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 7620516   94 KRAIVNQRLFFDASVIYASIANVSRPFWINGVtEVPQEKLDAVHQGLKLLETFLGNSPYLAGDSLTLADLSTGPTVSAVp 173
Cdd:cd03177   2 KRAIVNQRLFFDSGTLYQRLRDYYYPILFGGA-EPPEEKLDKLEEALEFLETFLEGSDYVAGDQLTIADLSLVATVSTL- 79

                        90       100       110
                ....*....|....*....|....*....|....*..
gi 7620516  174 AAVDIDPATYPKVTAWLDRLNKLPYYKEINEAPAQSY 210
Cdd:cd03177  80 EVVGFDLSKYPNVAAWYERLKALPPGEEENGEGAKEL 116

Glutathione S-transferase, N-terminal domain;

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 7620516      8 LYGTDLSPCVRTVKLTLKVLNLDYEYKEVNLQageHLSEEYVKKNPQHTVPMLDDNGTFIWDSHAIAAYLVDKYA 82
Cdd:pfam13417   1 LYGFPGSPYARRVRIALNEKGLPYEFVPIPPG---DHPPELLAKNPLGKVPVLEDDGGILCESLAIIDYLEELYP 72

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 7620516   94 KRAIVNQRLFFDASVIYASIANVSRPFWINGVtEVPQEKLDAVHQGLKLLETFLGNSPYLAGDSLTLADLSTGPTVSAVp 173
Cdd:cd03177   2 KRAIVNQRLFFDSGTLYQRLRDYYYPILFGGA-EPPEEKLDKLEEALEFLETFLEGSDYVAGDQLTIADLSLVATVSTL- 79

                        90       100       110
                ....*....|....*....|....*....|....*..
gi 7620516  174 AAVDIDPATYPKVTAWLDRLNKLPYYKEINEAPAQSY 210
Cdd:cd03177  80 EVVGFDLSKYPNVAAWYERLKALPPGEEENGEGAKEL 116

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 7620516    6 IVLYGTDLSPCVRTVKLTLKVLNLDYEYKEVNLQAGEHlsEEYVKKNPQHTVPMLDDNGTFIWDSHAIAAYL 77
Cdd:cd00570   1 LKLYYFPGSPRSLRVRLALEEKGLPYELVPVDLGEGEQ--EEFLALNPLGKVPVLEDGGLVLTESLAILEYL 70

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        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 7620516    6 IVLYGTDLSPCVRTVKLTLKVLNLDYEYKEVNLQAGEHLSEEYVKKNPQHTVPMLDDNGTFIWDSHAIAAYL 77
Cdd:cd03042   1 MILYSYFRSSASYRVRIALNLKGLDYEYVPVNLLKGEQLSPAYRALNPQGLVPTLVIDGLVLTQSLAIIEYL 72

glutathione transferase;

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 7620516     1 MSSSGIVLYGTD--LSPCVRTVKLTLKVLNLDYEYKEVNLQAGEHLSEEYVKKNPQHTVPMLDDNGTFIWDSHAIAAYLV 78
Cdd:PRK15113   1 MSKPAITLYSDAhfFSPYVMSAFVALQEKGLPFELKTVDLDAGEHLQPTYQGYSLTRRVPTLQHDDFELSESSAIAEYLE 80

                         90       100
                 ....*....|....*....|....
gi 7620516    79 DKYAKSD--ELYPKDLAKRAIVNQ 100
Cdd:PRK15113  81 ERFAPPAweRIYPADLQARARARQ 104

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        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 7620516    6 IVLYGTDlSPCVRTVKLTLKVLNLDYEYKEVNLQAGEHLSEEYVKKNPQHTVPMLDDN---GTFIWDSHAIAAYLVDKYA 82
Cdd:cd03048   2 ITLYTHG-TPNGFKVSIMLEELGLPYEIHPVDISKGEQKKPEFLKINPNGRIPAIVDHngtPLTVFESGAILLYLAEKYD 80

                .
gi 7620516   83 K 83
Cdd:cd03048  81 K 81

glutathione S-transferase

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 7620516     8 LYGTDLSpCVRTVKLTLKVLNLDYEYKEVNLQAGEHLSEEYVKKNPQHTVPMLDDNGTFIWDSHAIAAYLVDKY-AKSDE 86
Cdd:PLN02395   5 VYGPAFA-SPKRALVTLIEKGVEFETVPVDLMKGEHKQPEYLALQPFGVVPVIVDGDYKIFESRAIMRYYAEKYrSQGPD 83

