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 930031290   3 QLFQFPLCPFSRKVRLLLGEKGIGYELVRESPWEQR-DEFLDMNPAGRTPVMrhRDRDQTLCDSWAICEYFE 73
Cdd:cd00570    2 KLYYFPGSPRSLRVRLALEEKGLPYELVPVDLGEGEqEEFLALNPLGKVPVL--EDGGLVLTESLAILEYLA 71

putative glutathione S-transferase; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 930031290  11 PFSRKVRLLLGEKGIGYELVRESPWEQRDEFLDMNPAGRTPVMRhRDRDQTLCDSWAICEYFEETVEKNPMIngSADNRA 90
Cdd:PRK10357  10 PFVRKISILLLEKGITFEFVNELPYNADNGVAQYNPLGKVPALV-TEEGECWFDSPIIAEYIELLNVAPAML--PRDPLA 86

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 930031290  91 --EIRRLVAWFDEqfFGDVVAPLMHERMRkrliyrqPPDGRVLREAMRL---ANTHLDYID-YLLDHNawIGGATMSLAD 164
Cdd:PRK10357  87 alRVRQLEALADG--IMDAALVSVREQAR-------PAAQQSEDELLRQrekINRSLDALEgYLVDGT--LKTDTVNLAT 155

                        170
                 ....*....|...
gi 930031290 165 LAAAAHISiadYL 177
Cdd:PRK10357 156 IAIACAVG---YL 165

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 930031290   3 QLFQFPLCPFSRKVRLLLGEKGIGYELVRESPWEQR-DEFLDMNPAGRTPVMrhRDRDQTLCDSWAICEYFE 73
Cdd:cd00570    2 KLYYFPGSPRSLRVRLALEEKGLPYELVPVDLGEGEqEEFLALNPLGKVPVL--EDGGLVLTESLAILEYLA 71

Glutathione S-transferase, N-terminal domain;

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 930031290    4 LFQFPLCPFSRKVRLLLGEKGIGYELVRESPWEQRDEFLDMNPAGRTPVMRHRDRdqTLCDSWAICEYFEETVEKNP 80
Cdd:pfam13417   1 LYGFPGSPYARRVRIALNEKGLPYEFVPIPPGDHPPELLAKNPLGKVPVLEDDGG--ILCESLAIIDYLEELYPGPP 75

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.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 930031290   3 QLFQFPLCPFSRKVRLLLGEKGIG--YELVRESPWEQRDEFLDMNPAGRTPVMRhRDRDQTLCDSWAICEY 71
Cdd:cd03049    2 KLLYSPTSPYVRKVRVAAHETGLGddVELVLVNPWSDDESLLAVNPLGKIPALV-LDDGEALFDSRVICEY 71

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.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 930031290   4 LFQFPLCPFSRKVRLLLGEKGIGYELVRESPWEQRDEFLDMNPAGRTPVMrhRDRDQTLCDSWAICEYFEE 74
Cdd:cd03059    3 LYSGPDDVYSHRVRIVLAEKGVSVEIIDVDPDNPPEDLAELNPYGTVPTL--VDRDLVLYESRIIMEYLDE 71

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 930031290    4 LFQFPLCPFSRKVRLLLGEKGIGYELVRESPW---EQRDEFLDMNPAGRTPVMRHrdRDQTLCDSWAICEYFEE 74
Cdd:pfam02798   5 LYGIRGSPRAHRIRWLLAEKGVEYEIVPLDFGagpEKSPELLKLNPLGKVPALED--GGKKLTESRAILEYIAR 76

glutathione S-transferase

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 930031290   8 PLCPFSRKVRLLLGEKGIGYELVRES--PWEQRD-EFLDMNPAGRTPVMRhrDRDQTLCDSWAICEYFEETVEKN--PMI 82
Cdd:PLN02395   8 PAFASPKRALVTLIEKGVEFETVPVDlmKGEHKQpEYLALQPFGVVPVIV--DGDYKIFESRAIMRYYAEKYRSQgpDLL 85

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 930031290  83 NGSADNRAEIRRlvaWFD---EQFFGDVVAPLMHERMRKRLIYrqPPDGRVLREAMRLANTHLDYIDYLLDHNAWIGGAT 159
Cdd:PLN02395  86 GKTIEERGQVEQ---WLDveaTSYHPPLLNLTLHILFASKMGF--PADEKVIKESEEKLAKVLDVYEARLSKSKYLAGDF 160

