBS domain, named after human CBS, is a small domain originally identified in cystathionine beta-synthase and is subsequently found in a wide range of different proteins. CBS domains usually occur in tandem repeats. They associate to form a so-called Bateman domain or a CBS pair based on crystallographic studies in bacteria. The CBS pair was used as a basis for this cd hierarchy since the human CBS proteins can adopt the typical core structure and form an intramolecular CBS pair. The interface between the two CBS domains forms a cleft that is a potential ligand binding site. The CBS pair coexists with a variety of other functional domains and this has been used to help in its classification here. It has been proposed that the CBS domain may play a regulatory role, although its exact function is unknown. Mutations of conserved residues within this domain are associated with a variety of human hereditary diseases, including congenital myotonia, idiopathic generalized epilepsy, hypercalciuric nephrolithiasis, and classic Bartter syndrome (CLC chloride channel family members), Wolff-Parkinson-White syndrome (gamma 2 subunit of AMP-activated protein kinase), retinitis pigmentosa (IMP dehydrogenase-1), and homocystinuria (cystathionine beta-synthase).бА0АкА0АаАCDDбАаАй}вА0А0АаАВcd04626, CBS_pair_13, The CBS domain, named after human CBS, is a small domain originally identified in cystathionine beta-synthase and is subsequently found in a wide range of different proteins. CBS domains usually occur in tandem repeats. They associate to form a so-called Bateman domain or a CBS pair based on crystallographic studies in bacteria. The CBS pair was used as a basis for this cd hierarchy since the human CBS proteins can adopt the typical core structure and form an intramolecular CBS pair. The interface between the two CBS domains forms a cleft that is a potential ligand binding site. The CBS pair coexists with a variety of other functional domains and this has been used to help in its classification here. It has been proposed that the CBS domain may play a regulatory role, although its exact function is unknown. Mutations of conserved residues within this domain are associated with a variety of human hereditary diseases, including congenital myotonia, idiopathic generalized epilepsy, hypercalciuric nephrolithiasis, and classic Bartter syndrome (CLC chloride channel family members), Wolff-Parkinson-White syndrome (gamma 2 subunit of AMP-activated protein kinase), retinitis pigmentosa (IMP dehydrogenase-1), and homocystinuria (cystathionine beta-synthase).бА0АкА0АаАCDDбАаАй~вА0А0АаАВcd04627, CBS_pair_14, The CBS domain, named after human CBS, is a small domain originally identified in cystathionine beta-synthase and is subsequently found in a wide range of different proteins. CBS domains usually occur in tandem repeats. They associate to form a so-called Bateman domain or a CBS pair based on crystallographic studies in bacteria. The CBS pair was used as a basis for this cd hierarchy since the human CBS proteins can adopt the typical core structure and form an intramolecular CBS pair. The interface between the two CBS domains forms a cleft that is a potential ligand binding site. The CBS pair coexists with a variety of other functional domains and this has been used to help in its classification here. It has been proposed that the CBS domain may play a regulatory role, although its exact function is unknown. Mutations of conserved residues within this domain are associated with a variety of human hereditary diseases, including congenital myotonia, idiopathic generalized epilepsy, hypercalciuric nephrolithiasis, and classic Bartter syndrome (CLC chloride channel family members), Wolff-Parkinson-White syndrome (gamma 2 subunit of AMP-activated protein kinase), retinitis pigmentosa (IMP dehydrogenase-1), and homocystinuria (cystathionine beta-synthase).бА0АкА0АаАCDDбАаАйвА0А0АаАВcd04629, CBS_pair_16, The CBS domain, named after human CBS, is a small domain originally identified in cystathionine beta-synthase and is subsequently found in a wide range of different proteins. CBS domains usually occur in tandem repeats. They associate to form a so-called Bateman domain or a CBS pair based on crystallographic studies in bacteria. The CBS pair was used as a basis for this cd hierarchy since the human CBS proteins can adopt the typical core structure and form an intramolecular CBS pair. The interface between the two CBS domains forms a cleft that is a potential ligand binding site. The CBS pair coexists with a variety of other functional domains and this has been used to help in its classification here. It has been proposed that the CBS domain may play a regulatory role, although its exact function is unknown. Mutations of conserved residues within this domain are associated with a variety of human hereditary diseases, including congenital myotonia, idiopathic generalized epilepsy, hypercalciuric nephrolithiasis, and classic Bartter syndrome (CLC chloride channel family members), Wolff-Parkinson-White syndrome (gamma 2 subunit of AMP-activated protein kinase), retinitis pigmentosa (IMP dehydrogenase-1), and homocystinuria (cystathionine beta-synthase).бА0АкА0АаАCDDбАаАйАвА0А0АаАВcd04630, CBS_pair_17, The CBS domain, named after human CBS, is a small domain originally identified in cystathionine beta-synthase and is subsequently found in a wide range of different proteins. CBS domains usually occur in tandem repeats. They associate to form a so-called Bateman domain or a CBS pair based on crystallographic studies in bacteria. The CBS pair was used as a basis for this cd hierarchy since the human CBS proteins can adopt the typical core structure and form an intramolecular CBS pair. The interface between the two CBS domains forms a cleft that is a potential ligand binding site. The CBS pair coexists with a variety of other functional domains and this has been used to help in its classification here. It has been proposed that the CBS domain may play a regulatory role, although its exact function is unknown. Mutations of conserved residues within this domain are associated with a variety of human hereditary diseases, including congenital myotonia, idiopathic generalized epilepsy, hypercalciuric nephrolithiasis, and classic Bartter syndrome (CLC chloride channel family members), Wolff-Parkinson-White syndrome (gamma 2 subunit of AMP-activated protein kinase), retinitis pigmentosa (IMP dehydrogenase-1), and homocystinuria (cystathionine beta-synthase).бА0АкА0АаАCDDбАаАйБвА0А0АаАВcd04631, CBS_pair_18, The CBS domain, named after human CBS, is a small domain originally identified in cystathionine beta-synthase and is subsequently found in a wide range of different proteins. CBS domains usually occur in tandem repeats. They associate to form a so-called Bateman domain or a CBS pair based on crystallographic studies in bacteria. The CBS pair was used as a basis for this cd hierarchy since the human CBS proteins can adopt the typical core structure and form an intramolecular CBS pair. The interface between the two CBS domains forms a cleft that is a potential ligand binding site. The CBS pair coexists with a variety of other functional domains and this has been used to help in its classification here. It has been proposed that the CBS domain may play a regulatory role, although its exact function is unknown. Mutations of conserved residues within this domain are associated with a variety of human hereditary diseases, including congenital myotonia, idiopathic generalized epilepsy, hypercalciuric nephrolithiasis, and classic Bartter syndrome (CLC chloride channel family members), Wolff-Parkinson-White syndrome (gamma 2 subunit of AMP-activated protein kinase), retinitis pigmentosa (IMP dehydrogenase-1), and homocystinuria (cystathionine beta-synthase).бА0АкА0АаАCDDбАаАйВвА0А0АаАВcd04632, CBS_pair_19, The CBS domain, named after human CBS, is a small domain originally identified in cystathionine beta-synthase and is subsequently found in a wide range of different proteins. CBS domains usually occur in tandem repeats. They associate to form a so-called Bateman domain or a CBS pair based on crystallographic studies in bacteria. The CBS pair was used as a basis for this cd hierarchy since the human CBS proteins can adopt the typical core structure and form an intramolecular CBS pair. The interface between the two CBS domains forms a cleft that is a potential ligand binding site. The CBS pair coexists with a variety of other functional domains and this has been used to help in its classification here. It has been proposed that the CBS domain may play a regulatory role, although its exact function is unknown. Mutations of conserved residues within this domain are associated with a variety of human hereditary diseases, including congenital myotonia, idiopathic generalized epilepsy, hypercalciuric nephrolithiasis, and classic Bartter syndrome (CLC chloride channel family members), Wolff-Parkinson-White syndrome (gamma 2 subunit of AMP-activated protein kinase), retinitis pigmentosa (IMP dehydrogenase-1), and homocystinuria (cystathionine beta-synthase).бА0АкА0АаАCDDбАаАйГвА0А0АаАВcd04633, CBS_pair_20, The CBS domain, named after human CBS, is a small domain originally identified in cystathionine beta-synthase and is subsequently found in a wide range of different proteins. CBS domains usually occur in tandem repeats. They associate to form a so-called Bateman domain or a CBS pair based on crystallographic studies in bacteria. The CBS pair was used as a basis for this cd hierarchy since the human CBS proteins can adopt the typical core structure and form an intramolecular CBS pair. The interface between the two CBS domains forms a cleft that is a potential ligand binding site. The CBS pair coexists with a variety of other functional domains and this has been used to help in its classification here. It has been proposed that the CBS domain may play a regulatory role, although its exact function is unknown. Mutations of conserved residues within this domain are associated with a variety of human hereditary diseases, including congenital myotonia, idiopathic generalized epilepsy, hypercalciuric nephrolithiasis, and classic Bartter syndrome (CLC chloride channel family members), Wolff-Parkinson-White syndrome (gamma 2 subunit of AMP-activated protein kinase), retinitis pigmentosa (IMP dehydrogenase-1), and homocystinuria (cystathionine beta-synthase).