C-terminal, alpha helical domain of Class Theta Glutathione S-transferases; Glutathione S-transferase (GST) C-terminal domain 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 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. 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 the 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 the aryl or alkyl sulfate esters.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21536248  92 RARVDEYLAWQHTALRSCCTRAMWQKMMFPVFLGQPVPPEMLASTLAELDGCLQVLEDKFLRNQAFLTGSHISVADLVAI 171
Cdd:cd03183   2 RARVDEYLAWQHTNLRLGCAAYFWQKVLLPLFGGTPVSPEKVKKAEENLEESLDLLENKFLKDKPFLAGDEISIADLSAI 81

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*
gi 21536248 172 TELMHPVSAGCKIFESRPKLAAWRQRVEAEvGESLFQEAHEVVLK 216
Cdd:cd03183  82 CEIMQPEAAGYDVFEGRPKLAAWRKRVKEA-GNPLFDEAHKVIYK 125

C-terminal, alpha helical domain of Class Theta Glutathione S-transferases; Glutathione S-transferase (GST) C-terminal domain 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 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. 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 the 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 the aryl or alkyl sulfate esters.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21536248  92 RARVDEYLAWQHTALRSCCTRAMWQKMMFPVFLGQPVPPEMLASTLAELDGCLQVLEDKFLRNQAFLTGSHISVADLVAI 171
Cdd:cd03183   2 RARVDEYLAWQHTNLRLGCAAYFWQKVLLPLFGGTPVSPEKVKKAEENLEESLDLLENKFLKDKPFLAGDEISIADLSAI 81

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*
gi 21536248 172 TELMHPVSAGCKIFESRPKLAAWRQRVEAEvGESLFQEAHEVVLK 216
Cdd:cd03183  82 CEIMQPEAAGYDVFEGRPKLAAWRKRVKEA-GNPLFDEAHKVIYK 125

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21536248   3 LELYLDLMSQPCRAVYIFAKKNGIPFQLRTIELLKGQQYTDSFAQVNPLRKVPALKDGDFVLAESVAILLYLSRKYKAPd 82
Cdd:COG0625   2 MKLYGSPPSPNSRRVRIALEEKGLPYELVPVDLAKGEQKSPEFLALNPLGKVPVLVDDGLVLTESLAILEYLAERYPEP- 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21536248  83 HWYPQDLQTRARVDEYLAWQHTALRSCCTRAMWQkmmfpvfLGQPVPPEMLASTLAELDGCLQVLEDKfLRNQAFLTGSH 162
Cdd:COG0625  81 PLLPADPAARARVRQWLAWADGDLHPALRNLLER-------LAPEKDPAAIARARAELARLLAVLEAR-LAGGPYLAGDR 152

                       170       180       190
                ....*....|....*....|....*....|....*...
gi 21536248 163 ISVADLVAITELMHPVSAGCKIfESRPKLAAWRQRVEA 200
Cdd:COG0625 153 FSIADIALAPVLRRLDRLGLDL-ADYPNLAAWLARLAA 189

glutathione S-transferase

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21536248    1 MGLELYLDLMSQPCRAVYIFAKKnGIPFQLRTIELLKGQQYTDSFAQVNPLRKVPALKDGDFVLAESVAILLYLSRKYKA 80
Cdd:PLN02395   1 MVLKVYGPAFASPKRALVTLIEK-GVEFETVPVDLMKGEHKQPEYLALQPFGVVPVIVDGDYKIFESRAIMRYYAEKYRS 79

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21536248   81 --PDhWYPQDLQTRARVDEYLAWQHTALRSCCTrAMWQKMMFPVFLGQPVPPEMLASTLAELDGCLQVLEDKFLRNQaFL 158
Cdd:PLN02395  80 qgPD-LLGKTIEERGQVEQWLDVEATSYHPPLL-NLTLHILFASKMGFPADEKVIKESEEKLAKVLDVYEARLSKSK-YL 156

                        170       180       190
                 ....*....|....*....|....*....|....*....
gi 21536248  159 TGSHISVADLVAI--TE-LMHPVSAGCKIfESRPKLAAW 194
Cdd:PLN02395 157 AGDFVSLADLAHLpfTEyLVGPIGKAYLI-KDRKHVSAW 194

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 21536248   116 QKMMFPVFLGQPVPPEMLASTLAELDGCLQVLEDKfLRNQAFLTGSHISVADLVAITEL-MHPVSAGCKIFESRPKLAAW 194
Cdd:pfam00043   7 QIALLPYVPPEEKKEPEVDEALEKVARVLSALEEV-LKGQTYLVGDKLTLADIALAPALlWLYELDPACLREKFPNLKAW 85

