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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 2024389789   4 KPRLTYVNGRGRMESIRWLLSAAGVEFEEIFLETREQLLKLCQDGSLLFHQLPLVEIDGMKLVQCRAILSYIAGKYNLY 82
Cdd:cd03077     1 KPVLHYFNGRGRMESIRWLLAAAGVEFEEKFIESAEDLEKLKKDGSLMFQQVPMVEIDGMKLVQTRAILNYIAGKYNLY 79

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.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 2024389789   4 KPRLTYVNGRGRMESIRWLLSAAGVEFEEIFLETREQLLKLCQDGSLLFHQLPLVEIDGMKLVQCRAILSYIAGKYNLY 82
Cdd:cd03077     1 KPVLHYFNGRGRMESIRWLLAAAGVEFEEKFIESAEDLEKLKKDGSLMFQQVPMVEIDGMKLVQTRAILNYIAGKYNLY 79

glutathione s-transferase; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024389789   7 LTYVNGRGRMESIRWLLSAAGVEF-EEIFLETREQLLKLC---QDGSLLFHQLPLVEIDGMKLVQCRAILSYIAGKYNLY 82
Cdd:PTZ00057    7 LYYFDARGKAELIRLIFAYLGIEYtDKRFGENGDAFIEFKnfkKEKDTPFEQVPILEMDNIIFAQSQAIVRYLSKKYKIC 86

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024389789  83 GKDLKERALIDMYVEGISDLMqlilvFPFSPPEAKEKNLATIAEKATERYFPVFEKVLKQHGQDFLVGNRFSWADVQLME 162
Cdd:PTZ00057   87 GESELNEFYADMIFCGVQDIH-----YKFNNTNLFKQNETTFLNEELPKWSGYFENILKKNHCNYFVGDNLTYADLAVFN 161

                         170       180       190
                  ....*....|....*....|....*....|....*.
gi 2024389789 163 AILAVEEKVPSVLSGFPQLQAFKTKMSNMPTIKKFL 198
Cdd:PTZ00057  162 LYDDIETKYPNSLKNFPLLKAHNEFISNLPNIKNYI 197

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        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 2024389789   7 LTYVNGRG--RMESIRWLLSAAGVEFEEIFLET---REQLLKLCQDGSLlfHQLPLVEIDGMKLVQCRAILSYIA 76
Cdd:pfam02798   3 LTLYGIRGspRAHRIRWLLAEKGVEYEIVPLDFgagPEKSPELLKLNPL--GKVPALEDGGKKLTESRAILEYIA 75

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.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 2024389789   4 KPRLTYVNGRGRMESIRWLLSAAGVEFEEIFLETREQLLKLCQDGSLLFHQLPLVEIDGMKLVQCRAILSYIAGKYNLY 82
Cdd:cd03077     1 KPVLHYFNGRGRMESIRWLLAAAGVEFEEKFIESAEDLEKLKKDGSLMFQQVPMVEIDGMKLVQTRAILNYIAGKYNLY 79

Glutathione S-transferase, C-terminal domain; This domain is closely related to pfam00043.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024389789 101 DLMQLILVFPFSPPEAKEKNL-ATIAEKATERYFPVFEKVLKQHGQDFLVGNRFSWADVQLMEAILAVEE-KVPSVLSGF 178
Cdd:pfam14497   2 DLHHPIASSLYYEDEKKKAKRrKEFREERLPKFLGYFEKVLNKNGGGYLVGDKLTYADLALFQVLDGLLYpKAPDALDKY 81

                          90       100
                  ....*....|....*....|.
gi 2024389789 179 PQLQAFKTKMSNMPTIKKFLQ 199
Cdd:pfam14497  82 PKLKALHERVAARPNIKAYLA 102

C-terminal, alpha helical domain of Class Sigma-like Glutathione S-transferases; Glutathione S-transferase (GST) C-terminal domain 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 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. 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-like members include the class II insect GSTs, S-crystallins from cephalopods, nematode-specific GSTs, 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. Members also include 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        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024389789  88 ERALIDMYVEGISDLMQLILVFPFSP-PEAKEKNLATIAEKATERYFPVFEKVLKQHGQDFLVGNRFSWADVQLMEAILA 166
Cdd:cd03192     2 EEARVDAIVDTIADLRAEFAPYFYEPdGEEKKEKKKEFLEEALPKFLGKFEKILKKSGGGYFVGDKLTWADLALFDVLDY 81

                          90       100
                  ....*....|....*....|...
gi 2024389789 167 VEEKVPS-VLSGFPQLQAFKTKM 188
Cdd:cd03192    82 LLYLLPKdLLEKYPKLKALRERV 104

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 2024389789 101 DLMQLILVFPFSPPEAKEKNLATIAEKATERYFPVFEKVLKqhGQDFLVGNRFSWADVQLMEAILAVEEKVPSVLS-GFP 179
Cdd:pfam00043   3 DLRMQIALLPYVPPEEKKEPEVDEALEKVARVLSALEEVLK--GQTYLVGDKLTLADIALAPALLWLYELDPACLReKFP 80