бА0АкА0АаАCDDбАаАйДвА0А0АаАВcd04634, CBS_pair_21, The CBS domain, named after human CBS, is a small domain originally identified in cystathionine beta-synthase and is subsequently found in a wide range of different proteins. CBS domains usually occur in tandem repeats. They associate to form a so-called Bateman domain or a CBS pair based on crystallographic studies in bacteria. The CBS pair was used as a basis for this cd hierarchy since the human CBS proteins can adopt the typical core structure and form an intramolecular CBS pair. The interface between the two CBS domains forms a cleft that is a potential ligand binding site. The CBS pair coexists with a variety of other functional domains and this has been used to help in its classification here. It has been proposed that the CBS domain may play a regulatory role, although its exact function is unknown. Mutations of conserved residues within this domain are associated with a variety of human hereditary diseases, including congenital myotonia, idiopathic generalized epilepsy, hypercalciuric nephrolithiasis, and classic Bartter syndrome (CLC chloride channel family members), Wolff-Parkinson-White syndrome (gamma 2 subunit of AMP-activated protein kinase), retinitis pigmentosa (IMP dehydrogenase-1), and homocystinuria (cystathionine beta-synthase).бА0АкА0АаАCDDбАаАйЕвА0А0АаАВcd04635, CBS_pair_22, The CBS domain, named after human CBS, is a small domain originally identified in cystathionine beta-synthase and is subsequently found in a wide range of different proteins. CBS domains usually occur in tandem repeats. They associate to form a so-called Bateman domain or a CBS pair based on crystallographic studies in bacteria. The CBS pair was used as a basis for this cd hierarchy since the human CBS proteins can adopt the typical core structure and form an intramolecular CBS pair. The interface between the two CBS domains forms a cleft that is a potential ligand binding site. The CBS pair coexists with a variety of other functional domains and this has been used to help in its classification here. It has been proposed that the CBS domain may play a regulatory role, although its exact function is unknown. Mutations of conserved residues within this domain are associated with a variety of human hereditary diseases, including congenital myotonia, idiopathic generalized epilepsy, hypercalciuric nephrolithiasis, and classic Bartter syndrome (CLC chloride channel family members), Wolff-Parkinson-White syndrome (gamma 2 subunit of AMP-activated protein kinase), retinitis pigmentosa (IMP dehydrogenase-1), and homocystinuria (cystathionine beta-synthase).бА0АкА0АаАCDDбАаАйЖвА0А0АаАВcd04636, CBS_pair_23, The CBS domain, named after human CBS, is a small domain originally identified in cystathionine beta-synthase and is subsequently found in a wide range of different proteins. CBS domains usually occur in tandem repeats. They associate to form a so-called Bateman domain or a CBS pair based on crystallographic studies in bacteria. The CBS pair was used as a basis for this cd hierarchy since the human CBS proteins can adopt the typical core structure and form an intramolecular CBS pair. The interface between the two CBS domains forms a cleft that is a potential ligand binding site. The CBS pair coexists with a variety of other functional domains and this has been used to help in its classification here. It has been proposed that the CBS domain may play a regulatory role, although its exact function is unknown. Mutations of conserved residues within this domain are associated with a variety of human hereditary diseases, including congenital myotonia, idiopathic generalized epilepsy, hypercalciuric nephrolithiasis, and classic Bartter syndrome (CLC chloride channel family members), Wolff-Parkinson-White syndrome (gamma 2 subunit of AMP-activated protein kinase), retinitis pigmentosa (IMP dehydrogenase-1), and homocystinuria (cystathionine beta-synthase).бА0АкА0АаАCDDбАаАйЗвА0А0АаАВcd04637, CBS_pair_24, The CBS domain, named after human CBS, is a small domain originally identified in cystathionine beta-synthase and is subsequently found in a wide range of different proteins. CBS domains usually occur in tandem repeats. They associate to form a so-called Bateman domain or a CBS pair based on crystallographic studies in bacteria. The CBS pair was used as a basis for this cd hierarchy since the human CBS proteins can adopt the typical core structure and form an intramolecular CBS pair. The interface between the two CBS domains forms a cleft that is a potential ligand binding site. The CBS pair coexists with a variety of other functional domains and this has been used to help in its classification here. It has been proposed that the CBS domain may play a regulatory role, although its exact function is unknown. Mutations of conserved residues within this domain are associated with a variety of human hereditary diseases, including congenital myotonia, idiopathic generalized epilepsy, hypercalciuric nephrolithiasis, and classic Bartter syndrome (CLC chloride channel family members), Wolff-Parkinson-White syndrome (gamma 2 subunit of AMP-activated protein kinase), retinitis pigmentosa (IMP dehydrogenase-1), and homocystinuria (cystathionine beta-synthase).бА0АкА0АаАCDDбАаАйИвА0А0АаАВcd04638, CBS_pair_25, The CBS domain, named after human CBS, is a small domain originally identified in cystathionine beta-synthase and is subsequently found in a wide range of different proteins. CBS domains usually occur in tandem repeats. They associate to form a so-called Bateman domain or a CBS pair based on crystallographic studies in bacteria. The CBS pair was used as a basis for this cd hierarchy since the human CBS proteins can adopt the typical core structure and form an intramolecular CBS pair. The interface between the two CBS domains forms a cleft that is a potential ligand binding site. The CBS pair coexists with a variety of other functional domains and this has been used to help in its classification here. It has been proposed that the CBS domain may play a regulatory role, although its exact function is unknown. Mutations of conserved residues within this domain are associated with a variety of human hereditary diseases, including congenital myotonia, idiopathic generalized epilepsy, hypercalciuric nephrolithiasis, and classic Bartter syndrome (CLC chloride channel family members), Wolff-Parkinson-White syndrome (gamma 2 subunit of AMP-activated protein kinase), retinitis pigmentosa (IMP dehydrogenase-1), and homocystinuria (cystathionine beta-synthase).бА0АкА0АаАCDDбАаАйЙвА0А0АаАВcd04639, CBS_pair_26, The CBS domain, named after human CBS, is a small domain originally identified in cystathionine beta-synthase and is subsequently found in a wide range of different proteins. CBS domains usually occur in tandem repeats. They associate to form a so-called Bateman domain or a CBS pair based on crystallographic studies in bacteria. The CBS pair was used as a basis for this cd hierarchy since the human CBS proteins can adopt the typical core structure and form an intramolecular CBS pair. The interface between the two CBS domains forms a cleft that is a potential ligand binding site. The CBS pair coexists with a variety of other functional domains and this has been used to help in its classification here. It has been proposed that the CBS domain may play a regulatory role, although its exact function is unknown. Mutations of conserved residues within this domain are associated with a variety of human hereditary diseases, including congenital myotonia, idiopathic generalized epilepsy, hypercalciuric nephrolithiasis, and classic Bartter syndrome (CLC chloride channel family members), Wolff-Parkinson-White syndrome (gamma 2 subunit of AMP-activated protein kinase), retinitis pigmentosa (IMP dehydrogenase-1), and homocystinuria (cystathionine beta-synthase).бА0АкА0АаАCDDбАаАйКвА0А0АаАВcd04640, CBS_pair_27, The CBS domain, named after human CBS, is a small domain originally identified in cystathionine beta-synthase and is subsequently found in a wide range of different proteins. CBS domains usually occur in tandem repeats. They associate to form a so-called Bateman domain or a CBS pair based on crystallographic studies in bacteria. The CBS pair was used as a basis for this cd hierarchy since the human CBS proteins can adopt the typical core structure and form an intramolecular CBS pair. The interface between the two CBS domains forms a cleft that is a potential ligand binding site. The CBS pair coexists with a variety of other functional domains and this has been used to help in its classification here. It has been proposed that the CBS domain may play a regulatory role, although its exact function is unknown. Mutations of conserved residues within this domain are associated with a variety of human hereditary diseases, including congenital myotonia, idiopathic generalized epilepsy, hypercalciuric nephrolithiasis, and classic Bartter syndrome (CLC chloride channel family members), Wolff-Parkinson-White syndrome (gamma 2 subunit of AMP-activated protein kinase), retinitis pigmentosa (IMP dehydrogenase-1), and homocystinuria (cystathionine beta-synthase).бА0АкА0АаАCDDбАаАйЛвА0А0АаАВcd04641, CBS_pair_28, The CBS domain, named after human CBS, is a small domain originally identified in cystathionine beta-synthase and is subsequently found in a wide range of different proteins. CBS domains usually occur in tandem repeats. They associate to form a so-called Bateman domain or a CBS pair based on crystallographic studies in bacteria. The CBS pair was used as a basis for this cd hierarchy since the human CBS proteins can adopt the typical core structure and form an intramolecular CBS pair. The interface between the two CBS domains forms a cleft that is a potential ligand binding site. The CBS pair coexists with a variety of other functional domains and this has been used to help in its classification here. It has been proposed that the CBS domain may play a regulatory role, although its exact function is unknown. Mutations of conserved residues within this domain are associated with a variety of human hereditary diseases, including congenital myotonia, idiopathic generalized epilepsy, hypercalciuric nephrolithiasis, and classic Bartter syndrome (CLC chloride channel family members), Wolff-Parkinson-White syndrome (gamma 2 subunit of AMP-activated protein kinase), retinitis pigmentosa (IMP dehydrogenase-1), and homocystinuria (cystathionine beta-synthase).бА0АкА0АаАCDDбАаАйМвА0А0АаАВcd04642, CBS_pair_29, The CBS domain, named after human CBS, is a small domain originally identified in cystathionine beta-synthase and is subsequently found in a wide range of different proteins. CBS domains usually occur in tandem repeats. They associate to form a so-called Bateman domain or a CBS pair based on crystallographic studies in bacteria. The CBS pair was used as a basis for this cd hierarchy since the human CBS proteins can adopt the typical core structure and form an intramolecular CBS pair. The interface between the two CBS domains forms a cleft that is a potential ligand binding site. The CBS pair coexists with a variety of other functional domains and this has been used to help in its classification here. It has been proposed that the CBS domain may play a regulatory role, although its exact function is unknown. Mutations of conserved residues within this domain are associated with a variety of human hereditary diseases, including congenital myotonia, idiopathic generalized epilepsy, hypercalciuric nephrolithiasis, and classic Bartter syndrome (CLC chloride channel family members), Wolff-Parkinson-White syndrome (gamma 2 subunit of AMP-activated protein kinase), retinitis pigmentosa (IMP dehydrogenase-1), and homocystinuria (cystathionine beta-synthase).