GST_N family, Class Pi subfamily; GSTs are cytosolic dimeric proteins involved in cellular detoxification by catalyzing the conjugation of glutathione (GSH) with a wide range of endogenous and xenobiotic alkylating agents, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress. The GST fold contains an N-terminal TRX-fold domain and a C-terminal alpha helical domain, with an active site located in a cleft between the two domains. Class Pi GST is a homodimeric eukaryotic protein. The human GSTP1 is mainly found in erythrocytes, kidney, placenta and fetal liver. It is involved in stress responses and in cellular proliferation pathways as an inhibitor of JNK (c-Jun N-terminal kinase). Following oxidative stress, monomeric GSTP1 dissociates from JNK and dimerizes, losing its ability to bind JNK and causing an increase in JNK activity, thereby promoting apoptosis. GSTP1 is expressed in various tumors and is the predominant GST in a wide range of cancer cells. It has been implicated in the development of multidrug-resistant tumours.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 25453420   3 PYTIVYFPVRGRCEATRMLLADQGQSWKEEVVTIDVWlQGSLKSTCLYGQLPKFEDGDLTLYQSNAILRHLGRS 76
Cdd:cd03076   1 PYTLTYFPVRGRAEAIRLLLADQGISWEEERVTYEEW-QESLKPKMLFGQLPCFKDGDLTLVQSNAILRHLGRK 73

GST_N family, Class Pi subfamily; GSTs are cytosolic dimeric proteins involved in cellular detoxification by catalyzing the conjugation of glutathione (GSH) with a wide range of endogenous and xenobiotic alkylating agents, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress. The GST fold contains an N-terminal TRX-fold domain and a C-terminal alpha helical domain, with an active site located in a cleft between the two domains. Class Pi GST is a homodimeric eukaryotic protein. The human GSTP1 is mainly found in erythrocytes, kidney, placenta and fetal liver. It is involved in stress responses and in cellular proliferation pathways as an inhibitor of JNK (c-Jun N-terminal kinase). Following oxidative stress, monomeric GSTP1 dissociates from JNK and dimerizes, losing its ability to bind JNK and causing an increase in JNK activity, thereby promoting apoptosis. GSTP1 is expressed in various tumors and is the predominant GST in a wide range of cancer cells. It has been implicated in the development of multidrug-resistant tumours.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 25453420   3 PYTIVYFPVRGRCEATRMLLADQGQSWKEEVVTIDVWlQGSLKSTCLYGQLPKFEDGDLTLYQSNAILRHLGRS 76
Cdd:cd03076   1 PYTLTYFPVRGRAEAIRLLLADQGISWEEERVTYEEW-QESLKPKMLFGQLPCFKDGDLTLVQSNAILRHLGRK 73

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 25453420   4 YTIVYFPVRGRCEATRMLLADQGQSWkeEVVTIDVWLQGSLKSTCL----YGQLPKFEDGDLTLYQSNAILRHLGR---S 76
Cdd:COG0625   2 MKLYGSPPSPNSRRVRIALEEKGLPY--ELVPVDLAKGEQKSPEFLalnpLGKVPVLVDDGLVLTESLAILEYLAErypE 79

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 25453420  77 LGLYGKDQKEAALVDMV----NDGVE-DLRCKYGTLIYTNYENGKDDYVKALPGHLKPFETLLsqnqGGKAFIVGNQISF 151
Cdd:COG0625  80 PPLLPADPAARARVRQWlawaDGDLHpALRNLLERLAPEKDPAAIARARAELARLLAVLEARL----AGGPYLAGDRFSI 155

                       170       180       190       200
                ....*....|....*....|....*....|....*....|...
gi 25453420 152 ADYNLLDLLLVHQVLAPGcLDNFPLLSAYVARLSARPKIKAFL 194
Cdd:COG0625 156 ADIALAPVLRRLDRLGLD-LADYPNLAAWLARLAARPAFQRAL 197

