Protein Disulfide Oxidoreductases and Other Proteins with a Thioredoxin fold; The thioredoxin (TRX)-like superfamily is a large, diverse group of proteins containing a TRX fold. Many members contain a classic TRX domain with a redox active CXXC motif. They function as protein disulfide oxidoreductases (PDOs), altering the redox state of target proteins via the reversible oxidation of their active site dithiol. The PDO members of this superfamily include the families of TRX, protein disulfide isomerase (PDI), tlpA, glutaredoxin, NrdH redoxin, and bacterial Dsb proteins (DsbA, DsbC, DsbG, DsbE, DsbDgamma). Members of the superfamily that do not function as PDOs but contain a TRX-fold domain include phosducins, peroxiredoxins, glutathione (GSH) peroxidases, SCO proteins, GSH transferases (GST, N-terminal domain), arsenic reductases, TRX-like ferredoxins and calsequestrin, among others.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958752219   3 MTLGYWDIRGL-----------------------------------------------PYLIDGSHKITQSNAILRYIAR 35
Cdd:cd03075     1 PTLGYWDIRGLaqpirllleytgekyeekryelgdapdydrsqwlnekfklgldfpnlPYYIDGDVKLTQSNAILRYIAR 80

                  ..
gi 1958752219  36 KH 37
Cdd:cd03075    81 KH 82

Glutathione S-transferase, C-terminal domain; GST conjugates reduced glutathione to a variety of targets including S-crystallin from squid, the eukaryotic elongation factor 1-gamma, the HSP26 family of stress-related proteins and auxin-regulated proteins in plants. Stringent starvation proteins in E. coli are also included in the alignment but are not known to have GST activity. The glutathione molecule binds in a cleft between N and C-terminal domains. The catalytically important residues are proposed to reside in the N-terminal domain. In plants, GSTs are encoded by a large gene family (48 GST genes in Arabidopsis) and can be divided into the phi, tau, theta, zeta, and lambda classes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958752219  58 MDVSNQLARVCYSPDFENLKAEYLEQLPGMMELFSQF---LGKQTWFVGEKITFVDFLAYDILDLHLIFEPKCL-DAFPN 133
Cdd:pfam00043   2 MDLRMQIALLPYVPPEEKKEPEVDEALEKVARVLSALeevLKGQTYLVGDKLTLADIALAPALLWLYELDPACLrEKFPN 81

                          90
                  ....*....|.
gi 1958752219 134 LKDFVARFEGL 144
Cdd:pfam00043  82 LKAWFERVAAR 92

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958752219   3 MTLGYWDIRGL-----------------------------------------------PYLIDGSHKITQSNAILRYIAR 35
Cdd:cd03075     1 PTLGYWDIRGLaqpirllleytgekyeekryelgdapdydrsqwlnekfklgldfpnlPYYIDGDVKLTQSNAILRYIAR 80

                  ..
gi 1958752219  36 KH 37
Cdd:cd03075    81 KH 82

Glutathione S-transferase, N-terminal domain; Function: conjugation of reduced glutathione to a variety of targets. Also included in the alignment, but not GSTs: S-crystallins from squid (similarity to GST previously noted); eukaryotic elongation factors 1-gamma (not known to have GST activity and similarity not previously recognized); HSP26 family of stress-related proteins including auxin-regulated proteins in plants and stringent starvation proteins in E. coli (not known to have GST activity and similarity not previously recognized). The glutathione molecule binds in a cleft between the N- and C-terminal domains - the catalytically important residues are proposed to reside in the N-terminal domain.

                          10        20
                  ....*....|....*....|...
gi 1958752219  13 LPYLIDGSHKITQSNAILRYIAR 35
Cdd:pfam02798  54 VPALEDGGKKLTESRAILEYIAR 76

Glutathione S-transferase, C-terminal domain; GST conjugates reduced glutathione to a variety of targets including S-crystallin from squid, the eukaryotic elongation factor 1-gamma, the HSP26 family of stress-related proteins and auxin-regulated proteins in plants. Stringent starvation proteins in E. coli are also included in the alignment but are not known to have GST activity. The glutathione molecule binds in a cleft between N and C-terminal domains. The catalytically important residues are proposed to reside in the N-terminal domain. In plants, GSTs are encoded by a large gene family (48 GST genes in Arabidopsis) and can be divided into the phi, tau, theta, zeta, and lambda classes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958752219  58 MDVSNQLARVCYSPDFENLKAEYLEQLPGMMELFSQF---LGKQTWFVGEKITFVDFLAYDILDLHLIFEPKCL-DAFPN 133
Cdd:pfam00043   2 MDLRMQIALLPYVPPEEKKEPEVDEALEKVARVLSALeevLKGQTYLVGDKLTLADIALAPALLWLYELDPACLrEKFPN 81

                          90
                  ....*....|.
gi 1958752219 134 LKDFVARFEGL 144
Cdd:pfam00043  82 LKAWFERVAAR 92

C-terminal, alpha helical domain of Class Pi Glutathione S-transferases; Glutathione S-transferase (GST) C-terminal domain 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 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. 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 tumors.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958752219  44 EEEKIRVDILENQAMDVSNQLARVCYsPDFENLKAEYLEQLPGMMELFSQFL---GKQTWFVGEKITFVDFLAYDILDLH 120
Cdd:cd03210     1 EKEAALIDMVNDGVEDLRLKYVRMIY-QNYEAGKDDYIKDLPEQLKPFEKLLaknNGKGFIVGDKISFADYNLFDLLDIH 79

