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 1622826146 132 LAHVIRLLLEYTDSSYEEKKYFREDAPDYDRSQWLNEKFKLGLDFPNLPYLIDGTHKITQSNAIMCYIARKH 203
Cdd:cd03075    11 LAQPIRLLLEYTGEKYEEKRYELGDAPDYDRSQWLNEKFKLGLDFPNLPYYIDGDVKLTQSNAILRYIARKH 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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1622826146 132 LAHVIRLLLEYTDSSYEEKKYFREDAPDYDRSQWLNEKFKLGLDFPNLPYLIDGTHKITQSNAIMCYIARKH 203
Cdd:cd03075    11 LAQPIRLLLEYTGEKYEEKRYELGDAPDYDRSQWLNEKFKLGLDFPNLPYYIDGDVKLTQSNAILRYIARKH 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 1622826146 120 PSLTRAAGPLSQLAHVIRLLLEYTDSSYEEKKYFREDAPDYDrSQWLNEKFklgldFPNLPYLIDGTHKITQSNAIMCYI 199
Cdd:pfam02798   1 MVLTLYGIRGSPRAHRIRWLLAEKGVEYEIVPLDFGAGPEKS-PELLKLNP-----LGKVPALEDGGKKLTESRAILEYI 74

                  ..
gi 1622826146 200 AR 201
Cdd:pfam02798  75 AR 76

glutathione s-transferase; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622826146 133 AHVIRLLLEYTDSSYEEKKyFREDAPDYdrSQWLNEKFKLGLDFPNLPYLIDGTHKITQSNAIMCYIARKHNLCGETEEE 212
Cdd:PTZ00057   16 AELIRLIFAYLGIEYTDKR-FGENGDAF--IEFKNFKKEKDTPFEQVPILEMDNIIFAQSQAIVRYLSKKYKICGESELN 92

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622826146 213 KIRVHIMKNQTMDNHMQLvmicHNPE-FEKLKPKYL-EELPEKLKLYSQFLGK--WPWFAGDTITFVDFLVYDVLDLHHT 288
Cdd:PTZ00057   93 EFYADMIFCGVQDIHYKF----NNTNlFKQNETTFLnEELPKWSGYFENILKKnhCNYFVGDNLTYADLAVFNLYDDIET 168

                         170       180       190
                  ....*....|....*....|....*....|....*..
gi 1622826146 289 FEPKCLDAFPNLK---DFISRFEGLEKISAYMKSSRF 322
Cdd:PTZ00057  169 KYPNSLKNFPLLKahnEFISNLPNIKNYISNRKESVY 205

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 1622826146 132 LAHVIRLLLEYTDSSYEEKKYFREDAPDYDRSQWLNEKFKLGLDFPNLPYLIDGTHKITQSNAIMCYIARKH 203
Cdd:cd03075    11 LAQPIRLLLEYTGEKYEEKRYELGDAPDYDRSQWLNEKFKLGLDFPNLPYYIDGDVKLTQSNAILRYIARKH 82

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

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622826146 132 LAHVIRLLLEYTDSSYEEKKYFREDAPDYDrsqwlnekFKLGLDFPNLPYLIDGTHKITQSNAIMCYIAR 201
Cdd:cd03039    11 RGEPIRLLLADAGVEYEDVRITYEEWPELD--------LKPTLPFGQLPVLEIDGKKLTQSNAILRYLAR 72

Glutathione S-transferase, C-terminal domain; GST conjugates reduced glutathione to a variety of targets including S-crystallin from squid, the eukaryotic elongation factor 1-gamma, the HSP26 family of stress-related proteins and auxin-regulated proteins in plants. Stringent starvation proteins in E. coli are also included in the alignment but are not known to have GST activity. The glutathione molecule binds in a cleft between N and C-terminal domains. The catalytically important residues are proposed to reside in the N-terminal domain. In plants, GSTs are encoded by a large gene family (48 GST genes in Arabidopsis) and can be divided into the phi, tau, theta, zeta, and lambda classes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622826146 224 MDNHMQLVMICHNPEFEKLKPKYLEELPEKLKLYSQF---LGKWPWFAGDTITFVDFLVYDVLDLHHTFEPKCL-DAFPN 299
Cdd:pfam00043   2 MDLRMQIALLPYVPPEEKKEPEVDEALEKVARVLSALeevLKGQTYLVGDKLTLADIALAPALLWLYELDPACLrEKFPN 81

                          90
                  ....*....|..
gi 1622826146 300 LKDFISRFEGLE 311
Cdd:pfam00043  82 LKAWFERVAARP 93

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 1622826146 120 PSLTRAAGPLSQLAHVIRLLLEYTDSSYEEKKYFREDAPDYDrSQWLNEKFklgldFPNLPYLIDGTHKITQSNAIMCYI 199
Cdd:pfam02798   1 MVLTLYGIRGSPRAHRIRWLLAEKGVEYEIVPLDFGAGPEKS-PELLKLNP-----LGKVPALEDGGKKLTESRAILEYI 74

                  ..
gi 1622826146 200 AR 201
Cdd:pfam02798  75 AR 76

glutathione s-transferase; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622826146 133 AHVIRLLLEYTDSSYEEKKyFREDAPDYdrSQWLNEKFKLGLDFPNLPYLIDGTHKITQSNAIMCYIARKHNLCGETEEE 212
Cdd:PTZ00057   16 AELIRLIFAYLGIEYTDKR-FGENGDAF--IEFKNFKKEKDTPFEQVPILEMDNIIFAQSQAIVRYLSKKYKICGESELN 92