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

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 25453420     2 PPYTIVYFPVRGRCEATRMLLADQGQSWkeEVVTIDVWLQGS----LKSTCLYGQLPKFEDGDLTLYQSNAILRHLGR 75
Cdd:pfam02798   1 MVLTLYGIRGSPRAHRIRWLLAEKGVEY--EIVPLDFGAGPEkspeLLKLNPLGKVPALEDGGKKLTESRAILEYIAR 76

GST_N family, Class Pi subfamily; GSTs are cytosolic dimeric proteins involved in cellular detoxification by catalyzing the conjugation of glutathione (GSH) with a wide range of endogenous and xenobiotic alkylating agents, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress. The GST fold contains an N-terminal TRX-fold domain and a C-terminal alpha helical domain, with an active site located in a cleft between the two domains. Class Pi GST is a homodimeric eukaryotic protein. The human GSTP1 is mainly found in erythrocytes, kidney, placenta and fetal liver. It is involved in stress responses and in cellular proliferation pathways as an inhibitor of JNK (c-Jun N-terminal kinase). Following oxidative stress, monomeric GSTP1 dissociates from JNK and dimerizes, losing its ability to bind JNK and causing an increase in JNK activity, thereby promoting apoptosis. GSTP1 is expressed in various tumors and is the predominant GST in a wide range of cancer cells. It has been implicated in the development of multidrug-resistant tumours.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 25453420   3 PYTIVYFPVRGRCEATRMLLADQGQSWKEEVVTIDVWlQGSLKSTCLYGQLPKFEDGDLTLYQSNAILRHLGRS 76
Cdd:cd03076   1 PYTLTYFPVRGRAEAIRLLLADQGISWEEERVTYEEW-QESLKPKMLFGQLPCFKDGDLTLVQSNAILRHLGRK 73

C-terminal, alpha helical domain of Class Mu Glutathione S-transferases; Glutathione S-transferase (GST) C-terminal domain family, Class Mu subfamily; GSTs are cytosolic dimeric proteins involved in cellular detoxification by catalyzing the conjugation of glutathione (GSH) with a wide range of endogenous and xenobiotic alkylating agents, including carcinogens, therapeutic drugs, environmental toxins, and products of oxidative stress. The GST fold contains an N-terminal 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 Mu subfamily is composed of eukaryotic GSTs. In rats, at least six distinct class Mu subunits have been identified, with homologous genes in humans for five of these subunits. Class Mu GSTs can form homodimers and heterodimers, giving a large number of possible isoenzymes that can be formed, all with overlapping activities but different substrate specificities. They are the most abundant GSTs in human liver, skeletal muscle and brain, and are believed to provide protection against diseases including cancer and neurodegenerative disorders. Some isoenzymes have additional specific functions. Human GST M1-1 acts as an endogenous inhibitor of ASK1 (apoptosis signal-regulating kinase 1) thereby suppressing ASK1-mediated cell death. Human GSTM2-2 and 3-3 have been identified as prostaglandin E2 synthases in the brain and may play crucial roles in temperature and sleep-wake regulation.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 25453420  85 KEAALVDMVNDGVEDLRCKYGTLIYT-NYENGKDDYVKALPGHLKPFETLLsqnqGGKAFIVGNQISFADYNLLDLLLVH 163
Cdd:cd03209   1 KERIRVDMLEQQAMDLRMGLIRICYSpDFEKLKPDYLEKLPDKLKLFSEFL----GDRPWFAGDKITYVDFLLYEALDQH 76

                        90       100       110       120
                ....*....|....*....|....*....|....*....|...
gi 25453420 164 QVLAPGCLDNFPLLSAYVARLSARPKIKAFLSSPDHLNRPING 206
Cdd:cd03209  77 RIFEPDCLDAFPNLKDFLERFEALPKISAYMKSDRFIKWPING 119