бА0АкА0АаАCDDбАаАйНвА0А0АаАВcd04643, CBS_pair_30, The CBS domain, named after human CBS, is a small domain originally identified in cystathionine beta-synthase and is subsequently found in a wide range of different proteins. CBS domains usually occur in tandem repeats. They associate to form a so-called Bateman domain or a CBS pair based on crystallographic studies in bacteria. The CBS pair was used as a basis for this cd hierarchy since the human CBS proteins can adopt the typical core structure and form an intramolecular CBS pair. The interface between the two CBS domains forms a cleft that is a potential ligand binding site. The CBS pair coexists with a variety of other functional domains and this has been used to help in its classification here. It has been proposed that the CBS domain may play a regulatory role, although its exact function is unknown. Mutations of conserved residues within this domain are associated with a variety of human hereditary diseases, including congenital myotonia, idiopathic generalized epilepsy, hypercalciuric nephrolithiasis, and classic Bartter syndrome (CLC chloride channel family members), Wolff-Parkinson-White syndrome (gamma 2 subunit of AMP-activated protein kinase), retinitis pigmentosa (IMP dehydrogenase-1), and homocystinuria (cystathionine beta-synthase).бА0АкА0АаАCDDбАаАйОвА0А0АаАВШcd04645, LbH_gamma_CA_like, Gamma carbonic anhydrase-like: This family is composed of gamma carbonic anhydrase (CA), Ferripyochelin Binding Protein (FBP), E. coli paaY protein, and similar proteins. CAs are zinc-containing enzymes that catalyze the reversible hydration of carbon dioxide in a two-step mechanism, involving the nucleophilic attack of a zinc-bound hydroxide ion on carbon dioxide, followed by the regeneration of the active site by ionization of the zinc-bound water molecule and removal of a proton from the active site. They are ubiquitous enzymes involved in fundamental processes like photosynthesis, respiration, pH homeostasis and ion transport. There are three evolutionary distinct groups - alpha, beta and gamma carbonic anhydrases - which show no significant sequence identity or structural similarity. Gamma CAs are trimeric enzymes with left-handed parallel beta helix (LbH) structural domain.бА0АкА0АаАCDDбАаАЖ╙вА0А0АаАВkcd04646, LbH_Dynactin_6, Dynactin 6 (or subunit p27): Dynactin is a major component of the activator complex that stimulates dynein-mediated vesicle transport. Dynactin is a heterocomplex of at least eight subunits, including a 150,000-MW protein called Glued, the actin-capping protein Arp1, and dynamatin. In vitro binding experiments show that dynactin enhances dynein-dependent motility, possibly through interaction with microtubules and vesicles. Subunit p27 is part of the pointed-end subcomplex in dynactin that also includes p25, p26, and Arp11. This subcomplex interacts with membranous cargoes. p25 and p27 contain the imperfect tandem repeats of a hexapeptide repeat motif (X-[STAV]-X-[LIV]-[GAED]-X), indicating a left-handed parallel beta helix (LbH) structural domain. Proteins containing hexapeptide repeats are often enzymes showing acyltransferase activity.бА0АкА0АаАCDDбАаАЖ╘вА0А0АаАВПcd04647, LbH_MAT_like, Maltose O-acyltransferase (MAT)-like: This family is composed of maltose O-acetyltransferase, galactoside O-acetyltransferase (GAT), xenobiotic acyltransferase (XAT) and similar proteins. MAT and GAT catalyze the CoA-dependent acetylation of the 6-hydroxyl group of their respective sugar substrates. MAT acetylates maltose and glucose exclusively while GAT specifically acetylates galactopyranosides. XAT catalyzes the CoA-dependent acetylation of a variety of hydroxyl-bearing acceptors such as chloramphenicol and streptogramin, among others. XATs are implicated in inactivating xenobiotics leading to xenobiotic resistance in patients. Members of this family contain a a left-handed parallel beta-helix (LbH) domain with at least 5 turns, each containing three imperfect tandem repeats of a hexapeptide repeat motif (X-[STAV]-X-[LIV]-[GAED]-X). They are trimeric in their active form.бА0АкА0АаАCDDбАаАЖ╒вА0А0АаАВ*cd04649, LbH_THP_succinylT_putative, Putative 2,3,4,5-tetrahydropyridine-2,6-dicarboxylate (THDP) N-succinyltransferase (THP succinyltransferase), C-terminal left-handed parallel alpha-helix (LbH) domain: This group is composed of mostly uncharacterized proteins containing an N-terminal domain of unknown function and a C-terminal LbH domain with similarity to THP succinyltransferase LbH. THP succinyltransferase catalyzes the conversion of tetrahydrodipicolinate and succinyl-CoA to N-succinyltetrahydrodipicolinate and CoA. It is the committed step in the succinylase pathway by which bacteria synthesize L-lysine and meso-diaminopimelate, a component of peptidoglycan. The enzyme is trimeric and displays the left-handed parallel alpha-helix (LbH) structural motif encoded by the hexapeptide repeat motif.бА0АкА0АаАCDDбАаАЖ╓вА0А0АаАВэcd04650, LbH_FBP, Ferripyochelin Binding Protein (FBP): FBP is an outer membrane protein which plays a role in iron acquisition. It binds iron when it is complexed with pyochelin. It adopts the left-handed parallel beta-helix (LbH) structure, and contains imperfect tandem repeats of a hexapeptide repeat motif (X-[STAV]-X-[LIV]-[GAED]-X). Proteins containing hexapeptide repeats are often enzymes showing acyltransferase activity. Acyltransferase activity has not been observed in this group.бА0АкА0АаАCDDбАаАЖ╫вА0А0АаАВNcd04651, LbH_G1P_AT_C, Glucose-1-phosphate adenylyltransferase, C-terminal Left-handed parallel beta helix (LbH) domain: Glucose-1-phosphate adenylyltransferase is also known as ADP-glucose synthase or ADP-glucose pyrophosphorylase. It catalyzes the first committed and rate-limiting step in starch biosynthesis in plants and glycogen biosynthesis in bacteria. It is the enzymatic site for regulation of storage polysaccharide accumulation in plants and bacteria. The enzyme is a homotetramer, with each subunit containing an N-terminal catalytic domain that resembles a dinucleotide-binding Rossmann fold and a C-terminal LbH fold domain with at 5 turns, each containing three imperfect tandem repeats of a hexapeptide repeat motif (X-[STAV]-X-[LIV]-[GAED]-X). The LbH domain is involved in cooperative allosteric regulation and oligomerization.бА0АкА0АаАCDDбАаАЖ╪вА0А0АаАВQcd04652, LbH_eIF2B_gamma_C, eIF-2B gamma subunit, C-terminal Left-handed parallel beta-Helix (LbH) domain: eIF-2B is a eukaryotic translation initiator, a guanine nucleotide exchange factor (GEF) composed of five different subunits (alpha, beta, gamma, delta and epsilon). eIF2B is important for regenerating GTP-bound eIF2 during the initiation process. This event is obligatory for eIF2 to bind initiator methionyl-tRNA, forming the ternary initiation complex. The eIF-2B gamma subunit contains an N-terminal domain that resembles a dinucleotide-binding Rossmann fold and a C-terminal LbH domain with 4 turns, each containing three imperfect tandem repeats of a hexapeptide repeat motif (X-[STAV]-X-[LIV]-[GAED]-X). The epsilon and gamma subunits form the catalytic subcomplex of eIF-2B, which binds eIF2 and catalyzes guanine nucleotide exchange.бА0АкА0АаАCDDбАаАЖ┘вА0А0АаАВqcd04657, Piwi_ago-like, Piwi_ago-like: PIWI domain, Argonaute-like subfamily. Argonaute is the central component of the RNA-induced silencing complex (RISC) and related complexes. The PIWI domain is the C-terminal portion of Argonaute and consists of two subdomains, one of which provides the 5' anchoring of the guide RNA and the other, the catalytic site for slicing.бА0АкА0АаАCDDбАаАйПвА0А0АаАВхcd04658, Piwi_piwi-like_Euk, Piwi_piwi-like_Euk: PIWI domain, Piwi-like subfamily found in eukaryotes. This domain is found in Piwi and closely related proteins, where it is believed to perform a crucial role in germline cells, via RNA silencing. RNA silencing refers to a group of related gene-silencing mechanisms mediated by short RNA molecules, including siRNAs, miRNAs, and heterochromatin-related guide RNAs. The mechanism in Piwi is believed to be similar to that in Argonaute, the central component of the RNA-induced silencing complex (RISC). The PIWI domain is the C-terminal portion of Argonaute and consists of two subdomains, one of which provides the 5' anchoring of the guide RNA and the other, the catalytic site for slicing.бА0АкА0АаАCDDбАаАйРвА0А0АаАВЄcd04659, Piwi_piwi-like_ProArk, Piwi_piwi-like_ProArk: PIWI domain, Piwi-like subfamily found in Archaea and Bacteria. RNA silencing refers to a group of related gene-silencing mechanisms mediated by short RNA molecules, including siRNAs, miRNAs, and heterochromatin-related guide RNAs. The central component of the RNA-induced silencing complex (RISC) and related complexes is Argonaute. The PIWI domain is the C-terminal portion of Argonaute and consists of two subdomains, one of which provides the 5' anchoring of the guide RNA and the other, the catalytic site for slicing. This domain is also found in closely related proteins, including the Piwi subfamily, where it is believed to perform a crucial role in germline cells, via a similar mechanism.бА0АкА0АаАCDDбАаАйСвА0А0АаАВХcd04660, nsLTP_like, nsLTP_like: Non-specific lipid-transfer protein (nsLTP)-like subfamily; composed of predominantly uncharacterized proteins with similarity to nsLTPs, including Medicago truncatula MtN5, the root-specific Phaseolus vulgaris PVR3, Antirrhinum majus FIL1, and Lilium longiflorum LIM3. Plant nsLTPs are small, soluble proteins that facilitate the transfer of fatty acids, phospholipids, glycolipids, and steroids between membranes. The MtN5 gene is induced during root nodule development. FIL1 is thought to be important in petal and stamen formation. The LIM3 gene is induced during the early prophase stage of meiosis in lily microsporocytes.бА0АкА0АаАCDDбАаАйТвА0А0АаАВMcd04661, MRP_L46, Mitochondrial ribosomal protein L46 (MRP L46) is a component of the large subunit (39S) of the mammalian mitochondrial ribosome and a member of the Nudix hydrolase superfamily. MRPs are thought to be involved in the maintenance of the mitochondrial DNA. In general, members of the Nudix superfamily require a divalent cation, such as Mg2+ or Mn2+, for activity and contain the Nudix motif, a highly conserved 23-residue block (GX5EX7REUXEEXGU, where U = I, L or V), which functions as a metal binding and catalytic site. MRP L46 appears to contain a modified nudix motif.