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 7620516    87 LYPKDLAKRAIVNQRLFFDASVIYASIANVSRPFWINGVTEVP---------QEKLDAVhqgLKLLETFLGNSPYLAGDS 157
Cdd:PLN02395  84 LLGKTIEERGQVEQWLDVEATSYHPPLLNLTLHILFASKMGFPadekvikesEEKLAKV---LDVYEARLSKSKYLAGDF 160

                        170       180       190       200       210
                 ....*....|....*....|....*....|....*....|....*....|.
gi 7620516   158 LTLADLSTGP----TVSAVPAAVDIDPATYpkVTAWLDRLNKLPYYKEINE 204
Cdd:PLN02395 161 VSLADLAHLPfteyLVGPIGKAYLIKDRKH--VSAWWDDISSRPAWKEVLA 209

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 7620516   94 KRAIVNQRLFFDASVIYASIANVsrpFW------INGVTEVPQEKLDA----VHQGLKLLET-FLGNSPYLAGDSLTLAD 162
Cdd:cd03183   1 KRARVDEYLAWQHTNLRLGCAAY---FWqkvllpLFGGTPVSPEKVKKaeenLEESLDLLENkFLKDKPFLAGDEISIAD 77

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|
gi 7620516  163 LstgptvSAV-----PAAVDIDP-ATYPKVTAWLDRLNK--LPYYKEINE 204
Cdd:cd03183  78 L------SAIceimqPEAAGYDVfEGRPKLAAWRKRVKEagNPLFDEAHK 121

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

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 7620516     14 SPCVRTVKLTLKVLNLDYEYKEVNLQaGEHLSEEYVKKNPQHTVPML-DDNGTFIWDSHAIAAYL 77
Cdd:pfam13409   2 SPFSHRVRLALEEKGLPYEIELVDLD-PKDKPPELLALNPLGTVPVLvLPDGTVLTDSLVILEYL 65

GST_N family, Saccharomyces cerevisiae GTT2-like subfamily; composed of predominantly uncharacterized proteins with similarity to the S. cerevisiae GST protein, GTT2. GSTs are cytosolic dimeric proteins involved in cellular detoxification by catalyzing the conjugation of glutathione (GSH) with a wide range of endogenous and xenobiotic alkylating agents, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress. GSTs also show GSH peroxidase activity and are involved in the synthesis of prostaglandins and leukotrienes. The GST fold contains an N-terminal TRX-fold domain and a C-terminal alpha helical domain, with an active site located in a cleft between the two domains. GTT2, a homodimer, exhibits GST activity with standard substrates. Strains with deleted GTT2 genes are viable but exhibit increased sensitivity to heat shock.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 7620516    8 LYGTDLSPCVRTVKLTLKVLNLDYEYKEVNLQAGEHLSEEYVKKNPQHTVPMLD-DNGTFIWDSHAIAAYL 77
Cdd:cd03051   3 LYDSPTAPNPRRVRIFLAEKGIDVPLVTVDLAAGEQRSPEFLAKNPAGTVPVLElDDGTVITESVAICRYL 73

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 7620516      4 SGIVLYGTDLSPCVRTVKLTLKVLNLDYEYKEVNLQAGEHLSEEYVKKNPQHTVPMLDDNGTFIWDSHAIAAYLVD 79
Cdd:pfam02798   1 MVLTLYGIRGSPRAHRIRWLLAEKGVEYEIVPLDFGAGPEKSPELLKLNPLGKVPALEDGGKKLTESRAILEYIAR 76

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        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 7620516   94 KRAIVNQRLFFDASVIYASIANVsrpFWINGVTEVPQEK-----LDAVHQGLKLLETFLGNSPYLAGDSLTLADLSTGPT 168
Cdd:cd03178   1 ERAEVLQWLFFQMSGLGPMFGQA---GHFLYFAPEKIPYaieryTDEVKRLYGVLDKRLSDRPYLAGEEYSIADIALYPW 77

                        90       100
                ....*....|....*....|....*....
gi 7620516  169 VSAVPAAVDIDPATYPKVTAWLDRLNKLP 197
Cdd:cd03178  78 THYADLGGFADLSEYPNVKRWLERIAARP 106