C-terminal, alpha helical domain of Class Sigma-like Glutathione S-transferases; Glutathione S-transferase (GST) C-terminal domain family, Class Sigma_like; composed of GSTs belonging to class Sigma and similar proteins, including GSTs from class Mu, Pi, and Alpha. GSTs are cytosolic dimeric proteins involved in cellular detoxification by catalyzing the conjugation of glutathione (GSH) with a wide range of endogenous and xenobiotic alkylating agents, including carcinogens, therapeutic drugs, environmental toxins, and products of oxidative stress. The GST fold contains an N-terminal thioredoxin-fold domain and a C-terminal alpha helical domain, with an active site located in a cleft between the two domains. GSH binds to the N-terminal domain while the hydrophobic substrate occupies a pocket in the C-terminal domain. Vertebrate class Sigma GSTs are characterized as GSH-dependent hematopoietic prostaglandin (PG) D synthases and are responsible for the production of PGD2 by catalyzing the isomerization of PGH2. The functions of PGD2 include the maintenance of body temperature, inhibition of platelet aggregation, bronchoconstriction, vasodilation, and mediation of allergy and inflammation. Other class Sigma-like members include the class II insect GSTs, S-crystallins from cephalopods, nematode-specific GSTs, and 28-kDa GSTs from parasitic flatworms. Drosophila GST2 is associated with indirect flight muscle and exhibits preference for catalyzing GSH conjugation to lipid peroxidation products, indicating an anti-oxidant role. S-crystallin constitutes the major lens protein in cephalopod eyes and is responsible for lens transparency and proper refractive index. The 28-kDa GST from Schistosoma is a multifunctional enzyme, exhibiting GSH transferase, GSH peroxidase, and PGD2 synthase activities, and may play an important role in host-parasite interactions. Members also include novel GSTs from the fungus Cunninghamella elegans, designated as class Gamma, and from the protozoan Blepharisma japonicum, described as a light-inducible GST.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 25453420  86 EAALVDMVNDGVEDLRCKYGTLIYT-----NYENGKDDYVKALPGHLKPFETLLSQNQGGkaFIVGNQISFADYNLLDLL 160
Cdd:cd03192   2 EEARVDAIVDTIADLRAEFAPYFYEpdgeeKKEKKKEFLEEALPKFLGKFEKILKKSGGG--YFVGDKLTWADLALFDVL 79

                        90       100
                ....*....|....*....|....
gi 25453420 161 LVHQVLAPGC-LDNFPLLSAYVAR 183
Cdd:cd03192  80 DYLLYLLPKDlLEKYPKLKALRER 103

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 25453420    97 VEDLRCKYGTLIYTNY-ENGKDDYVKALPGHLKPFETLLSQnQGGKAFIVGNQISFADYNLLDLLLVHQVLAPGCL-DNF 174
Cdd:pfam00043   1 LMDLRMQIALLPYVPPeEKKEPEVDEALEKVARVLSALEEV-LKGQTYLVGDKLTLADIALAPALLWLYELDPACLrEKF 79

                          90
                  ....*....|....
gi 25453420   175 PLLSAYVARLSARP 188
Cdd:pfam00043  80 PNLKAWFERVAARP 93

glutathione s-transferase; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 25453420    6 IVYFPVRGRCEATRMLLADQGQSWKEEV--VTIDVWLQGS---LKSTCLYGQLPKFEDGDLTLYQSNAILRHLGRSLGLY 80
Cdd:PTZ00057   7 LYYFDARGKAELIRLIFAYLGIEYTDKRfgENGDAFIEFKnfkKEKDTPFEQVPILEMDNIIFAQSQAIVRYLSKKYKIC 86

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 25453420   81 GKDQKEAALVDMVNDGVEDLRCKYGTliyTNY--ENGKDDYVKALPGHLKPFETLLSQNQGGkaFIVGNQISFADYNLLD 158
Cdd:PTZ00057  87 GESELNEFYADMIFCGVQDIHYKFNN---TNLfkQNETTFLNEELPKWSGYFENILKKNHCN--YFVGDNLTYADLAVFN 161