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|
gi 1958752219 121 LIFEPKCLDAFPNLKDFVARFEGLKKISVYMKTSRFLRTP 160
Cdd:cd03210    80 LVLAPGCLDAFPLLKAFVERLSARPKLKAYLESDAFKNRP 119

Glutathione S-transferase [Posttranslational modification, protein turnover, chaperones];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958752219  14 PYLIDGSHKITQSNAILRYIARKH---NLCGETEEEKIRVDILENQAM-DVSNQLARV---CYSPDFENLKAEYLEQLPG 86
Cdd:COG0625    54 PVLVDDGLVLTESLAILEYLAERYpepPLLPADPAARARVRQWLAWADgDLHPALRNLlerLAPEKDPAAIARARAELAR 133

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 1958752219  87 MMELFSQFLGKQTWFVGEKITFVDFLAYDILDLHLIFEPKcLDAFPNLKDFVARFE 142
Cdd:COG0625   134 LLAVLEARLAGGPYLAGDRFSIADIALAPVLRRLDRLGLD-LADYPNLAAWLARLA 188

C-terminal, alpha helical domain of the Glutathione S-transferase family; Glutathione S-transferase (GST) family, C-terminal alpha helical domain; a large, diverse group of 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. In addition, GSTs also show GSH peroxidase activity and are involved in the synthesis of prostaglandins and leukotrienes. This family, also referred to as soluble GSTs, is the largest family of GSH transferases and is only distantly related to the mitochondrial GSTs (GSTK). Soluble GSTs bear no structural similarity to microsomal GSTs (MAPEG family) and display additional activities unique to their group, such as catalyzing thiolysis, reduction and isomerization of certain compounds. 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. Based on sequence similarity, different classes of GSTs have been identified, which display varying tissue distribution, substrate specificities and additional specific activities. In humans, GSTs display polymorphisms which may influence individual susceptibility to diseases such as cancer, arthritis, allergy and sclerosis. Some GST family members with non-GST functions include glutaredoxin 2, the CLIC subfamily of anion channels, prion protein Ure2p, crystallins, metaxins, stringent starvation protein A, and aminoacyl-tRNA synthetases.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1958752219  71 PDFENLKAEYLEQLPGMMELFSQFLGKQTWFVGEKITFVDFLAYDILDLHLIFEPKC--LDAFPNLKDFVAR 140
Cdd:cd00299    28 PKDEAAVEAAREELPALLAALEQLLAGRPYLAGDQFSLADVALAPVLARLEALGPYYdlLDEYPRLKAWYDR 99

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.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1958752219   3 MTLGYWDIRG---------------------------------------LPYLIDGSHKITQSNAILRYIAR 35
Cdd:cd03039     1 YKLTYFNIRGrgepirllladagveyedvrityeewpeldlkptlpfgqLPVLEIDGKKLTQSNAILRYLAR 72

Glutathione S-transferase, N-terminal domain; Function: conjugation of reduced glutathione to a variety of targets. Also included in the alignment, but not GSTs: S-crystallins from squid (similarity to GST previously noted); eukaryotic elongation factors 1-gamma (not known to have GST activity and similarity not previously recognized); HSP26 family of stress-related proteins including auxin-regulated proteins in plants and stringent starvation proteins in E. coli (not known to have GST activity and similarity not previously recognized). The glutathione molecule binds in a cleft between the N- and C-terminal domains - the catalytically important residues are proposed to reside in the N-terminal domain.

                          10        20
                  ....*....|....*....|...
gi 1958752219  13 LPYLIDGSHKITQSNAILRYIAR 35
Cdd:pfam02798  54 VPALEDGGKKLTESRAILEYIAR 76

Glutathione S-transferase (GST) family, N-terminal domain; a large, diverse group of 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. In addition, GSTs also show GSH peroxidase activity and are involved in the synthesis of prostaglandins and leukotrienes. This family, also referred to as soluble GSTs, is the largest family of GSH transferases and is only distantly related to the mitochondrial GSTs (GSTK subfamily, a member of the DsbA family). Soluble GSTs bear no structural similarity to microsomal GSTs (MAPEG family) and display additional activities unique to their group, such as catalyzing thiolysis, reduction and isomerization of certain compounds. 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. Based on sequence similarity, different classes of GSTs have been identified, which display varying tissue distribution, substrate specificities and additional specific activities. In humans, GSTs display polymorphisms which may influence individual susceptibility to diseases such as cancer, arthritis, allergy and sclerosis. Some GST family members with non-GST functions include glutaredoxin 2, the CLIC subfamily of anion channels, prion protein Ure2p, crystallins, metaxin 2 and stringent starvation protein A.

                          10        20
                  ....*....|....*....|..
gi 1958752219  13 LPYLIDGSHKITQSNAILRYIA 34
Cdd:cd00570    50 VPVLEDGGLVLTESLAILEYLA 71

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.

                          10        20
                  ....*....|....*....|...
gi 1958752219  14 PYLIDGSHKITQSNAILRYIARK 36
Cdd:cd03053    54 PALEDGDLKLFESRAITRYLAEK 76

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.

                          10        20
                  ....*....|....*....|....
gi 1958752219  14 PYLIDGSHKITQSNAILRYIARKH 37
Cdd:cd03046    52 PVLVDGDLVLTESAAIILYLAEKY 75