бА0АкА0АаАCDDбАаАйУвА0А0АаАВфcd04662, Nudix_Hydrolase_5, Members of the Nudix hydrolase superfamily catalyze the hydrolysis of NUcleoside DIphosphates linked to other moieties, X. Enzymes belonging to this superfamily require a divalent cation, such as Mg2+ or Mn2+, for their activity and contain a highly conserved 23-residue nudix motif (GX5EX7REUXEEXGU, where U = I, L or V), which functions as a metal binding and catalytic site. Substrates of nudix hydrolases include intact and oxidatively damaged nucleoside triphosphates, dinucleoside polyphosphates, nucleotide-sugars and dinucleotide enzymes. These substrates are metabolites or cell signaling molecules that require regulation during different stages of the cell cycle or during periods of stress. In general, the role of the nudix hydrolase is to sanitize the nucleotide pools and to maintain cell viability, thereby serving as surveillance & "house-cleaning" enzymes. Substrate specificity is used to define families within the superfamily. Differences in substrate specificity are determined by the N-terminal extension or by residues in variable loop regions. Mechanistically, substrate hydrolysis occurs by a nucleophilic substitution reaction, with variation in the numbers and roles of divalent cations required.бА0АкА0АаАCDDбАаАйФвА0А0АаАВ╒cd04663, Nudix_Hydrolase_6, Members of the Nudix hydrolase superfamily catalyze the hydrolysis of NUcleoside DIphosphates linked to other moieties, X. Enzymes belong to this superfamily requires a divalent cation, such as Mg2+ or Mn2+ for their activity and contain a highly conserved 23-residue nudix motif (GX5EX7REUXEEXGU, U=I, L or V) which functions as metal binding and catalytic site. Substrates of nudix hydrolase include intact and oxidatively damaged nucleoside triphosphates, dinucleoside polyphosphates, nucleotide-sugars and dinucleotide enzymes. These substrates are metabolites or cell signaling molecules that require regulation during different stages of the cell cycle or during periods of stress. In general, the role of the nudix hydrolase is to sanitize the nucleotide pools and to maintain cell viability, thereby serving as surveillance & "house-cleaning" enzymes. Substrate specificity is used to define families within the superfamily. Differences in substrate specificity are determined by the N-terminal extension or by residues in variable loop regions. Mechanistically, substrate hydrolysis occurs by a nucleophilic substitution reaction, with variation in the numbers and roles of divalent cations required.бА0АкА0АаАCDDбАаАйХвА0А0АаАВфcd04664, Nudix_Hydrolase_7, Members of the Nudix hydrolase superfamily catalyze the hydrolysis of NUcleoside DIphosphates linked to other moieties, X. Enzymes belonging to this superfamily require a divalent cation, such as Mg2+ or Mn2+, for their activity and contain a highly conserved 23-residue nudix motif (GX5EX7REUXEEXGU, where U = I, L or V), which functions as a metal binding and catalytic site. Substrates of nudix hydrolases include intact and oxidatively damaged nucleoside triphosphates, dinucleoside polyphosphates, nucleotide-sugars and dinucleotide enzymes. These substrates are metabolites or cell signaling molecules that require regulation during different stages of the cell cycle or during periods of stress. In general, the role of the nudix hydrolase is to sanitize the nucleotide pools and to maintain cell viability, thereby serving as surveillance & "house-cleaning" enzymes. Substrate specificity is used to define families within the superfamily. Differences in substrate specificity are determined by the N-terminal extension or by residues in variable loop regions. Mechanistically, substrate hydrolysis occurs by a nucleophilic substitution reaction, with variation in the numbers and roles of divalent cations required.бА0АкА0АаАCDDбАаАйЦвА0А0АаАВфcd04665, Nudix_Hydrolase_8, Members of the Nudix hydrolase superfamily catalyze the hydrolysis of NUcleoside DIphosphates linked to other moieties, X. Enzymes belonging to this superfamily require a divalent cation, such as Mg2+ or Mn2+, for their activity and contain a highly conserved 23-residue nudix motif (GX5EX7REUXEEXGU, where U = I, L or V), which functions as a metal binding and catalytic site. Substrates of nudix hydrolases include intact and oxidatively damaged nucleoside triphosphates, dinucleoside polyphosphates, nucleotide-sugars and dinucleotide enzymes. These substrates are metabolites or cell signaling molecules that require regulation during different stages of the cell cycle or during periods of stress. In general, the role of the nudix hydrolase is to sanitize the nucleotide pools and to maintain cell viability, thereby serving as surveillance & "house-cleaning" enzymes. Substrate specificity is used to define families within the superfamily. Differences in substrate specificity are determined by the N-terminal extension or by residues in variable loop regions. Mechanistically, substrate hydrolysis occurs by a nucleophilic substitution reaction, with variation in the numbers and roles of divalent cations required.бА0АкА0АаАCDDбАаАйЧвА0А0АаАВфcd04666, Nudix_Hydrolase_9, Members of the Nudix hydrolase superfamily catalyze the hydrolysis of NUcleoside DIphosphates linked to other moieties, X. Enzymes belonging to this superfamily require a divalent cation, such as Mg2+ or Mn2+, for their activity and contain a highly conserved 23-residue nudix motif (GX5EX7REUXEEXGU, where U = I, L or V), which functions as a metal binding and catalytic site. Substrates of nudix hydrolases include intact and oxidatively damaged nucleoside triphosphates, dinucleoside polyphosphates, nucleotide-sugars and dinucleotide enzymes. These substrates are metabolites or cell signaling molecules that require regulation during different stages of the cell cycle or during periods of stress. In general, the role of the nudix hydrolase is to sanitize the nucleotide pools and to maintain cell viability, thereby serving as surveillance & "house-cleaning" enzymes. Substrate specificity is used to define families within the superfamily. Differences in substrate specificity are determined by the N-terminal extension or by residues in variable loop regions. Mechanistically, substrate hydrolysis occurs by a nucleophilic substitution reaction, with variation in the numbers and roles of divalent cations required.бА0АкА0АаАCDDбАаАйШвА0А0АаАВхcd04667, Nudix_Hydrolase_10, Members of the Nudix hydrolase superfamily catalyze the hydrolysis of NUcleoside DIphosphates linked to other moieties, X. Enzymes belonging to this superfamily require a divalent cation, such as Mg2+ or Mn2+, for their activity and contain a highly conserved 23-residue nudix motif (GX5EX7REUXEEXGU, where U = I, L or V), which functions as a metal binding and catalytic site. Substrates of nudix hydrolases include intact and oxidatively damaged nucleoside triphosphates, dinucleoside polyphosphates, nucleotide-sugars and dinucleotide enzymes. These substrates are metabolites or cell signaling molecules that require regulation during different stages of the cell cycle or during periods of stress. In general, the role of the nudix hydrolase is to sanitize the nucleotide pools and to maintain cell viability, thereby serving as surveillance & "house-cleaning" enzymes. Substrate specificity is used to define families within the superfamily. Differences in substrate specificity are determined by the N-terminal extension or by residues in variable loop regions. Mechanistically, substrate hydrolysis occurs by a nucleophilic substitution reaction, with variation in the numbers and roles of divalent cations required.бА0АкА0АаАCDDбАаАйЩвА0А0АаАВхcd04669, Nudix_Hydrolase_11, Members of the Nudix hydrolase superfamily catalyze the hydrolysis of NUcleoside DIphosphates linked to other moieties, X. Enzymes belonging to this superfamily require a divalent cation, such as Mg2+ or Mn2+, for their activity and contain a highly conserved 23-residue nudix motif (GX5EX7REUXEEXGU, where U = I, L or V), which functions as a metal binding and catalytic site. Substrates of nudix hydrolases include intact and oxidatively damaged nucleoside triphosphates, dinucleoside polyphosphates, nucleotide-sugars and dinucleotide enzymes. These substrates are metabolites or cell signaling molecules that require regulation during different stages of the cell cycle or during periods of stress. In general, the role of the nudix hydrolase is to sanitize the nucleotide pools and to maintain cell viability, thereby serving as surveillance & "house-cleaning" enzymes. Substrate specificity is used to define families within the superfamily. Differences in substrate specificity are determined by the N-terminal extension or by residues in variable loop regions. Mechanistically, substrate hydrolysis occurs by a nucleophilic substitution reaction, with variation in the numbers and roles of divalent cations required.бА0АкА0АаАCDDбАаАйЪвА0А0АаАВхcd04670, Nudix_Hydrolase_12, Members of the Nudix hydrolase superfamily catalyze the hydrolysis of NUcleoside DIphosphates linked to other moieties, X. Enzymes belonging to this superfamily require a divalent cation, such as Mg2+ or Mn2+, for their activity and contain a highly conserved 23-residue nudix motif (GX5EX7REUXEEXGU, where U = I, L or V), which functions as a metal binding and catalytic site. Substrates of nudix hydrolases include intact and oxidatively damaged nucleoside triphosphates, dinucleoside polyphosphates, nucleotide-sugars and dinucleotide enzymes. These substrates are metabolites or cell signaling molecules that require regulation during different stages of the cell cycle or during periods of stress. In general, the role of the nudix hydrolase is to sanitize the nucleotide pools and to maintain cell viability, thereby serving as surveillance & "house-cleaning" enzymes. Substrate specificity is used to define families within the superfamily. Differences in substrate specificity are determined by the N-terminal extension or by residues in variable loop regions. Mechanistically, substrate hydrolysis occurs by a nucleophilic substitution reaction, with variation in the numbers and roles of divalent cations required.бА0АкА0АаАCDDбАаАйЫвА0А0АаАВхcd04671, Nudix_Hydrolase_13, Members of the Nudix hydrolase superfamily catalyze the hydrolysis of NUcleoside DIphosphates linked to other moieties, X. Enzymes belonging to this superfamily require a divalent cation, such as Mg2+ or Mn2+, for their activity and contain a highly conserved 23-residue nudix motif (GX5EX7REUXEEXGU, where U = I, L or V), which functions as a metal binding and catalytic site. Substrates of nudix hydrolases include intact and oxidatively damaged nucleoside triphosphates, dinucleoside polyphosphates, nucleotide-sugars and dinucleotide enzymes. These substrates are metabolites or cell signaling molecules that require regulation during different stages of the cell cycle or during periods of stress. In general, the role of the nudix hydrolase is to sanitize the nucleotide pools and to maintain cell viability, thereby serving as surveillance & "house-cleaning" enzymes. Substrate specificity is used to define families within the superfamily. Differences in substrate specificity are determined by the N-terminal extension or by residues in variable loop regions. Mechanistically, substrate hydrolysis occurs by a nucleophilic substitution reaction, with variation in the numbers and roles of divalent cations required.