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622826146 213 KIRVHIMKNQTMDNHMQLvmicHNPE-FEKLKPKYL-EELPEKLKLYSQFLGK--WPWFAGDTITFVDFLVYDVLDLHHT 288
Cdd:PTZ00057   93 EFYADMIFCGVQDIHYKF----NNTNlFKQNETTFLnEELPKWSGYFENILKKnhCNYFVGDNLTYADLAVFNLYDDIET 168

                         170       180       190
                  ....*....|....*....|....*....|....*..
gi 1622826146 289 FEPKCLDAFPNLK---DFISRFEGLEKISAYMKSSRF 322
Cdd:PTZ00057  169 KYPNSLKNFPLLKahnEFISNLPNIKNYISNRKESVY 205

C-terminal, alpha helical domain of the Glutathione S-transferase family; Glutathione S-transferase (GST) family, C-terminal alpha helical domain; a large, diverse group of cytosolic dimeric proteins involved in cellular detoxification by catalyzing the conjugation of glutathione (GSH) with a wide range of endogenous and xenobiotic alkylating agents, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress. In addition, GSTs also show GSH peroxidase activity and are involved in the synthesis of prostaglandins and leukotrienes. This family, also referred to as soluble GSTs, is the largest family of GSH transferases and is only distantly related to the mitochondrial GSTs (GSTK). Soluble GSTs bear no structural similarity to microsomal GSTs (MAPEG family) and display additional activities unique to their group, such as catalyzing thiolysis, reduction and isomerization of certain compounds. The GST fold contains an N-terminal thioredoxin-fold domain and a C-terminal alpha helical domain, with an active site located in a cleft between the two domains. GSH binds to the N-terminal domain while the hydrophobic substrate occupies a pocket in the C-terminal domain. Based on sequence similarity, different classes of GSTs have been identified, which display varying tissue distribution, substrate specificities and additional specific activities. In humans, GSTs display polymorphisms which may influence individual susceptibility to diseases such as cancer, arthritis, allergy and sclerosis. Some GST family members with non-GST functions include glutaredoxin 2, the CLIC subfamily of anion channels, prion protein Ure2p, crystallins, metaxins, stringent starvation protein A, and aminoacyl-tRNA synthetases.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1622826146 237 PEFEKLKPKYLEELPEKLKLYSQFLGKWPWFAGDTITFVDFLVYDVLDLH--HTFEPKCLDAFPNLKDFISR 306
Cdd:cd00299    28 PKDEAAVEAAREELPALLAALEQLLAGRPYLAGDQFSLADVALAPVLARLeaLGPYYDLLDEYPRLKAWYDR 99

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        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1622826146 246 YLEELPEKLKLYSQFLGKWPWFAGDTITFVDFLVYDVLDLH-----HTFEPKCLDA-FPNLKDFISRF 307
Cdd:cd03193    20 IYELALEDLEALSTLLGDKKFLFGDKPTSVDATVFAHLASIlyppeDSPLLRVLVAsSPNLVEYCERI 87

GST_N family, Class Alpha 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 Alpha subfamily is composed of eukaryotic GSTs which can form homodimer and heterodimers. There are at least six types of class Alpha GST subunits in rats, four of which have human counterparts, resulting in many possible isoenzymes with different activities, tissue distribution and substrate specificities. Human GSTA1-1 and GSTA2-2 show high GSH peroxidase activity. GSTA3-3 catalyzes the isomerization of intermediates in steroid hormone biosynthesis. GSTA4-4 preferentially catalyzes the GSH conjugation of alkenals.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1622826146 136 IRLLLEYTDSSYEEKkyFREDAPDYDRSQwlnekfKLG-LDFPNLPYL-IDGThKITQSNAIMCYIARKHNL 205
Cdd:cd03077    16 IRWLLAAAGVEFEEK--FIESAEDLEKLK------KDGsLMFQQVPMVeIDGM-KLVQTRAILNYIAGKYNL 78

C-terminal, alpha helical domain of Class Beta Glutathione S-transferases; Glutathione S-transferase (GST) C-terminal domain family, Class Beta subfamily; GSTs are cytosolic dimeric proteins involved in cellular detoxification by catalyzing the conjugation of glutathione (GSH) with a wide range of endogenous and xenobiotic alkylating agents, including carcinogens, therapeutic drugs, environmental toxins, and products of oxidative stress. The GST fold contains an N-terminal thioredoxin-fold domain and a C-terminal alpha helical domain, with an active site located in a cleft between the two domains. GSH binds to the N-terminal domain while the hydrophobic substrate occupies a pocket in the C-terminal domain. Unlike mammalian GSTs which detoxify a broad range of compounds, the bacterial class Beta GSTs exhibit GSH conjugating activity with a narrow range of substrates. In addition to GSH conjugation, they are involved in the protection against oxidative stress and are able to bind antibiotics and reduce the antimicrobial activity of beta-lactam drugs, contributing to antibiotic resistance. The structure of the Proteus mirabilis enzyme reveals that the cysteine in the active site forms a covalent bond with GSH. One member of this subfamily is a GST from Burkholderia xenovorans LB400 that is encoded by the bphK gene and is part of the biphenyl catabolic pathway.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1622826146 240 EKLKPKYLEELPEKLKLYSQFLGKWPWFAGDTITFVDFLVYDVLDLHHTFePKCLDAFPNLKDFISR 306
Cdd:cd03188    37 EEVKAAARERLERRLAYLDAQLAGGPYLLGDQFSVADAYLFVVLRWARAV-GLDLSDWPHLAAYLAR 102