C-terminal, alpha helical domain of Escherichia coli YfcG Glutathione S-transferases and related uncharacterized proteins; Glutathione S-transferase (GST) C-terminal domain family, YfcG-like subfamily; composed of the Escherichia coli YfcG and related 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 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. YfcG is one of nine GST homologs in Escherichia coli. It is expressed predominantly during the late stationary phase where the predominant form of GSH is glutathionylspermidine (GspSH), suggesting that YfcG might interact with GspSH. It has very low or no GSH transferase or peroxidase activity, but displays a unique disulfide bond reductase activity that is comparable to thioredoxins (TRXs) and glutaredoxins (GRXs). However, unlike TRXs and GRXs, YfcG does not contain a redox active cysteine residue and may use a bound thiol disulfide couple such as 2GSH/GSSG for activity. The crystal structure of YcfG reveals a bound GSSG molecule in its active site. The actual physiological substrates for YfcG are yet to be identified.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*
gi 7620516  143 LETFLGNSPYLAGDSLTLADLSTGPTVSAVPaAVDIDPATYPKVTAWLDRLNKLP 197
Cdd:cd10291  52 LDRRLAKSKYLAGDEYSIADIAIWPWVARHE-WQGIDLADFPNLKRWFERLAARP 105

GST_N family, Class Beta subfamily; GSTs are cytosolic dimeric proteins involved in cellular detoxification by catalyzing the conjugation of glutathione (GSH) with a wide range of endogenous and xenobiotic alkylating agents, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress. The GST fold contains an N-terminal TRX-fold domain and a C-terminal alpha helical domain, with an active site located in a cleft between the two domains. Unlike mammalian GSTs which detoxify a broad range of compounds, the bacterial class Beta GSTs exhibit limited GSH conjugating activity with a narrow range of substrates. In addition to GSH conjugation, they also bind antibiotics and reduce the antimicrobial activity of beta-lactam drugs. The structure of the Proteus mirabilis enzyme reveals that the cysteine in the active site forms a covalent bond with GSH.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 7620516    8 LYGTDLSpCVRTVKLTLKVLNLDYEYKEVNLQAGEHLSEEYVKKNPQHTVPML-DDNGTFIWDSHAIAAYLVDKY 81
Cdd:cd03057   3 LYYSPGA-CSLAPHIALEELGLPFELVRVDLRTKTQKGADYLAINPKGQVPALvLDDGEVLTESAAILQYLADLH 76

C-terminal, alpha helical domain of GTT2-like Glutathione S-transferases; Glutathione S-transferase (GST) C-terminal domain family, Saccharomyces cerevisiae GTT2-like subfamily; composed of predominantly uncharacterized proteins with similarity to the Saccharomyces cerevisiae GST protein, GTT2. GSTs are cytosolic dimeric proteins involved in cellular detoxification by catalyzing the conjugation of glutathione (GSH) with a wide range of endogenous and xenobiotic alkylating agents, including carcinogens, therapeutic drugs, environmental toxins, and products of oxidative stress. GSTs also show GSH peroxidase activity and are involved in the synthesis of prostaglandins and leukotrienes. The GST fold contains an N-terminal thioredoxin-fold domain and a C-terminal alpha helical domain, with an active site located in a cleft between the two domains. GSH binds to the N-terminal domain while the hydrophobic substrate occupies a pocket in the C-terminal domain. GTT2, a homodimer, exhibits GST activity with standard substrates. Strains with deleted GTT2 genes are viable but exhibit increased sensitivity to heat shock.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 7620516  122 INGVTEVPQEKLDAVHQGLKLLETFLGNSPYLAGDSLTLADLSTGPTVS-AVPAAVDIDPATyPKVTAWLDRL 193
Cdd:cd03182  39 EVQVPEWGERNKKRVIDFLPVLDKRLAESPYVAGDRFSIADITAFVALDfAKNLKLPVPEEL-TALRRWYERM 110

C-terminal, alpha helical domain of GTT1-like Glutathione S-transferases; Glutathione S-transferase (GST) C-terminal domain 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 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. 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        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 7620516  136 VHQGLKLLETFLGNSPYLAGDSLTLADLSTGPTVSAVPAAVDiDPATYPKVTAWLDRLNKLP 197
Cdd:cd03189  63 LKRHLDFLEDHLAKHPYFAGDELTAADIMMSFPLEAALARGP-LLEQYPNIAAYLERIEARP 123