бА0АкА0АаАCDDбАаАйЬвА0А0АаАВхcd04672, Nudix_Hydrolase_14, Members of the Nudix hydrolase superfamily catalyze the hydrolysis of NUcleoside DIphosphates linked to other moieties, X. Enzymes belonging to this superfamily require a divalent cation, such as Mg2+ or Mn2+, for their activity and contain a highly conserved 23-residue nudix motif (GX5EX7REUXEEXGU, where U = I, L or V), which functions as a metal binding and catalytic site. Substrates of nudix hydrolases include intact and oxidatively damaged nucleoside triphosphates, dinucleoside polyphosphates, nucleotide-sugars and dinucleotide enzymes. These substrates are metabolites or cell signaling molecules that require regulation during different stages of the cell cycle or during periods of stress. In general, the role of the nudix hydrolase is to sanitize the nucleotide pools and to maintain cell viability, thereby serving as surveillance & "house-cleaning" enzymes. Substrate specificity is used to define families within the superfamily. Differences in substrate specificity are determined by the N-terminal extension or by residues in variable loop regions. Mechanistically, substrate hydrolysis occurs by a nucleophilic substitution reaction, with variation in the numbers and roles of divalent cations required.бА0АкА0АаАCDDбАаАйЭвА0А0АаАВхcd04673, Nudix_Hydrolase_15, Members of the Nudix hydrolase superfamily catalyze the hydrolysis of NUcleoside DIphosphates linked to other moieties, X. Enzymes belonging to this superfamily require a divalent cation, such as Mg2+ or Mn2+, for their activity and contain a highly conserved 23-residue nudix motif (GX5EX7REUXEEXGU, where U = I, L or V), which functions as a metal binding and catalytic site. Substrates of nudix hydrolases include intact and oxidatively damaged nucleoside triphosphates, dinucleoside polyphosphates, nucleotide-sugars and dinucleotide enzymes. These substrates are metabolites or cell signaling molecules that require regulation during different stages of the cell cycle or during periods of stress. In general, the role of the nudix hydrolase is to sanitize the nucleotide pools and to maintain cell viability, thereby serving as surveillance & "house-cleaning" enzymes. Substrate specificity is used to define families within the superfamily. Differences in substrate specificity are determined by the N-terminal extension or by residues in variable loop regions. Mechanistically, substrate hydrolysis occurs by a nucleophilic substitution reaction, with variation in the numbers and roles of divalent cations required.бА0АкА0АаАCDDбАаАйЮвА0А0АаАВхcd04674, Nudix_Hydrolase_16, Members of the Nudix hydrolase superfamily catalyze the hydrolysis of NUcleoside DIphosphates linked to other moieties, X. Enzymes belonging to this superfamily require a divalent cation, such as Mg2+ or Mn2+, for their activity and contain a highly conserved 23-residue nudix motif (GX5EX7REUXEEXGU, where U = I, L or V), which functions as a metal binding and catalytic site. Substrates of nudix hydrolases include intact and oxidatively damaged nucleoside triphosphates, dinucleoside polyphosphates, nucleotide-sugars and dinucleotide enzymes. These substrates are metabolites or cell signaling molecules that require regulation during different stages of the cell cycle or during periods of stress. In general, the role of the nudix hydrolase is to sanitize the nucleotide pools and to maintain cell viability, thereby serving as surveillance & "house-cleaning" enzymes. Substrate specificity is used to define families within the superfamily. Differences in substrate specificity are determined by the N-terminal extension or by residues in variable loop regions. Mechanistically, substrate hydrolysis occurs by a nucleophilic substitution reaction, with variation in the numbers and roles of divalent cations required.бА0АкА0АаАCDDбАаАйЯвА0А0АаАВхcd04676, Nudix_Hydrolase_17, Members of the Nudix hydrolase superfamily catalyze the hydrolysis of NUcleoside DIphosphates linked to other moieties, X. Enzymes belonging to this superfamily require a divalent cation, such as Mg2+ or Mn2+, for their activity and contain a highly conserved 23-residue nudix motif (GX5EX7REUXEEXGU, where U = I, L or V), which functions as a metal binding and catalytic site. Substrates of nudix hydrolases include intact and oxidatively damaged nucleoside triphosphates, dinucleoside polyphosphates, nucleotide-sugars and dinucleotide enzymes. These substrates are metabolites or cell signaling molecules that require regulation during different stages of the cell cycle or during periods of stress. In general, the role of the nudix hydrolase is to sanitize the nucleotide pools and to maintain cell viability, thereby serving as surveillance & "house-cleaning" enzymes. Substrate specificity is used to define families within the superfamily. Differences in substrate specificity are determined by the N-terminal extension or by residues in variable loop regions. Mechanistically, substrate hydrolysis occurs by a nucleophilic substitution reaction, with variation in the numbers and roles of divalent cations required.бА0АкА0АаАCDDбАаАйавА0А0АаАВхcd04677, Nudix_Hydrolase_18, Members of the Nudix hydrolase superfamily catalyze the hydrolysis of NUcleoside DIphosphates linked to other moieties, X. Enzymes belonging to this superfamily require a divalent cation, such as Mg2+ or Mn2+, for their activity and contain a highly conserved 23-residue nudix motif (GX5EX7REUXEEXGU, where U = I, L or V), which functions as a metal binding and catalytic site. Substrates of nudix hydrolases include intact and oxidatively damaged nucleoside triphosphates, dinucleoside polyphosphates, nucleotide-sugars and dinucleotide enzymes. These substrates are metabolites or cell signaling molecules that require regulation during different stages of the cell cycle or during periods of stress. In general, the role of the nudix hydrolase is to sanitize the nucleotide pools and to maintain cell viability, thereby serving as surveillance & "house-cleaning" enzymes. Substrate specificity is used to define families within the superfamily. Differences in substrate specificity are determined by the N-terminal extension or by residues in variable loop regions. Mechanistically, substrate hydrolysis occurs by a nucleophilic substitution reaction, with variation in the numbers and roles of divalent cations required.бА0АкА0АаАCDDбАаАйбвА0А0АаАВхcd04678, Nudix_Hydrolase_19, Members of the Nudix hydrolase superfamily catalyze the hydrolysis of NUcleoside DIphosphates linked to other moieties, X. Enzymes belonging to this superfamily require a divalent cation, such as Mg2+ or Mn2+, for their activity and contain a highly conserved 23-residue nudix motif (GX5EX7REUXEEXGU, where U = I, L or V), which functions as a metal binding and catalytic site. Substrates of nudix hydrolases include intact and oxidatively damaged nucleoside triphosphates, dinucleoside polyphosphates, nucleotide-sugars and dinucleotide enzymes. These substrates are metabolites or cell signaling molecules that require regulation during different stages of the cell cycle or during periods of stress. In general, the role of the nudix hydrolase is to sanitize the nucleotide pools and to maintain cell viability, thereby serving as surveillance & "house-cleaning" enzymes. Substrate specificity is used to define families within the superfamily. Differences in substrate specificity are determined by the N-terminal extension or by residues in variable loop regions. Mechanistically, substrate hydrolysis occurs by a nucleophilic substitution reaction, with variation in the numbers and roles of divalent cations required.бА0АкА0АаАCDDбАаАйввА0А0АаАВхcd04679, Nudix_Hydrolase_20, Members of the Nudix hydrolase superfamily catalyze the hydrolysis of NUcleoside DIphosphates linked to other moieties, X. Enzymes belonging to this superfamily require a divalent cation, such as Mg2+ or Mn2+, for their activity and contain a highly conserved 23-residue nudix motif (GX5EX7REUXEEXGU, where U = I, L or V), which functions as a metal binding and catalytic site. Substrates of nudix hydrolases include intact and oxidatively damaged nucleoside triphosphates, dinucleoside polyphosphates, nucleotide-sugars and dinucleotide enzymes. These substrates are metabolites or cell signaling molecules that require regulation during different stages of the cell cycle or during periods of stress. In general, the role of the nudix hydrolase is to sanitize the nucleotide pools and to maintain cell viability, thereby serving as surveillance & "house-cleaning" enzymes. Substrate specificity is used to define families within the superfamily. Differences in substrate specificity are determined by the N-terminal extension or by residues in variable loop regions. Mechanistically, substrate hydrolysis occurs by a nucleophilic substitution reaction, with variation in the numbers and roles of divalent cations required.бА0АкА0АаАCDDбАаАйгвА0А0АаАВхcd04680, Nudix_Hydrolase_21, Members of the Nudix hydrolase superfamily catalyze the hydrolysis of NUcleoside DIphosphates linked to other moieties, X. Enzymes belonging to this superfamily require a divalent cation, such as Mg2+ or Mn2+, for their activity and contain a highly conserved 23-residue nudix motif (GX5EX7REUXEEXGU, where U = I, L or V), which functions as a metal binding and catalytic site. Substrates of nudix hydrolases include intact and oxidatively damaged nucleoside triphosphates, dinucleoside polyphosphates, nucleotide-sugars and dinucleotide enzymes. These substrates are metabolites or cell signaling molecules that require regulation during different stages of the cell cycle or during periods of stress. In general, the role of the nudix hydrolase is to sanitize the nucleotide pools and to maintain cell viability, thereby serving as surveillance & "house-cleaning" enzymes. Substrate specificity is used to define families within the superfamily. Differences in substrate specificity are determined by the N-terminal extension or by residues in variable loop regions. Mechanistically, substrate hydrolysis occurs by a nucleophilic substitution reaction, with variation in the numbers and roles of divalent cations required.