                        170       180       190       200       210
                 ....*....|....*....|....*....|....*....|....*....|..
gi 930031290 160 MSLADLaaaAHISIADYLGGIDWLAH-----AQTADWYRKFKSRPSFRPLLA 206
Cdd:PLN02395 161 VSLADL---AHLPFTEYLVGPIGKAYlikdrKHVSAWWDDISSRPAWKEVLA 209

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        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 930031290   4 LFQFPLCPFSRKVRLLLGEKGIGYELVRESPW--EQRD-EFLDMNPAGRTPVMrhRDRDQTLCDSWAICEYFEE 74
Cdd:cd03053    4 LYGAAMSTCVRRVLLCLEEKGVDYELVPVDLTkgEHKSpEHLARNPFGQIPAL--EDGDLKLFESRAITRYLAE 75

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.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 930031290   1 MWQLFQFPlCPFSRKVRLLLGEKGIGYEL--VRESPWEQRD-EFLDMNPAGRTPVMRHRDR-DQTLCDSWAICEYFEET 75
Cdd:cd03048    1 MITLYTHG-TPNGFKVSIMLEELGLPYEIhpVDISKGEQKKpEFLKINPNGRIPAIVDHNGtPLTVFESGAILLYLAEK 78

stringent starvation protein A; Provisional

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 930031290   4 LFQFPLCPFSRKVRLLLGEKGIGYELVRESPWEQRDEFLDMNPAGRTPVMrhRDRDQTLCDSWAICEYFEE 74
Cdd:PRK09481  13 LFSGPTDIYSHQVRIVLAEKGVSVEIEQVEKDNLPQDLIDLNPYQSVPTL--VDRELTLYESRIIMEYLDE 81

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.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 930031290  18 LLLGEKGIGYE--LVRESPWEQRDEFLDMNPAGRTPVMRHRDRdqTLCDSWAICEY 71
Cdd:cd03043   18 LLLKAAGIPFEeiLVPLYTPDTRARILEFSPTGKVPVLVDGGI--VVWDSLAICEY 71

glutathione S-transferase DHAR1

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 930031290  10 CPFSRKVRLLLGEKGIGYELVRESPWEQRDEFLDMNPAGRTPVMRHRDRDQTlcDSWAICEYFEETVEKNPM 81
Cdd:PLN02378  20 CPFSQRALLTLEEKSLTYKIHLINLSDKPQWFLDISPQGKVPVLKIDDKWVT--DSDVIVGILEEKYPDPPL 89

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.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 930031290   4 LFQFPLCPFSRKVRLLLGEKGIGYELVRESPWEQ---RDEFLDMNPAGRTPVMrhRDRDQTLCDSWAICEY 71
Cdd:cd03045    3 LYYLPGSPPCRAVLLTAKALGLELNLKEVNLMKGehlKPEFLKLNPQHTVPTL--VDNGFVLWESHAILIY 71

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.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 930031290  13 SRKVRLLLGEKGIGYELVRES-PWEQRDE--FLDMNPAGRTPVMRHRDRdqTLCDSWAICEYFE 73
Cdd:cd03052   12 SQKVRLVIAEKGLRCEEYDVSlPLSEHNEpwFMRLNPTGEVPVLIHGDN--IICDPTQIIDYLE 73

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.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*..
gi 930031290   1 MWQLFQFPLCPFSRKVRLLLGEKGIGYELV---RESPweQRDEFLDM 44
Cdd:cd03041    1 PLELYEFEGSPFCRLVREVLTELELDVILYpcpKGSP--KRDKFLEK 45

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.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 930031290 121 IYRQPPDGRV---LREAMRLANTHLDYIDYLLDHNAWIGGATMSLADLAAAAHISiADYLGGIDWLAHAQTADWYRKFKS 197
Cdd:cd03180   28 LVRTPPEQRDpaaIAASLAACNKLMAILDAQLARQAYLAGDRFTLADIALGCSVY-RWLELPIERPALPHLERWYARLSQ 106

                 ....
gi 930031290 198 RPSF 201
Cdd:cd03180  107 RPAF 110

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.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 930031290 129 RVLREAMRLanthLDYIDYLLDHNAWIGGATMSLADLAAAAHISIADYLGGIDWLAHAQTADWYRKFKSRPSFRP 203
Cdd:cd03178   40 RYTDEVKRL----YGVLDKRLSDRPYLAGEEYSIADIALYPWTHYADLGGFADLSEYPNVKRWLERIAARPAVQK 110