C-terminal, alpha helical domain of Class Tau Glutathione S-transferases; Glutathione S-transferase (GST) C-terminal domain family, Class Tau subfamily; GSTs are cytosolic dimeric proteins involved in cellular detoxification by catalyzing the conjugation of glutathione (GSH) with a wide range of endogenous and xenobiotic alkylating agents, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress. The GST fold contains an N-terminal 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 plant-specific class Tau GST subfamily has undergone extensive gene duplication. The Arabidopsis and Oryza genomes contain 28 and 40 Tau GSTs, respectively. They are primarily responsible for herbicide detoxification together with class Phi GSTs, showing class specificity in substrate preference. Tau enzymes are highly efficient in detoxifying diphenylether and aryloxyphenoxypropionate herbicides. In addition, Tau GSTs play important roles in intracellular signalling, biosynthesis of anthocyanin, responses to soil stresses and responses to auxin and cytokinin hormones.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 7620516  130 QEK-LDAVHQGLKLLET-FLGNSPYLAGDSLTLADLSTGPTVSAVPAA------VDIDPATYPKVTAWLDRLNKLPYYKE 201
Cdd:cd03185  33 QEKaVEEALEALKVLEEeLKGGKPFFGGDTIGYLDIALGSFLGWFKAIeevggvKLLDEEKFPLLAAWAERFLEREAVKE 112

                        90
                ....*....|....
gi 7620516  202 iNEAPAQSYVAFLR 215
Cdd:cd03185 113 -VLPDRDKLVEFLK 125

GST_N family, Class Tau subfamily; GSTs are cytosolic dimeric proteins involved in cellular detoxification by catalyzing the conjugation of glutathione (GSH) with a wide range of endogenous and xenobiotic alkylating agents, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress. The GST fold contains an N-terminal TRX-fold domain and a C-terminal alpha helical domain, with an active site located in a cleft between the two domains. The plant-specific class Tau GST subfamily has undergone extensive gene duplication. The Arabidopsis and Oryza genomes contain 28 and 40 Tau GSTs, respectively. They are primarily responsible for herbicide detoxification together with class Phi GSTs, showing class specificity in substrate preference. Tau enzymes are highly efficient in detoxifying diphenylether and aryloxyphenoxypropionate herbicides. In addition, Tau GSTs play important roles in intracellular signalling, biosynthesis of anthocyanin, responses to soil stresses and responses to auxin and cytokinin hormones.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 7620516    6 IVLYGTDLSPCVRTVKLTLKVLNLDYEYKEVNLQAGehlSEEYVKKNPQH-TVPMLDDNGTFIWDSHAIAAYL 77
Cdd:cd03058   1 VKLLGAWASPFVLRVRIALALKGVPYEYVEEDLGNK---SELLLASNPVHkKIPVLLHNGKPICESLIIVEYI 70

Glutaredoxin [Posttranslational modification, protein turnover, chaperones];

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 7620516    6 IVLYGTDLSP-CVRTVKLtLKVLNLDYEykEVNLQAGEHLSEEYVKKNPQHTVPMLDDNGTFI--WDSHAIAAYL 77
Cdd:COG0695   2 VTLYTTPGCPyCARAKRL-LDEKGIPYE--EIDVDEDPEAREELRERSGRRTVPVIFIGGEHLggFDEGELDALL 73

C-terminal, alpha helical domain of an unknown subfamily 5 of Glutathione S-transferases; Glutathione S-transferase (GST) C-terminal domain family, unknown subfamily 5; 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
                ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 7620516  140 LKLLETFLGNSPYLAGDSLTLADLstgptvsAV-P-----AAVDI---DPATYPKVTAWLDRL 193
Cdd:cd03196  50 LAELEARLSQHAYLFGDRPSLADY-------AIfPfvrqfAHVDRdwfDASPYPNLRRWLNRF 105

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

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 7620516    140 LKLLETFL--GNSPYLAGDSLTLADLSTGPTVSAV--PAAVDIdPATYPKVTAWLDRLNKLP 197
Cdd:pfam14497  35 LGYFEKVLnkNGGGYLVGDKLTYADLALFQVLDGLlyPKAPDA-LDKYPKLKALHERVAARP 95