бА0АкА0АаАCDDбАаАйдвА0А0АаАВхcd04681, Nudix_Hydrolase_22, Members of the Nudix hydrolase superfamily catalyze the hydrolysis of NUcleoside DIphosphates linked to other moieties, X. Enzymes belonging to this superfamily require a divalent cation, such as Mg2+ or Mn2+, for their activity and contain a highly conserved 23-residue nudix motif (GX5EX7REUXEEXGU, where U = I, L or V), which functions as a metal binding and catalytic site. Substrates of nudix hydrolases include intact and oxidatively damaged nucleoside triphosphates, dinucleoside polyphosphates, nucleotide-sugars and dinucleotide enzymes. These substrates are metabolites or cell signaling molecules that require regulation during different stages of the cell cycle or during periods of stress. In general, the role of the nudix hydrolase is to sanitize the nucleotide pools and to maintain cell viability, thereby serving as surveillance & "house-cleaning" enzymes. Substrate specificity is used to define families within the superfamily. Differences in substrate specificity are determined by the N-terminal extension or by residues in variable loop regions. Mechanistically, substrate hydrolysis occurs by a nucleophilic substitution reaction, with variation in the numbers and roles of divalent cations required.бА0АкА0АаАCDDбАаАйевА0А0АаАВхcd04682, Nudix_Hydrolase_23, Members of the Nudix hydrolase superfamily catalyze the hydrolysis of NUcleoside DIphosphates linked to other moieties, X. Enzymes belonging to this superfamily require a divalent cation, such as Mg2+ or Mn2+, for their activity and contain a highly conserved 23-residue nudix motif (GX5EX7REUXEEXGU, where U = I, L or V), which functions as a metal binding and catalytic site. Substrates of nudix hydrolases include intact and oxidatively damaged nucleoside triphosphates, dinucleoside polyphosphates, nucleotide-sugars and dinucleotide enzymes. These substrates are metabolites or cell signaling molecules that require regulation during different stages of the cell cycle or during periods of stress. In general, the role of the nudix hydrolase is to sanitize the nucleotide pools and to maintain cell viability, thereby serving as surveillance & "house-cleaning" enzymes. Substrate specificity is used to define families within the superfamily. Differences in substrate specificity are determined by the N-terminal extension or by residues in variable loop regions. Mechanistically, substrate hydrolysis occurs by a nucleophilic substitution reaction, with variation in the numbers and roles of divalent cations required.бА0АкА0АаАCDDбАаАйжвА0А0АаАВхcd04683, Nudix_Hydrolase_24, Members of the Nudix hydrolase superfamily catalyze the hydrolysis of NUcleoside DIphosphates linked to other moieties, X. Enzymes belonging to this superfamily require a divalent cation, such as Mg2+ or Mn2+, for their activity and contain a highly conserved 23-residue nudix motif (GX5EX7REUXEEXGU, where U = I, L or V), which functions as a metal binding and catalytic site. Substrates of nudix hydrolases include intact and oxidatively damaged nucleoside triphosphates, dinucleoside polyphosphates, nucleotide-sugars and dinucleotide enzymes. These substrates are metabolites or cell signaling molecules that require regulation during different stages of the cell cycle or during periods of stress. In general, the role of the nudix hydrolase is to sanitize the nucleotide pools and to maintain cell viability, thereby serving as surveillance & "house-cleaning" enzymes. Substrate specificity is used to define families within the superfamily. Differences in substrate specificity are determined by the N-terminal extension or by residues in variable loop regions. Mechanistically, substrate hydrolysis occurs by a nucleophilic substitution reaction, with variation in the numbers and roles of divalent cations required.бА0АкА0АаАCDDбАаАйзвА0А0АаАВЕcd04684, Nudix_Hydrolase_25, Contains a crystal structure of the Nudix hydrolase from Enterococcus faecalis, which has an unknown function. In general, members of the Nudix hydrolase superfamily catalyze the hydrolysis of NUcleoside DIphosphates linked to other moieties, X. Enzymes belonging to this superfamily require a divalent cation, such as Mg2+ or Mn2+, for their activity. They also contain a highly conserved 23-residue nudix motif (GX5EX7REUXEEXGU, where U = I, L or V), which forms a structural motif that functions as a metal binding and catalytic site. Substrates of nudix hydrolases include intact and oxidatively damaged nucleoside triphosphates, dinucleoside polyphosphates, nucleotide-sugars and dinucleotide enzymes. These substrates are metabolites or cell signaling molecules that require regulation during different stages of the cell cycle or during periods of stress. In general, the role of the nudix hydrolase is to sanitize the nucleotide pools and to maintain cell viability, thereby serving as surveillance & "house-cleaning" enzymes. Substrate specificity is used to define families within the superfamily. Differences in substrate specificity are determined by the N-terminal extension or by residues in variable loop regions. Mechanistically, substrate hydrolysis occurs by a nucleophilic substitution reaction, with variation in the numbers and roles of divalent cations required.бА0АкА0АаАCDDбАаАйивА0А0АаАВцcd04685, Nudix_Hydrolase_26, Members of the Nudix hydrolase superfamily catalyze the hydrolysis of NUcleoside DIphosphates linked to other moieties, X. Enzymes belonging to this superfamily requires a divalent cation, such as Mg2+ or Mn2+, for their activity and contain a highly conserved 23-residue nudix motif (GX5EX7REUXEEXGU, where U = I, L or V), which functions as a metal binding and catalytic site. Substrates of nudix hydrolases include intact and oxidatively damaged nucleoside triphosphates, dinucleoside polyphosphates, nucleotide-sugars and dinucleotide enzymes. These substrates are metabolites or cell signaling molecules that require regulation during different stages of the cell cycle or during periods of stress. In general, the role of the nudix hydrolase is to sanitize the nucleotide pools and to maintain cell viability, thereby serving as surveillance & "house-cleaning" enzymes. Substrate specificity is used to define families within the superfamily. Differences in substrate specificity are determined by the N-terminal extension or by residues in variable loop regions. Mechanistically, substrate hydrolysis occurs by a nucleophilic substitution reaction, with variation in the numbers and roles of divalent cations required.бА0АкА0АаАCDDбАаАййвА0А0АаАВхcd04686, Nudix_Hydrolase_27, Members of the Nudix hydrolase superfamily catalyze the hydrolysis of NUcleoside DIphosphates linked to other moieties, X. Enzymes belonging to this superfamily require a divalent cation, such as Mg2+ or Mn2+, for their activity and contain a highly conserved 23-residue nudix motif (GX5EX7REUXEEXGU, where U = I, L or V), which functions as a metal binding and catalytic site. Substrates of nudix hydrolases include intact and oxidatively damaged nucleoside triphosphates, dinucleoside polyphosphates, nucleotide-sugars and dinucleotide enzymes. These substrates are metabolites or cell signaling molecules that require regulation during different stages of the cell cycle or during periods of stress. In general, the role of the nudix hydrolase is to sanitize the nucleotide pools and to maintain cell viability, thereby serving as surveillance & "house-cleaning" enzymes. Substrate specificity is used to define families within the superfamily. Differences in substrate specificity are determined by the N-terminal extension or by residues in variable loop regions. Mechanistically, substrate hydrolysis occurs by a nucleophilic substitution reaction, with variation in the numbers and roles of divalent cations required.бА0АкА0АаАCDDбАаАйквА0А0АаАВхcd04687, Nudix_Hydrolase_28, Members of the Nudix hydrolase superfamily catalyze the hydrolysis of NUcleoside DIphosphates linked to other moieties, X. Enzymes belonging to this superfamily require a divalent cation, such as Mg2+ or Mn2+, for their activity and contain a highly conserved 23-residue nudix motif (GX5EX7REUXEEXGU, where U = I, L or V), which functions as a metal binding and catalytic site. Substrates of nudix hydrolases include intact and oxidatively damaged nucleoside triphosphates, dinucleoside polyphosphates, nucleotide-sugars and dinucleotide enzymes. These substrates are metabolites or cell signaling molecules that require regulation during different stages of the cell cycle or during periods of stress. In general, the role of the nudix hydrolase is to sanitize the nucleotide pools and to maintain cell viability, thereby serving as surveillance & "house-cleaning" enzymes. Substrate specificity is used to define families within the superfamily. Differences in substrate specificity are determined by the N-terminal extension or by residues in variable loop regions. Mechanistically, substrate hydrolysis occurs by a nucleophilic substitution reaction, with variation in the numbers and roles of divalent cations required.бА0АкА0АаАCDDбАаАйлвА0А0АаАВхcd04688, Nudix_Hydrolase_29, Members of the Nudix hydrolase superfamily catalyze the hydrolysis of NUcleoside DIphosphates linked to other moieties, X. Enzymes belonging to this superfamily require a divalent cation, such as Mg2+ or Mn2+, for their activity and contain a highly conserved 23-residue nudix motif (GX5EX7REUXEEXGU, where U = I, L or V), which functions as a metal binding and catalytic site. Substrates of nudix hydrolases include intact and oxidatively damaged nucleoside triphosphates, dinucleoside polyphosphates, nucleotide-sugars and dinucleotide enzymes. These substrates are metabolites or cell signaling molecules that require regulation during different stages of the cell cycle or during periods of stress. In general, the role of the nudix hydrolase is to sanitize the nucleotide pools and to maintain cell viability, thereby serving as surveillance & "house-cleaning" enzymes. Substrate specificity is used to define families within the superfamily. Differences in substrate specificity are determined by the N-terminal extension or by residues in variable loop regions. Mechanistically, substrate hydrolysis occurs by a nucleophilic substitution reaction, with variation in the numbers and roles of divalent cations required.