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        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 182890420   3 MKLAYWDIRGLAQPIRLLLEYTGTKYEEKFYTCGEAPNYDKSCWFNEKSKLGMDFPNLPYLEDGDRKIVQSNAIMRYIAR 82
Cdd:cd03075    1 PTLGYWDIRGLAQPIRLLLEYTGEKYEEKRYELGDAPDYDRSQWLNEKFKLGLDFPNLPYYIDGDVKLTQSNAILRYIAR 80

                 ..
gi 182890420  83 KH 84
Cdd:cd03075   81 KH 82

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        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 182890420   3 MKLAYWDIRGLAQPIRLLLEYTGTKYEEKFYTCGEAPNYDKSCWFNEKSKLGMDFPNLPYLEDGDRKIVQSNAIMRYIAR 82
Cdd:cd03075    1 PTLGYWDIRGLAQPIRLLLEYTGEKYEEKRYELGDAPDYDRSQWLNEKFKLGLDFPNLPYYIDGDVKLTQSNAILRYIAR 80

                 ..
gi 182890420  83 KH 84
Cdd:cd03075   81 KH 82

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 182890420  105 MDFRNGFVQLCYLDFDKNKSSYC-----EKLSGTLKQFSDFL--GDRKWFAGDKITFVDFIMYELLDQHR-MFEPACLDD 176
Cdd:pfam14497   1 HDLHHPIASSLYYEDEKKKAKRRkefreERLPKFLGYFEKVLnkNGGGYLVGDKLTYADLALFQVLDGLLyPKAPDALDK 80

                          90       100
                  ....*....|....*....|...
gi 182890420  177 FKNLRCFLDHFESLEKIAEYMKS 199
Cdd:pfam14497  81 YPKLKALHERVAARPNIKAYLAS 103

glutathione s-transferase; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 182890420   5 LAYWDIRGLAQPIRLLLEYTGTKYEEKFYtcgeAPNYDKSCWF-NEKSKLGMDFPNLPYLEDGDRKIVQSNAIMRYIARK 83
Cdd:PTZ00057   7 LYYFDARGKAELIRLIFAYLGIEYTDKRF----GENGDAFIEFkNFKKEKDTPFEQVPILEMDNIIFAQSQAIVRYLSKK 82

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 182890420  84 HNLCGETEEEQMRVDILENQAMDFRNGFVQLCYldFDKNKSSYC-EKLSGTLKQFSDFL--GDRKWFAGDKITFVDFIMY 160
Cdd:PTZ00057  83 YKICGESELNEFYADMIFCGVQDIHYKFNNTNL--FKQNETTFLnEELPKWSGYFENILkkNHCNYFVGDNLTYADLAVF 160

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|.
gi 182890420 161 ELLDQHRMFEPACLDDFKNLRCFLDHFESLEKIAEYMkSNR 201
Cdd:PTZ00057 161 NLYDDIETKYPNSLKNFPLLKAHNEFISNLPNIKNYI-SNR 200

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        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 182890420   3 MKLAYWDIRGLAQPIRLLLEYTGTKYEEKFYTCGEAPNYDKSCWFNEKSKLGMDFPNLPYLEDGDRKIVQSNAIMRYIAR 82
Cdd:cd03075    1 PTLGYWDIRGLAQPIRLLLEYTGEKYEEKRYELGDAPDYDRSQWLNEKFKLGLDFPNLPYYIDGDVKLTQSNAILRYIAR 80

                 ..
gi 182890420  83 KH 84
Cdd:cd03075   81 KH 82

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        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 182890420    3 MKLAYWDIRG--LAQPIRLLLEYTGTKYEEKFYTCGEAPNYDkSCWFNEKSklgmdFPNLPYLEDGDRKIVQSNAIMRYI 80
Cdd:pfam02798   1 MVLTLYGIRGspRAHRIRWLLAEKGVEYEIVPLDFGAGPEKS-PELLKLNP-----LGKVPALEDGGKKLTESRAILEYI 74

                  ..
gi 182890420   81 AR 82
Cdd:pfam02798  75 AR 76

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 182890420   3 MKLAYWDIRGLAQPIRLLLEYTGTKYEEKFYtcGEAPNYDKSCWFNEKSKLGMdfpnLPYLEDGDRKIVQSNAIMRYIAR 82
Cdd:COG0625    2 MKLYGSPPSPNSRRVRIALEEKGLPYELVPV--DLAKGEQKSPEFLALNPLGK----VPVLVDDGLVLTESLAILEYLAE 75

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 182890420  83 KH---NLCGETEEEQMRVDILENQAMD-----FRNGFVQLCYLDFDKNKSSYCEKLSGTLKQFSDFLGDRKWFAGDKITF 154
Cdd:COG0625   76 RYpepPLLPADPAARARVRQWLAWADGdlhpaLRNLLERLAPEKDPAAIARARAELARLLAVLEARLAGGPYLAGDRFSI 155

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|....*..
gi 182890420 155 VDFIMYELLDQHRMFEPAcLDDFKNLRCFLDHFESLEKIAEYMKSNR 201
Cdd:COG0625  156 ADIALAPVLRRLDRLGLD-LADYPNLAAWLARLAARPAFQRALAAAE 201