                  ....*.
gi 21536248   195 RQRVEA 200
Cdd:pfam00043  86 FERVAA 91

C-terminal, alpha helical domain of Class Theta Glutathione S-transferases; Glutathione S-transferase (GST) C-terminal domain 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 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. 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 the 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 the aryl or alkyl sulfate esters.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21536248  92 RARVDEYLAWQHTALRSCCTRAMWQKMMFPVFLGQPVPPEMLASTLAELDGCLQVLEDKFLRNQAFLTGSHISVADLVAI 171
Cdd:cd03183   2 RARVDEYLAWQHTNLRLGCAAYFWQKVLLPLFGGTPVSPEKVKKAEENLEESLDLLENKFLKDKPFLAGDEISIADLSAI 81

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*
gi 21536248 172 TELMHPVSAGCKIFESRPKLAAWRQRVEAEvGESLFQEAHEVVLK 216
Cdd:cd03183  82 CEIMQPEAAGYDVFEGRPKLAAWRKRVKEA-GNPLFDEAHKVIYK 125

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21536248   3 LELYLDLMSQPCRAVYIFAKKNGIPFQLRTIELLKGQQYTDSFAQVNPLRKVPALKDGDFVLAESVAILLYLSRKYKAPd 82
Cdd:COG0625   2 MKLYGSPPSPNSRRVRIALEEKGLPYELVPVDLAKGEQKSPEFLALNPLGKVPVLVDDGLVLTESLAILEYLAERYPEP- 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21536248  83 HWYPQDLQTRARVDEYLAWQHTALRSCCTRAMWQkmmfpvfLGQPVPPEMLASTLAELDGCLQVLEDKfLRNQAFLTGSH 162
Cdd:COG0625  81 PLLPADPAARARVRQWLAWADGDLHPALRNLLER-------LAPEKDPAAIARARAELARLLAVLEAR-LAGGPYLAGDR 152

                       170       180       190
                ....*....|....*....|....*....|....*...
gi 21536248 163 ISVADLVAITELMHPVSAGCKIfESRPKLAAWRQRVEA 200
Cdd:COG0625 153 FSIADIALAPVLRRLDRLGLDL-ADYPNLAAWLARLAA 189

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 21536248   3 LELYLDLMSQPCRAVYIFAKKNGIPFQLRTIELLKGQQYTDSFAQVNPLRKVPALKDGDFVLAESVAILLYL 74
Cdd:cd03045   1 IDLYYLPGSPPCRAVLLTAKALGLELNLKEVNLMKGEHLKPEFLKLNPQHTVPTLVDNGFVLWESHAILIYL 72

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.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 21536248   3 LELYLDLMSQPCRAVYIFAKKNGIPFQLRTIELLKGQQYTDSFAQVNPLRKVPALKDGDFVLAESVAILLYLS 75
Cdd:cd03056   1 MKLYGFPLSGNCYKVRLLLALLGIPYEWVEVDILKGETRTPEFLALNPNGEVPVLELDGRVLAESNAILVYLA 73

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.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 21536248  25 GIPFQLRTIELLKGQQYTDSFAQVNPLRKVPALKDGDFVLAESVAILLYL 74
Cdd:cd03042  23 GLDYEYVPVNLLKGEQLSPAYRALNPQGLVPTLVIDGLVLTQSLAIIEYL 72

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 21536248   3 LELYLDLMSQPCRAVYIFAKKNGIPFQLRTIELLKGQQYTDSFAQVNPLRKVPALKDGDFVLAESVAILLYLSRK 77
Cdd:cd03053   2 LKLYGAAMSTCVRRVLLCLEEKGVDYELVPVDLTKGEHKSPEHLARNPFGQIPALEDGDLKLFESRAITRYLAEK 76

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
                  ....*....|....*....|....*....|....*....|....*....|..
gi 21536248    25 GIPFQLRTIELLKGQQYTDSFAQVNPLRKVPALKDGDFVLAESVAILLYLSR 76
Cdd:pfam02798  25 GVEYEIVPLDFGAGPEKSPELLKLNPLGKVPALEDGGKKLTESRAILEYIAR 76

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.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21536248 118 MMFPV-FLGQPVPPEMLAStlaeLDGCLQVLEdKFLRNQAFLTGSHISVADLVAITElmhpVSA--GCKIFESR-PKLAA 193
Cdd:cd03177  24 YYYPIlFGGAEPPEEKLDK----LEEALEFLE-TFLEGSDYVAGDQLTIADLSLVAT----VSTleVVGFDLSKyPNVAA 94

                        90       100
                ....*....|....*....|
gi 21536248 194 WRQRVEAEV-GESLFQEAHE 212
Cdd:cd03177  95 WYERLKALPpGEEENGEGAK 114

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 21536248  21 AKKNGIPFQLRTIELLKGQQYTDsFAQVNPLRKVPALKDGDFVLAESVAILLYL 74
Cdd:cd03043  20 LKAAGIPFEEILVPLYTPDTRAR-ILEFSPTGKVPVLVDGGIVVWDSLAICEYL 72