бА0АкА0АаАCDDбАаАймвА0А0АаАВуcd04689, Nudix_Hydrolase_30, Members of the Nudix hydrolase superfamily catalyze the hydrolysis of NUcleoside DIphosphates linked to other moieties, X. Enzymes belonging to this superfamily require a divalent cation, such as Mg2+ or Mn2+, for their activity and contain a highly conserved 23-residue nudix motif (GX5EX7REUXEEXGU, where U=I, L or V), which functions as a metal binding and catalytic site. Substrates of nudix hydrolases include intact and oxidatively damaged nucleoside triphosphates, dinucleoside polyphosphates, nucleotide-sugars and dinucleotide enzymes. These substrates are metabolites or cell signaling molecules that require regulation during different stages of the cell cycle or during periods of stress. In general, the role of the nudix hydrolase is to sanitize the nucleotide pools and to maintain cell viability, thereby serving as surveillance & "house-cleaning" enzymes. Substrate specificity is used to define families within the superfamily. Differences in substrate specificity are determined by the N-terminal extension or by residues in variable loop regions. Mechanistically, substrate hydrolysis occurs by a nucleophilic substitution reaction, with variation in the numbers and roles of divalent cations required.бА0АкА0АаАCDDбАаАйнвА0А0АаАВхcd04690, Nudix_Hydrolase_31, Members of the Nudix hydrolase superfamily catalyze the hydrolysis of NUcleoside DIphosphates linked to other moieties, X. Enzymes belonging to this superfamily require a divalent cation, such as Mg2+ or Mn2+, for their activity and contain a highly conserved 23-residue nudix motif (GX5EX7REUXEEXGU, where U = I, L or V), which functions as a metal binding and catalytic site. Substrates of nudix hydrolases include intact and oxidatively damaged nucleoside triphosphates, dinucleoside polyphosphates, nucleotide-sugars and dinucleotide enzymes. These substrates are metabolites or cell signaling molecules that require regulation during different stages of the cell cycle or during periods of stress. In general, the role of the nudix hydrolase is to sanitize the nucleotide pools and to maintain cell viability, thereby serving as surveillance & "house-cleaning" enzymes. Substrate specificity is used to define families within the superfamily. Differences in substrate specificity are determined by the N-terminal extension or by residues in variable loop regions. Mechanistically, substrate hydrolysis occurs by a nucleophilic substitution reaction, with variation in the numbers and roles of divalent cations required.бА0АкА0АаАCDDбАаАйовА0А0АаАВхcd04691, Nudix_Hydrolase_32, Members of the Nudix hydrolase superfamily catalyze the hydrolysis of NUcleoside DIphosphates linked to other moieties, X. Enzymes belonging to this superfamily require a divalent cation, such as Mg2+ or Mn2+, for their activity and contain a highly conserved 23-residue nudix motif (GX5EX7REUXEEXGU, where U = I, L or V), which functions as a metal binding and catalytic site. Substrates of nudix hydrolases include intact and oxidatively damaged nucleoside triphosphates, dinucleoside polyphosphates, nucleotide-sugars and dinucleotide enzymes. These substrates are metabolites or cell signaling molecules that require regulation during different stages of the cell cycle or during periods of stress. In general, the role of the nudix hydrolase is to sanitize the nucleotide pools and to maintain cell viability, thereby serving as surveillance & "house-cleaning" enzymes. Substrate specificity is used to define families within the superfamily. Differences in substrate specificity are determined by the N-terminal extension or by residues in variable loop regions. Mechanistically, substrate hydrolysis occurs by a nucleophilic substitution reaction, with variation in the numbers and roles of divalent cations required.бА0АкА0АаАCDDбАаАйпвА0А0АаАВхcd04692, Nudix_Hydrolase_33, Members of the Nudix hydrolase superfamily catalyze the hydrolysis of NUcleoside DIphosphates linked to other moieties, X. Enzymes belonging to this superfamily require a divalent cation, such as Mg2+ or Mn2+, for their activity and contain a highly conserved 23-residue nudix motif (GX5EX7REUXEEXGU, where U = I, L or V), which functions as a metal binding and catalytic site. Substrates of nudix hydrolases include intact and oxidatively damaged nucleoside triphosphates, dinucleoside polyphosphates, nucleotide-sugars and dinucleotide enzymes. These substrates are metabolites or cell signaling molecules that require regulation during different stages of the cell cycle or during periods of stress. In general, the role of the nudix hydrolase is to sanitize the nucleotide pools and to maintain cell viability, thereby serving as surveillance & "house-cleaning" enzymes. Substrate specificity is used to define families within the superfamily. Differences in substrate specificity are determined by the N-terminal extension or by residues in variable loop regions. Mechanistically, substrate hydrolysis occurs by a nucleophilic substitution reaction, with variation in the numbers and roles of divalent cations required.бА0АкА0АаАCDDбАаАй░вА0А0АаАВхcd04693, Nudix_Hydrolase_34, Members of the Nudix hydrolase superfamily catalyze the hydrolysis of NUcleoside DIphosphates linked to other moieties, X. Enzymes belonging to this superfamily require a divalent cation, such as Mg2+ or Mn2+, for their activity and contain a highly conserved 23-residue nudix motif (GX5EX7REUXEEXGU, where U = I, L or V), which functions as a metal binding and catalytic site. Substrates of nudix hydrolases include intact and oxidatively damaged nucleoside triphosphates, dinucleoside polyphosphates, nucleotide-sugars and dinucleotide enzymes. These substrates are metabolites or cell signaling molecules that require regulation during different stages of the cell cycle or during periods of stress. In general, the role of the nudix hydrolase is to sanitize the nucleotide pools and to maintain cell viability, thereby serving as surveillance & "house-cleaning" enzymes. Substrate specificity is used to define families within the superfamily. Differences in substrate specificity are determined by the N-terminal extension or by residues in variable loop regions. Mechanistically, substrate hydrolysis occurs by a nucleophilic substitution reaction, with variation in the numbers and roles of divalent cations required.бА0АкА0АаАCDDбАаАй▒вА0А0АаАВхcd04694, Nudix_Hydrolase_35, Members of the Nudix hydrolase superfamily catalyze the hydrolysis of NUcleoside DIphosphates linked to other moieties, X. Enzymes belonging to this superfamily require a divalent cation, such as Mg2+ or Mn2+, for their activity and contain a highly conserved 23-residue nudix motif (GX5EX7REUXEEXGU, where U = I, L or V), which functions as a metal binding and catalytic site. Substrates of nudix hydrolases include intact and oxidatively damaged nucleoside triphosphates, dinucleoside polyphosphates, nucleotide-sugars and dinucleotide enzymes. These substrates are metabolites or cell signaling molecules that require regulation during different stages of the cell cycle or during periods of stress. In general, the role of the nudix hydrolase is to sanitize the nucleotide pools and to maintain cell viability, thereby serving as surveillance & "house-cleaning" enzymes. Substrate specificity is used to define families within the superfamily. Differences in substrate specificity are determined by the N-terminal extension or by residues in variable loop regions. Mechanistically, substrate hydrolysis occurs by a nucleophilic substitution reaction, with variation in the numbers and roles of divalent cations required.бА0АкА0АаАCDDбАаАй▓вА0А0АаАВхcd04695, Nudix_Hydrolase_36, Members of the Nudix hydrolase superfamily catalyze the hydrolysis of NUcleoside DIphosphates linked to other moieties, X. Enzymes belonging to this superfamily require a divalent cation, such as Mg2+ or Mn2+, for their activity and contain a highly conserved 23-residue nudix motif (GX5EX7REUXEEXGU, where U = I, L or V), which functions as a metal binding and catalytic site. Substrates of nudix hydrolases include intact and oxidatively damaged nucleoside triphosphates, dinucleoside polyphosphates, nucleotide-sugars and dinucleotide enzymes. These substrates are metabolites or cell signaling molecules that require regulation during different stages of the cell cycle or during periods of stress. In general, the role of the nudix hydrolase is to sanitize the nucleotide pools and to maintain cell viability, thereby serving as surveillance & "house-cleaning" enzymes. Substrate specificity is used to define families within the superfamily. Differences in substrate specificity are determined by the N-terminal extension or by residues in variable loop regions. Mechanistically, substrate hydrolysis occurs by a nucleophilic substitution reaction, with variation in the numbers and roles of divalent cations required.бА0АкА0АаАCDDбАаАй│вА0А0АаАВхcd04696, Nudix_Hydrolase_37, Members of the Nudix hydrolase superfamily catalyze the hydrolysis of NUcleoside DIphosphates linked to other moieties, X. Enzymes belonging to this superfamily require a divalent cation, such as Mg2+ or Mn2+, for their activity and contain a highly conserved 23-residue nudix motif (GX5EX7REUXEEXGU, where U = I, L or V), which functions as a metal binding and catalytic site. Substrates of nudix hydrolases include intact and oxidatively damaged nucleoside triphosphates, dinucleoside polyphosphates, nucleotide-sugars and dinucleotide enzymes. These substrates are metabolites or cell signaling molecules that require regulation during different stages of the cell cycle or during periods of stress. In general, the role of the nudix hydrolase is to sanitize the nucleotide pools and to maintain cell viability, thereby serving as surveillance & "house-cleaning" enzymes. Substrate specificity is used to define families within the superfamily. Differences in substrate specificity are determined by the N-terminal extension or by residues in variable loop regions. Mechanistically, substrate hydrolysis occurs by a nucleophilic substitution reaction, with variation in the numbers and roles of divalent cations required.бА0АкА0АаАCDDбАаАй┤вА0А0АаАВхcd04697, Nudix_Hydrolase_38, Members of the Nudix hydrolase superfamily catalyze the hydrolysis of NUcleoside DIphosphates linked to other moieties, X. Enzymes belonging to this superfamily require a divalent cation, such as Mg2+ or Mn2+, for their activity and contain a highly conserved 23-residue nudix motif (GX5EX7REUXEEXGU, where U = I, L or V), which functions as a metal binding and catalytic site. Substrates of nudix hydrolases include intact and oxidatively damaged nucleoside triphosphates, dinucleoside polyphosphates, nucleotide-sugars and dinucleotide enzymes. These substrates are metabolites or cell signaling molecules that require regulation during different stages of the cell cycle or during periods of stress. In general, the role of the nudix hydrolase is to sanitize the nucleotide pools and to maintain cell viability, thereby serving as surveillance & "house-cleaning" enzymes. Substrate specificity is used to define families within the superfamily. Differences in substrate specificity are determined by the N-terminal extension or by residues in variable loop regions. Mechanistically, substrate hydrolysis occurs by a nucleophilic substitution reaction, with variation in the numbers and roles of divalent cations required.