                          90
                  ....*....|...
gi 2024389789 180 QLQAFKTKMSNMP 192
Cdd:pfam00043  81 NLKAWFERVAARP 93

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        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 2024389789   7 LTYVNGRG--RMESIRWLLSAAGVEFEEIFLET---REQLLKLCQDGSLlfHQLPLVEIDGMKLVQCRAILSYIA 76
Cdd:pfam02798   3 LTLYGIRGspRAHRIRWLLAEKGVEYEIVPLDFgagPEKSPELLKLNPL--GKVPALEDGGKKLTESRAILEYIA 75

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        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 2024389789   5 PRLTYVNGRGRMESIRWLLSAAGVEFEEIFLETREQLLKLCQDGSlLFHQLPLVEIDGMKLVQCRAILSYIA 76
Cdd:cd00570     1 LKLYYFPGSPRSLRVRLALEEKGLPYELVPVDLGEGEQEEFLALN-PLGKVPVLEDGGLVLTESLAILEYLA 71

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.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 2024389789   4 KPRLTYVNGRGRMESIRWLLSAAGVEFEEIFL--ETREQLLKlcqdGSLLFHQLPLVEIDGMKLVQCRAILSYIAGK 78
Cdd:cd03076     1 PYTLTYFPVRGRAEAIRLLLADQGISWEEERVtyEEWQESLK----PKMLFGQLPCFKDGDLTLVQSNAILRHLGRK 73

C-terminal, alpha helical domain of fungal Ure2p Glutathione S-transferases; Glutathione S-transferase (GST) C-terminal domain family, Ure2p subfamily; composed of the Saccharomyces cerevisiae Ure2p and related fungal 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. 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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024389789 125 AEK---ATERY-------FPVFEKVLKQHGQDFLVGNRFSWADV------QLMEAILAVEEKVPSvlSGFPQLQAFKTKM 188
Cdd:cd10293    31 AEKvpsAIERYtneirrvLGVLETALAERYRVWLVGDKFTIADLafvpwnNVVDMIFIDPELDIK--KEFPHVYKWLKRM 108

                  ....*...
gi 2024389789 189 SNMPTIKK 196
Cdd:cd10293   109 LARPAVKK 116

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024389789  88 ERALIDMYVEGISDLMQLilvFPF--SPPEAKEKNLATIAEKATERYFPVFEKVLKqhGQDFLVGNRFSWADVQLMEAIL 165
Cdd:cd10295     3 EQCLVDALVDTLDDFMSC---FPWaeKKQDVKEKMFNEALTGPAPHLLKDLDTYLG--GREWLVGKSVTWADFYWDTCST 77

                          90       100
                  ....*....|....*....|..
gi 2024389789 166 AVEEKVPSVLSGFPQLQAFKTK 187
Cdd:cd10295    78 TLLSFKPDLLKNYPRLVALRDK 99

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        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024389789  89 RALIDMYVEGISDLMQLILVFPFSPPEAKEKNLATiAEKATERYFPVFEKVLKQHGqdFLVGNRFSWADVQLMEAILAVE 168
Cdd:cd00299     2 RALEDWADATLAPPLVRLLYLEKVPLPKDEAAVEA-AREELPALLAALEQLLAGRP--YLAGDQFSLADVALAPVLARLE 78

                          90
                  ....*....|....*...
gi 2024389789 169 --EKVPSVLSGFPQLQAF 184
Cdd:cd00299    79 alGPYYDLLDEYPRLKAW 96

C-terminal, alpha helical domain of Class Beta Glutathione S-transferases; Glutathione S-transferase (GST) C-terminal domain 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 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. Unlike mammalian GSTs which detoxify a broad range of compounds, the bacterial class Beta GSTs exhibit GSH conjugating activity with a narrow range of substrates. In addition to GSH conjugation, they are involved in the protection against oxidative stress and are able to bind antibiotics and reduce the antimicrobial activity of beta-lactam drugs, contributing to antibiotic resistance. The structure of the Proteus mirabilis enzyme reveals that the cysteine in the active site forms a covalent bond with GSH. One member of this subfamily is a GST from Burkholderia xenovorans LB400 that is encoded by the bphK gene and is part of the biphenyl catabolic pathway.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024389789 112 SPPEAKEKNLATIAEKateryFPVFEKVLKqhGQDFLVGNRFSWADvqlmeAILAVE----EKVPSVLSGFPQLQAFKTK 187
Cdd:cd03188    35 LAEEVKAAARERLERR-----LAYLDAQLA--GGPYLLGDQFSVAD-----AYLFVVlrwaRAVGLDLSDWPHLAAYLAR 102

                          90
                  ....*....|.
gi 2024389789 188 MSNMPTIKKFL 198
Cdd:cd03188   103 VAARPAVQAAL 113