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 157822007   3 VTLGYWDIRGLGHAIRLLLEYTETSYEEKRYAMGDAPDYDRSQWLDDKFKLDLDFPNLPYLIDGSHKVTQSNAILRYLGR 82
Cdd:cd03075    1 PTLGYWDIRGLAQPIRLLLEYTGEKYEEKRYELGDAPDYDRSQWLNEKFKLGLDFPNLPYYIDGDVKLTQSNAILRYIAR 80

                 ..
gi 157822007  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 157822007   3 VTLGYWDIRGLGHAIRLLLEYTETSYEEKRYAMGDAPDYDRSQWLDDKFKLDLDFPNLPYLIDGSHKVTQSNAILRYLGR 82
Cdd:cd03075    1 PTLGYWDIRGLAQPIRLLLEYTGEKYEEKRYELGDAPDYDRSQWLNEKFKLGLDFPNLPYYIDGDVKLTQSNAILRYIAR 80

                 ..
gi 157822007  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 157822007    4 TLGYWDIRG--LGHAIRLLLEYTETSYEEKRYAMGDAPDYDrSQWLDDKFkldldFPNLPYLIDGSHKVTQSNAILRYLG 81
Cdd:pfam02798   2 VLTLYGIRGspRAHRIRWLLAEKGVEYEIVPLDFGAGPEKS-PELLKLNP-----LGKVPALEDGGKKLTESRAILEYIA 75

                  .
gi 157822007   82 R 82
Cdd:pfam02798  76 R 76

glutathione s-transferase; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157822007   3 VTLGYWDIRGLGHAIRLLLEYTETSYEEKRYAM-GDApdydRSQWLDDKFKLDLDFPNLPYLIDGSHKVTQSNAILRYLG 81
Cdd:PTZ00057   5 IVLYYFDARGKAELIRLIFAYLGIEYTDKRFGEnGDA----FIEFKNFKKEKDTPFEQVPILEMDNIIFAQSQAIVRYLS 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157822007  82 RKHNLCGETEEERIRVDILEKQVMDTRIQMGTlcySPDFEKRKPEFL-KGLPDQLKLYSEFLGKQ--PWFAGDKITFADF 158
Cdd:PTZ00057  81 KKYKICGESELNEFYADMIFCGVQDIHYKFNN---TNLFKQNETTFLnEELPKWSGYFENILKKNhcNYFVGDNLTYADL 157

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|....
gi 157822007 159 LVYDVLDQHRMFEPKCLDAFPNLMDFVVHFEGLKKISAYMKTSR 202
Cdd:PTZ00057 158 AVFNLYDDIETKYPNSLKNFPLLKAHNEFISNLPNIKNYISNRK 201

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 157822007   3 VTLGYWDIRGLGHAIRLLLEYTETSYEEKRYAMGDAPDYDRSQWLDDKFKLDLDFPNLPYLIDGSHKVTQSNAILRYLGR 82
Cdd:cd03075    1 PTLGYWDIRGLAQPIRLLLEYTGEKYEEKRYELGDAPDYDRSQWLNEKFKLGLDFPNLPYYIDGDVKLTQSNAILRYIAR 80

                 ..
gi 157822007  83 KH 84
Cdd:cd03075   81 KH 82

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 157822007  104 VMDTRIQMGTLCYSPDFEKRKPEFLKGLPDQLKLYSEF---LGKQPWFAGDKITFADFLVYDVLDQHRMFEPKCL-DAFP 179
Cdd:pfam00043   1 LMDLRMQIALLPYVPPEEKKEPEVDEALEKVARVLSALeevLKGQTYLVGDKLTLADIALAPALLWLYELDPACLrEKFP 80

                          90
                  ....*....|..
gi 157822007  180 NLMDFVVHFEGL 191
Cdd:pfam00043  81 NLKAWFERVAAR 92

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157822007  105 MDTRIQMGTLCYSPD---FEKRKPEFLKG-LPDQLKLYSEFL--GKQPWFAGDKITFADFLVYDVLDQHR-MFEPKCLDA 177
Cdd:pfam14497   1 HDLHHPIASSLYYEDekkKAKRRKEFREErLPKFLGYFEKVLnkNGGGYLVGDKLTYADLALFQVLDGLLyPKAPDALDK 80