бА0АкА0АаАCDDбАаАй╡вА0А0АаАВхcd04699, Nudix_Hydrolase_39, Members of the Nudix hydrolase superfamily catalyze the hydrolysis of NUcleoside DIphosphates linked to other moieties, X. Enzymes belonging to this superfamily require a divalent cation, such as Mg2+ or Mn2+, for their activity and contain a highly conserved 23-residue nudix motif (GX5EX7REUXEEXGU, where U = I, L or V), which functions as a metal binding and catalytic site. Substrates of nudix hydrolases include intact and oxidatively damaged nucleoside triphosphates, dinucleoside polyphosphates, nucleotide-sugars and dinucleotide enzymes. These substrates are metabolites or cell signaling molecules that require regulation during different stages of the cell cycle or during periods of stress. In general, the role of the nudix hydrolase is to sanitize the nucleotide pools and to maintain cell viability, thereby serving as surveillance & "house-cleaning" enzymes. Substrate specificity is used to define families within the superfamily. Differences in substrate specificity are determined by the N-terminal extension or by residues in variable loop regions. Mechanistically, substrate hydrolysis occurs by a nucleophilic substitution reaction, with variation in the numbers and roles of divalent cations required.бА0АкА0АаАCDDбАаАй╢вА0А0АаАВ,cd04700, DR1025_like, DR1025 from Deinococcus radiodurans, a member of the Nudix hydrolase superfamily, show nucleoside triphosphatase and dinucleoside polyphosphate pyrophosphatase activities. Like other enzymes belonging to this superfamily, it requires a divalent cation, in this case Mg2+, for its activity. It also contains a highly conserved 23-residue nudix motif (GX5EX7REUXEEXGU, where U = I, L or V), which functions as a metal binding and catalytic site. In general, substrates of nudix hydrolases include intact and oxidatively damaged nucleoside triphosphates, dinucleoside polyphosphates, nucleotide-sugars and dinucleotide enzymes. These substrates are metabolites or cell signaling molecules that require regulation during different stages of the cell cycle or during periods of stress. In general, the role of the nudix hydrolase is to sanitize the nucleotide pools and to maintain cell viability, thereby serving as surveillance & "house-cleaning" enzymes. Substrate specificity is used to define families within the superfamily. Differences in substrate specificity are determined by the N-terminal extension or by residues in variable loop regions. Mechanistically, substrate hydrolysis occurs by a nucleophilic substitution reaction, with variation in the numbers and roles of divalent cations required.бА0АкА0АаАCDDбАаАй╖вА0А0АаАВвА0А0АаАВ╛cd04760, BAH_Dnmt1_I, BAH, or Bromo Adjacent Homology domain, first copy present in DNA (Cytosine-5)-methyltransferases from Bilateria, Dnmt1 and similar proteins. DNA methylation, or the covalent addition of a methyl group to cytosine within the context of the CpG dinucleotide, has profound effects on the genome. These effects include transcriptional repression via inhibition of transcription factor binding, the recruitment of methyl-binding proteins and their associated chromatin remodeling factors, X chromosome inactivation, imprinting, and the suppression of parasitic DNA sequences. DNA methylation is also essential for proper embryonic development and is an important player in both DNA repair and genome stability. BAH domains are found in a variety of proteins playing roles in transcriptional silencing and the remodeling of chromatin. It is assumed that in most or all of these instances the BAH domain mediates protein-protein interactions.бА0АкА0АаАCDDбАаАйывА0А0АаАВдcd04761, HTH_MerR-SF, Helix-Turn-Helix DNA binding domain of transcription regulators from the MerR superfamily. Helix-turn-helix (HTH) transcription regulator MerR superfamily, N-terminal domain. The MerR family transcription regulators have been shown to mediate responses to stress including exposure to heavy metals, drugs, or oxygen radicals in eubacterial and some archaeal species. They regulate transcription of multidrug/metal ion transporter genes and oxidative stress regulons by reconfiguring the spacer between the -35 and -10 promoter elements. A typical MerR regulator is comprised of two distinct domains that harbor the regulatory (effector-binding) site and the active (DNA-binding) site. Their N-terminal domains are homologous and contain a DNA-binding winged HTH motif, while the C-terminal domains are often dissimilar and bind specific coactivator molecules such as metal ions, drugs, and organic substrates.бА0АкА0АаАCDDбАаА вА0А0АаАВ5cd04762, HTH_MerR-trunc, Helix-Turn-Helix DNA binding domain of truncated MerR-like proteins. Proteins in this family mostly have a truncated helix-turn-helix (HTH) MerR-like domain. They lack a portion of the C-terminal region, called Wing 2 and the long dimerization helix that is typically present in MerR-like proteins. These truncated domains are found in response regulator receiver (REC) domain proteins (i.e., CheY), cytosine-C5 specific DNA methylases, IS607 transposase-like proteins, and RacA, a bacterial protein that anchors chromosomes to cell poles.бА0АкА0АаАCDDбАаА вА0А0АаАВ$cd04763, HTH_MlrA-like, Helix-Turn-Helix DNA binding domain of MlrA-like transcription regulators. Helix-turn-helix (HTH) transcription regulator MlrA (merR-like regulator A) and related proteins, N-terminal domain. The MlrA protein, also known as YehV, has been shown to control cell-cell aggregation by co-regulating the expression of curli and extracellular matrix production in Escherichia coli and Salmonella typhimurium. Its close homolog, CarA from Myxococcus xanthus, is involved in activation of the carotenoid biosynthesis genes by light. These proteins belong to the MerR superfamily of transcription regulators that promote expression of several stress regulon genes by reconfiguring the spacer between the -35 and -10 promoter elements. Their conserved N-terminal domains contain predicted HTH motifs that mediate DNA binding, while the dissimilar C-terminal domains bind specific coactivator molecules. Many MlrA-like proteins in this group appear to lack the long dimerization helix seen in the N-terminal domains of typical MerR-like proteins.бА0АкА0АаАCDDбАаА вА0А0АаАВУcd04764, HTH_MlrA-like_sg1, Helix-Turn-Helix DNA binding domain of putative MlrA-like transcription regulators. Putative helix-turn-helix (HTH) MlrA-like transcription regulators (subgroup 1). The MlrA protein, also known as YehV, has been shown to control cell-cell aggregation by co-regulating the expression of curli and extracellular matrix production in Escherichia coli and Salmonella typhimurium. These proteins belong to the MerR superfamily of transcription regulators that promote expression of several stress regulon genes by reconfiguring the spacer between the -35 and -10 promoter elements. Their conserved N-terminal domains contain predicted HTH motifs that mediate DNA binding, while the dissimilar C-terminal domains bind specific coactivator molecules. Many MlrA-like proteins in this group appear to lack the long dimerization helix seen in the N-terminal domains of typical MerR-like proteins.бА0АкА0АаАCDDбАаА вА0А0АаАВcd04765, HTH_MlrA-like_sg2, Helix-Turn-Helix DNA binding domain of putative MlrA-like transcription regulators. Putative helix-turn-helix (HTH) MlrA-like transcription regulators (subgroup 2), N-terminal domain. The MlrA protein, also known as YehV, has been shown to control cell-cell aggregation by co-regulating the expression of curli and extracellular matrix production in Escherichia coli and Salmonella typhimurium. These proteins belong to the MerR superfamily of transcription regulators that promote expression of several stress regulon genes by reconfiguring the spacer between the -35 and -10 promoter elements. Their conserved N-terminal domains contain predicted HTH motifs that mediate DNA binding, while the dissimilar C-terminal domains bind specific coactivator molecules.бА0АкА0АаАCDDбАаА вА0А0АаАВ}cd04766, HTH_HspR, Helix-Turn-Helix DNA binding domain of the HspR transcription regulator. Helix-turn-helix (HTH) transcription regulator HspR, N-terminal domain. Heat shock protein regulators (HspR) have been shown to regulate expression of specific regulons in response to high temperature or high osmolarity in Streptomyces and Helicobacter, respectively. These proteins share the N-terminal DNA binding domain with other transcription regulators of the MerR superfamily that promote transcription by reconfiguring the spacer between the -35 and -10 promoter elements. A typical MerR regulator is comprised of distinct domains that harbor the regulatory (effector-binding) site and the active (DNA-binding) site. Their conserved N-terminal domains contain predicted winged HTH motifs that mediate DNA binding, while the dissimilar C-terminal domains bind specific coactivator molecules.бА0АкА0АаАCDDбАаА вА0А0АаАВcd04767, HTH_HspR-like_MBC, Helix-Turn-Helix DNA binding domain of putative HspR-like transcription regulators. Putative helix-turn-helix (HTH) transcription regulator HspR-like proteins. Unlike the characterized HspR, these proteins have a C-terminal domain with putative metal binding cysteines (MBC). Heat shock protein regulators (HspR) have been shown to regulate expression of specific regulons in response to high temperature or high osmolarity in Streptomyces and Helicobacter, respectively. These proteins share the N-terminal DNA binding domain with other transcription regulators of the MerR superfamily that promote transcription by reconfiguring the spacer between the -35 and -10 promoter elements. A typical MerR regulator is comprised of distinct domains that harbor the regulatory (effector-binding) site and the active (DNA-binding) site. Their conserved N-terminal domains contain predicted winged HTH motifs that mediate DNA binding, while the dissimilar C-terminal domains bind specific coactivator molecules.бА0АкА0АаАCDDбАаА вА0А0АаАВйcd04768, HTH_BmrR-like, Helix-Turn-Helix DNA binding domain of BmrR-like transcription regulators. Helix-turn-helix (HTH) BmrR-like transcription regulators (TipAL, Mta, SkgA, BmrR, and BltR), N-terminal domain. These proteins have been shown to regulate expression of specific regulons in response to various toxic substances, antibiotics, or oxygen radicals in Bacillus subtilis, Streptomyces, and Caulobacter crescentus. They are comprised of two distinct domains that harbor the regulatory (effector-binding) site and the active (DNA-binding) site. Their conserved N-terminal domains contain HTH motifs that mediate DNA binding, while the C-terminal domains are often unrelated and bind specific coactivator molecules. These proteins share the N-terminal DNA binding domain with other transcription regulators of the MerR superfamily that promote transcription by reconfiguring the spacer between the -35 and -10 promoter elements.бА0АкА0АаАCDDбАаА вА