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.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|..
gi 21536248  38 GQQY----TDSFAQVNPLRKVPALKDGDFVLAESVAILLYLS 75
Cdd:cd03047  32 GGQFggldTPEFLAMNPNGRVPVLEDGDFVLWESNAILRYLA 73

Glutathione S-transferase, N-terminal domain;

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 21536248     5 LYLDLMSQPCRAVYIFAKKNGIPFQLRTIELlkgQQYTDSFAQVNPLRKVPALKDGDFVLAESVAILLYLSRKYKAP 81
Cdd:pfam13417   1 LYGFPGSPYARRVRIALNEKGLPYEFVPIPP---GDHPPELLAKNPLGKVPVLEDDGGILCESLAIIDYLEELYPGP 74

Glutathione S-transferase, N-terminal domain; This family is closely related to pfam02798.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 21536248    14 CRAVYIFAKKNGIPFQLRTIELlKGQQYTDSFAQVNPLRKVPALKDGD-FVLAESVAILLYL 74
Cdd:pfam13409   5 SHRVRLALEEKGLPYEIELVDL-DPKDKPPELLALNPLGTVPVLVLPDgTVLTDSLVILEYL 65

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 21536248 113 AMWQKMMFPVFLGQPVPPEMLASTLAELDGCLQVLEdKFLRNQAFLTGSHISVADLVAITELMH--PVSAGCKIFESRPK 190
Cdd:cd00299  14 PPLVRLLYLEKVPLPKDEAAVEAAREELPALLAALE-QLLAGRPYLAGDQFSLADVALAPVLARleALGPYYDLLDEYPR 92

                ....*...
gi 21536248 191 LAAWRQRV 198
Cdd:cd00299  93 LKAWYDRL 100

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 21536248  92 RARVDEYLAWQHTALrscctramwQKMMFPVF-----LGQPVPPEMLASTLAELDGCLQVLEDKfLRNQAFLTGSHISVA 166
Cdd:cd03188   3 RARLLEWLNFIASEL---------HKAFGPLFyparwADDALAEEVKAAARERLERRLAYLDAQ-LAGGPYLLGDQFSVA 72

                        90       100       110
                ....*....|....*....|....*....|....*....
gi 21536248 167 DLVAITEL----MHPVSAgckifESRPKLAAWRQRVEAE 201
Cdd:cd03188  73 DAYLFVVLrwarAVGLDL-----SDWPHLAAYLARVAAR 106

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.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 21536248  14 CRAVYIFAKKNGIPFQLRTIellkgqqytdSFAQVNPLRKVPALKDGDFVLAESVAILLYLSRK 77
Cdd:cd03054  19 CLKVETYLRMAGIPYEVVFS----------SNPWRSPTGKLPFLELNGEKIADSEKIIEYLKKK 72

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 21536248  12 QPCRavYIFAKKnGIPFQLRTIEllKGQQYTDSFAQVNPLRKVPALKDGDFVLAESVAILLYLSR 76
Cdd:cd03039  13 EPIR--LLLADA-GVEYEDVRIT--YEEWPELDLKPTLPFGQLPVLEIDGKKLTQSNAILRYLAR 72

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 21536248   116 QKMMFPVFLGQPVPPEMLASTLAELDGCLQVLEDKfLRNQAFLTGSHISVADLVAITEL-MHPVSAGCKIFESRPKLAAW 194
Cdd:pfam00043   7 QIALLPYVPPEEKKEPEVDEALEKVARVLSALEEV-LKGQTYLVGDKLTLADIALAPALlWLYELDPACLREKFPNLKAW 85

                  ....*.
gi 21536248   195 RQRVEA 200
Cdd:pfam00043  86 FERVAA 91

glutathione s-transferase; Provisional

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 21536248   30 LRTIELLKGQQYTDSFAQVN----------------PLRKVPALKDGDFVLAESVAILLYLSRKYK 79
Cdd:PTZ00057  19 IRLIFAYLGIEYTDKRFGENgdafiefknfkkekdtPFEQVPILEMDNIIFAQSQAIVRYLSKKYK 84

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 21536248  14 CRAVYIFAKKNGIPFQLrtiELLKGQQYTDSFAQVNPLRKVPALKDGDFVLAESVAILLYLSRK 77
Cdd:cd03076  13 AEAIRLLLADQGISWEE---ERVTYEEWQESLKPKMLFGQLPCFKDGDLTLVQSNAILRHLGRK 73

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

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 21536248   137 LAELDGCLQVLEDkFLRNQAFLTGSHISVADLVAIT--ELMHPVSAGCKIFESRPKLAAWRQR 197
Cdd:pfam13410   6 REQLRAALDALEA-RLADGPGLLGDRPTLADIALAPvlARLDAAYPGLDLREGYPRLRAWLER 67