Glutathione S-transferase C-terminal-like, alpha helical domain of Aminoacyl tRNA synthetase complex-Interacting Multifunctional Protein 2; Glutathione S-transferase (GST) C-terminal domain family, Aminoacyl tRNA synthetase complex-Interacting Multifunctional Protein (AIMP) 2 subfamily; AIMPs are non-enzymatic cofactors that play critical roles in the assembly and formation of a macromolecular multi-tRNA synthetase protein complex that functions as a molecular hub to coordinate protein synthesis. There are three AIMPs, named AIMP1-3, which play diverse regulatory roles. AIMP2, also called p38 or JTV-1, contains a C-terminal domain with similarity to the C-terminal alpha helical domain of GSTs. It plays an important role in the control of cell fate via antiproliferative (by enhancing the TGF-beta signal) and proapoptotic (activation of p53 and TNF-alpha) activities. Its roles in the control of cell proliferation and death suggest that it is a potent tumor suppressor. AIMP2 heterozygous mice with lower than normal expression of AIMP2 show high susceptibility to tumorigenesis. AIMP2 is also a substrate of Parkin, an E3 ubiquitin ligase that is involved in the ubiquitylation and proteasomal degradation of its substrates. Mutations in the Parkin gene is found in 50% of patients with autosomal-recessive early-onset parkinsonism. The accumulation of AIMP2, due to impaired Parkin function, may play a role in the pathogenesis of Parkinson's disease.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*
gi 7620516  139 GLKLLETFLGNSPYLAGDSLTLAD-------LSTGPTvSAVPAAV 176
Cdd:cd03200  43 VLRALNSALGRSPWLVGSEPTVADialwsavLQTGLA-SGAPANV 86

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 7620516    8 LYGTDLSPCVRTVKLTL--KVLNLDYEYKEVNLQAGEhlsEEYVKKNPQHTVPML-DDNGTFIWDSHAIAAYL 77
Cdd:cd03049   3 LLYSPTSPYVRKVRVAAheTGLGDDVELVLVNPWSDD---ESLLAVNPLGKIPALvLDDGEALFDSRVICEYL 72

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        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 7620516    6 IVLYGTDLSPCVRTVKLTLKVLNLDYEYkeVNLQAGEHLSEEYVKKNPQHTVPMLDD--NGTFIWDSHAIAAYLVDKY 81
Cdd:cd03041   2 LELYEFEGSPFCRLVREVLTELELDVIL--YPCPKGSPKRDKFLEKGGKVQVPYLVDpnTGVQMFESADIVKYLFKTY 77

GST_N family, Class Omega subfamily; GSTs are cytosolic dimeric proteins involved in cellular detoxification by catalyzing the conjugation of glutathione (GSH) with a wide range of endogenous and xenobiotic alkylating agents, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress. The GST fold contains an N-terminal TRX-fold domain and a C-terminal alpha helical domain, with an active site located in a cleft between the two domains. Class Omega GSTs show little or no GSH-conjugating activity towards standard GST substrates. Instead, they catalyze the GSH dependent reduction of protein disulfides, dehydroascorbate and monomethylarsonate, activities which are more characteristic of glutaredoxins. They contain a conserved cysteine equivalent to the first cysteine in the CXXC motif of glutaredoxins, which is a redox active residue capable of reducing GSH mixed disulfides in a monothiol mechanism. Polymorphisms of the class Omega GST genes may be associated with the development of some types of cancer and the age-at-onset of both Alzheimer's and Parkinson's diseases.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 7620516    6 IVLYGTDLSPCVRTVKLTLKVLNLDYEYKEVNLQageHLSEEYVKKNPQHTVPMLD-DNGTFIWDSHAIAAYL 77
Cdd:cd03055  19 IRLYSMRFCPYAQRARLVLAAKNIPHEVININLK---DKPDWFLEKNPQGKVPALEiDEGKVVYESLIICEYL 88

C-terminal, alpha helical domain of Class Zeta Glutathione S-transferases; Glutathione S-transferase (GST) C-terminal domain 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 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 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        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 7620516   92 LAKRAIVNQrlffDASVIYASIA---NVSRPFWINGVTEVPQEKLDA-----VHQGLKLLETFLGNS--PYLAGDSLTLA 161
Cdd:cd03191   1 PKKRARVRA----IALIIACDIHplqNLRVLKYLTEKLGVSEEEKLAwaqhwIERGFQALEKLLASTagKYCVGDEPTLA 76