                          90       100
                  ....*....|....*....|..
gi 157822007  178 FPNLMDFVVHFEGLKKISAYMK 199
Cdd:pfam14497  81 YPKLKALHERVAARPNIKAYLA 102

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 157822007  92 EERIRVDILEKQVMDTRIQMGTLCYSPD----FEKRKPEFLKGLPDQLKLYSEFLGKQ--PWFAGDKITFADFLVYDVLD 165
Cdd:cd03192    1 EEEARVDAIVDTIADLRAEFAPYFYEPDgeekKEKKKEFLEEALPKFLGKFEKILKKSggGYFVGDKLTWADLALFDVLD 80

                         90       100
                 ....*....|....*....|.
gi 157822007 166 QHRMFEPKC-LDAFPNLMDFV 185
Cdd:cd03192   81 YLLYLLPKDlLEKYPKLKALR 101

glutathione s-transferase; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157822007   3 VTLGYWDIRGLGHAIRLLLEYTETSYEEKRYAM-GDApdydRSQWLDDKFKLDLDFPNLPYLIDGSHKVTQSNAILRYLG 81
Cdd:PTZ00057   5 IVLYYFDARGKAELIRLIFAYLGIEYTDKRFGEnGDA----FIEFKNFKKEKDTPFEQVPILEMDNIIFAQSQAIVRYLS 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 157822007  82 RKHNLCGETEEERIRVDILEKQVMDTRIQMGTlcySPDFEKRKPEFL-KGLPDQLKLYSEFLGKQ--PWFAGDKITFADF 158
Cdd:PTZ00057  81 KKYKICGESELNEFYADMIFCGVQDIHYKFNN---TNLFKQNETTFLnEELPKWSGYFENILKKNhcNYFVGDNLTYADL 157

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|....
gi 157822007 159 LVYDVLDQHRMFEPKCLDAFPNLMDFVVHFEGLKKISAYMKTSR 202
Cdd:PTZ00057 158 AVFNLYDDIETKYPNSLKNFPLLKAHNEFISNLPNIKNYISNRK 201

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 157822007   3 VTLGYWDIRGLGHAIRLLLEYTETSYEEKRYAMGDAPDYDrsqwlddkFKLDLDFPNLPYLIDGSHKVTQSNAILRYL 80
Cdd:cd00570    1 LKLYYFPGSPRSLRVRLALEEKGLPYELVPVDLGEGEQEE--------FLALNPLGKVPVLEDGGLVLTESLAILEYL 70

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 157822007 116 YSPDFEKRKPEFLKGLPDQLK-LYSEFLGKQPWFAGDKITFADFLVYDVLDQHRMfepkcldafpnlMDFVVhFEGLKKI 194
Cdd:cd03183   35 GTPVSPEKVKKAEENLEESLDlLENKFLKDKPFLAGDEISIADLSAICEIMQPEA------------AGYDV-FEGRPKL 101

                 ....*...
gi 157822007 195 SAYMKTSR 202
Cdd:cd03183  102 AAWRKRVK 109

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        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 157822007 107 TRIQMGTLCYSPDFEKRKPEFLKGLPDQLKLYSEFLGKQPWFAGDKITFADFLVYDVLDQHRMFepKCLDAFPNLMDFV 185
Cdd:cd03207   17 LNKALGRFFEPPWGEPAIAAAYGDLDERLAALEAALAGRPYLVGERFSAADLLLASVLRWARAF--GLLPEYPALRAYV 93

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 157822007 135 LKLYSEFLGKQPWFAGDKITFADFLVYDVLDQHRM-----FEPKCLDA-FPNLMDFV 185
Cdd:cd03193   28 LEALSTLLGDKKFLFGDKPTSVDATVFAHLASILYppedsPLLRVLVAsSPNLVEYC 84

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
                 ....*....|....*....|....*....|....*....|...
gi 157822007 142 LGKQPWFAGDKITFADFLVYDVLDQHRMFePKCLDAFPNLMDF 184
Cdd:cd03188   58 LAGGPYLLGDQFSVADAYLFVVLRWARAV-GLDLSDWPHLAAY 99