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        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 182890420   4 KLAYWDIRGLAQPIRLLLEYTGTKYEEKFYTCGEapnydkscWFnEKSKLGMDFPNLPYLEDGDRKIVQSNAIMRYIARK 83
Cdd:cd03076    3 TLTYFPVRGRAEAIRLLLADQGISWEEERVTYEE--------WQ-ESLKPKMLFGQLPCFKDGDLTLVQSNAILRHLGRK 73

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 182890420   3 MKLAYWDIRGLAQPIRLLLEYTGTKYEEKFYTCGEAPNYdkscWFNEKSKLGMdfpnLPYLEDGDRKIVQSNAIMRYIA 81
Cdd:cd00570    1 LKLYYFPGSPRSLRVRLALEEKGLPYELVPVDLGEGEQE----EFLALNPLGK----VPVLEDGGLVLTESLAILEYLA 71

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 182890420  92 EEQMRVDILENQAMDFRNGFVQLCY-----LDFDKNKSSYCEKLSGTLKQFSDFLGDRK--WFAGDKITFVDFIMYELLD 164
Cdd:cd03192    1 EEEARVDAIVDTIADLRAEFAPYFYepdgeEKKEKKKEFLEEALPKFLGKFEKILKKSGggYFVGDKLTWADLALFDVLD 80

                         90       100
                 ....*....|....*....|....
gi 182890420 165 QHRMFEPAC-LDDFKNLRCFLDHF 187
Cdd:cd03192   81 YLLYLLPKDlLEKYPKLKALRERV 104

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 182890420  17 IRLLLEYTGTKYEEKF--YTCGEapnyDKSCWFNEKSKLGmdfpNLPYLEDGDRKIVQSNAIMRYIARK 83
Cdd:cd03053   16 VLLCLEEKGVDYELVPvdLTKGE----HKSPEHLARNPFG----QIPALEDGDLKLFESRAITRYLAEK 76

glutathione S-transferase

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 182890420  57 FPNLPYLEDGDRKIVQSNAIMRYIARKH-----NLCGETEEEQMRVD-ILENQAMDFRNGFVQLCY-------LDFDKN- 122
Cdd:PLN02395  50 FGVVPVIVDGDYKIFESRAIMRYYAEKYrsqgpDLLGKTIEERGQVEqWLDVEATSYHPPLLNLTLhilfaskMGFPADe 129

                         90       100       110
                 ....*....|....*....|....*....|....*..
gi 182890420 123 ---KSSYcEKLSGTLKQFSDFLGDRKWFAGDKITFVD 156
Cdd:PLN02395 130 kviKESE-EKLAKVLDVYEARLSKSKYLAGDFVSLAD 165

glutathione S-transferase

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 182890420  57 FPNLPYLEDGDRKIVQSNAIMRYIARKH-----NLCGETEEEQMRVDILENQAMDFRNGFVQLCYLD--FDKNKSSYCE- 128
Cdd:PLN02473  51 FGQVPAIEDGDLKLFESRAIARYYATKYadqgtDLLGKTLEHRAIVDQWVEVENNYFYAVALPLVINlvFKPRLGEPCDv 130

                         90       100       110
                 ....*....|....*....|....*....|....*..
gi 182890420 129 --------KLSGTLKQFSDFLGDRKWFAGDKITFVDF 157
Cdd:PLN02473 131 alveelkvKFDKVLDVYENRLATNRYLGGDEFTLADL 167

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 182890420  17 IRLLLEYTGTKYEEKF--YTCGEApnydKSCWFNEKSKLGMdfpnLPYLEDGDRKIVQSNAIMRYIA 81
Cdd:cd03056   15 VRLLLALLGIPYEWVEvdILKGET----RTPEFLALNPNGE----VPVLELDGRVLAESNAILVYLA 73

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
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 182890420 128 EKLSGTLKQFSDFLGDRKWFAGDKITFVDFIMYELLDQHRMFEPAC--LDDFKNLR 181
Cdd:cd00299   39 EELPALLAALEQLLAGRPYLAGDQFSLADVALAPVLARLEALGPYYdlLDEYPRLK 94

C-terminal, alpha helical domain of Metaxin and related proteins; Glutathione S-transferase (GST) C-terminal domain 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. Other members are the cadmium-inducible lysosomal protein CDR-1 and its homologs from C. elegans, and the failed axon connections (fax) protein from Drosophila. CDR-1 is an integral membrane protein that functions to protect against cadmium toxicity and may also have a role in osmoregulation to maintain salt balance in C. elegans. The fax gene of Drosophila was identified as a genetic modifier of Abelson (Abl) tyrosine kinase. The fax protein is localized in cellular membranes and is expressed in embryonic mesoderm and axons of the central nervous system.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 182890420 138 SDFLGDRKWFAGDKITFVD--------FIMYELLDQhrmFEPACLD-DFKNLRCFLD 185
Cdd:cd03193   32 STLLGDKKFLFGDKPTSVDatvfahlaSILYPPEDS---PLLRVLVaSSPNLVEYCE 85