                        90       100       110
                ....*....|....*....|....*....|....*..
gi 7620516  162 DLSTGPTV-SAVPAAVDIDPatYPKVTAWLDRLNKLP 197
Cdd:cd03191  77 DICLVPQVyNARRFGVDLSP--YPTIVRINEACLELP 111

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
                ....*....|....*....|....*..
gi 7620516  140 LKLLETFLG--NSPYLAGDSLTLADLS 164
Cdd:cd03192  48 LGKFEKILKksGGGYFVGDKLTWADLA 74

GST_N family, Beta etherase LigE subfamily; composed of proteins similar to Sphingomonas paucimobilis beta etherase, LigE, a GST-like protein that catalyzes the cleavage of the beta-aryl ether linkages present in low-moleculer weight lignins using GSH as the hydrogen donor. This reaction is an essential step in the degradation of lignin, a complex phenolic polymer that is the most abundant aromatic material in the biosphere. The beta etherase activity of LigE is enantioselective and it complements the activity of the other GST family beta etherase, LigF.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 7620516    6 IVLY---GTD----LSPCVRTVKLTLKVLNLDY-----EYKEVNLQAGEHlseeyvKKNPQHTVPML-DDNGTFIWDSHA 72
Cdd:cd03038   1 ITLYdlaGKDpvraFSPNVWKTRLALNHKGLEYktvpvEFPDIPPILGEL------TSGGFYTVPVIvDGSGEVIGDSFA 74

                ....*....
gi 7620516   73 IAAYLVDKY 81
Cdd:cd03038  75 IAEYLEEAY 83

NrdH-redoxin (NrdH) family; NrdH is a small monomeric protein with a conserved redox active CXXC motif within a TRX fold, characterized by a glutaredoxin (GRX)-like sequence and TRX-like activity profile. In vitro, it displays protein disulfide reductase activity that is dependent on TRX reductase, not glutathione (GSH). It is part of the NrdHIEF operon, where NrdEF codes for class Ib ribonucleotide reductase (RNR-Ib), an efficient enzyme at low oxygen levels. Under these conditions when GSH is mostly conjugated to spermidine, NrdH can still function and act as a hydrogen donor for RNR-Ib. It has been suggested that the NrdHEF system may be the oldest RNR reducing system, capable of functioning in a microaerophilic environment, where GSH was not yet available. NrdH from Corynebacterium ammoniagenes can form domain-swapped dimers, although it is unknown if this happens in vivo. Domain-swapped dimerization, which results in the blocking of the TRX reductase binding site, could be a mechanism for regulating the oxidation state of the protein.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 7620516    6 IVLYGT-DLSPCVRTVKLtLKVLNLDYEykEVNLQAGEHLSEEYVKKNPQHTVPMLDDNGT 65
Cdd:cd02976   2 VTVYTKpDCPYCKATKRF-LDERGIPFE--EVDVDEDPEALEELKKLNGYRSVPVVVIGDE 59

Glutaredoxin (GRX) family; composed of GRX, approximately 10 kDa in size, and proteins containing a GRX or GRX-like domain. GRX is a glutathione (GSH) dependent reductase, catalyzing the disulfide reduction of target proteins such as ribonucleotide reductase. It contains a redox active CXXC motif in a TRX fold and uses a similar dithiol mechanism employed by TRXs for intramolecular disulfide bond reduction of protein substrates. Unlike TRX, GRX has preference for mixed GSH disulfide substrates, in which it uses a monothiol mechanism where only the N-terminal cysteine is required. The flow of reducing equivalents in the GRX system goes from NADPH -> GSH reductase -> GSH -> GRX -> protein substrates. By altering the redox state of target proteins, GRX is involved in many cellular functions including DNA synthesis, signal transduction and the defense against oxidative stress. Different classes are known including human GRX1 and GRX2, as well as E. coli GRX1 and GRX3, which are members of this family. E. coli GRX2, however, is a 24-kDa protein that belongs to the GSH S-transferase (GST) family.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 7620516    6 IVLYGTDLSP-CVRTVKLtLKvlNLDYEYKEVNLQAGEHLSEEYVKKNPQHTVPMLDDNGTFIWDS 70
Cdd:cd02066   2 VVVFSKSTCPyCKRAKRL-LE--SLGIEFEEIDILEDGELREELKELSGWPTVPQIFINGEFIGGY 64