                        170       180       190
                 ....*....|....*....|....*....|....*...
gi 25453420  159 LLLVHQVLAPGCLDNFPLLSAYVARLSARPKIKAFLSS 196
Cdd:PTZ00057 162 LYDDIETKYPNSLKNFPLLKAHNEFISNLPNIKNYISN 199

GST_N family, Class Mu subfamily; GSTs are cytosolic dimeric proteins involved in cellular detoxification by catalyzing the conjugation of glutathione (GSH) with a wide range of endogenous and xenobiotic alkylating agents, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress. The GST fold contains an N-terminal TRX-fold domain and a C-terminal alpha helical domain, with an active site located in a cleft between the two domains. The class Mu subfamily is composed of eukaryotic GSTs. In rats, at least six distinct class Mu subunits have been identified, with homologous genes in humans for five of these subunits. Class Mu GSTs can form homodimers and heterodimers, giving a large number of possible isoenzymes that can be formed, all with overlapping activities but different substrate specificities. They are the most abundant GSTs in human liver, skeletal muscle and brain, and are believed to provide protection against diseases including cancer and neurodegenerative disorders. Some isoenzymes have additional specific functions. Human GST M1-1 acts as an endogenous inhibitor of ASK1 (apoptosis signal-regulating kinase 1), thereby suppressing ASK1-mediated cell death. Human GSTM2-2 and 3-3 have been identified as prostaglandin E2 synthases in the brain and may play crucial roles in temperature and sleep-wake regulation.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 25453420   5 TIVYFPVRGRCEATRMLLADQGQSWKEEVVTID--------VWLQGSLKSTCLYGQLPKFEDGDLTLYQSNAILRHLGR 75
Cdd:cd03075   2 TLGYWDIRGLAQPIRLLLEYTGEKYEEKRYELGdapdydrsQWLNEKFKLGLDFPNLPYYIDGDVKLTQSNAILRYIAR 80

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
                ....*....|....*....|....*....|....*....|....*....
gi 25453420  32 EVVTIDvWLQGSLKSTCL-----YGQLPKFEDGDLTLYQSNAILRHLGR 75
Cdd:cd03053  28 ELVPVD-LTKGEHKSPEHlarnpFGQIPALEDGDLKLFESRAITRYLAE 75

C-terminal, alpha helical domain of an unknown subfamily 8 of Glutathione S-transferases; Glutathione S-transferase (GST) C-terminal domain family, unknown subfamily 8; composed of Agrobacterium tumefaciens GST and other 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. The three-dimensional structure of Agrobacterium tumefaciens GST has been determined but there is no information on its functional characterization.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|
gi 25453420 134 LSQNQGGKAFIVGNQISFADynlldlLLVHQVLAP----GCLDNFPLLSAYVARLSARPK 189
Cdd:cd03207  48 LEAALAGRPYLVGERFSAAD------LLLASVLRWarafGLLPEYPALRAYVARCTARPA 101

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 25453420 117 DDYVKALPGHLKPFETLLSQNqggKAFIVGNQISFAdynllDLLLVH---QVLAPGC--LDNFPLLSAYVARLSAR 187
Cdd:cd03183  44 KKAEENLEESLDLLENKFLKD---KPFLAGDEISIA-----DLSAICeimQPEAAGYdvFEGRPKLAAWRKRVKEA 111

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
                ....*....|....*....|....
gi 25453420  51 GQLPKFEDGDLTLYQSNAILRHLG 74
Cdd:cd03047  50 GRVPVLEDGDFVLWESNAILRYLA 73

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 25453420   4 YTIVYFPVRGRCEATRMLLADQGQSWkeEVVTIDVwLQGSLKSTCL-----YGQLPKFEDGDLTLYQSNAILRHL 73
Cdd:cd03056   1 MKLYGFPLSGNCYKVRLLLALLGIPY--EWVEVDI-LKGETRTPEFlalnpNGEVPVLELDGRVLAESNAILVYL 72