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 28948614  87 KERAEISMLEGAVLDIRYGVSRIAYSKDFETLKVDFLSKLPEMLKMFEDRLCHKTYLNGDHVTHPDFMLYDALDVVLYMD 166
Cdd:cd03209   1 KERIRVDMLEQQAMDLRMGLIRICYSPDFEKLKPDYLEKLPDKLKLFSEFLGDRPWFAGDKITYVDFLLYEALDQHRIFE 80

                        90       100       110       120
                ....*....|....*....|....*....|....*....|.
gi 28948614 167 PMCLDAFPKLVCFKKRIEAIPQIDKYLKSSKYIAWPLQGWQ 207
Cdd:cd03209  81 PDCLDAFPNLKDFLERFEALPKISAYMKSDRFIKWPINGWK 121

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 28948614  87 KERAEISMLEGAVLDIRYGVSRIAYSKDFETLKVDFLSKLPEMLKMFEDRLCHKTYLNGDHVTHPDFMLYDALDVVLYMD 166
Cdd:cd03209   1 KERIRVDMLEQQAMDLRMGLIRICYSPDFEKLKPDYLEKLPDKLKLFSEFLGDRPWFAGDKITYVDFLLYEALDQHRIFE 80

                        90       100       110       120
                ....*....|....*....|....*....|....*....|.
gi 28948614 167 PMCLDAFPKLVCFKKRIEAIPQIDKYLKSSKYIAWPLQGWQ 207
Cdd:cd03209  81 PDCLDAFPNLKDFLERFEALPKISAYMKSDRFIKWPINGWK 121

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 28948614   101 DIRYGVSRIAYSKD---FETLKVDFLSK-LPEMLKMFEDRLCHK--TYLNGDHVTHPDFMLYDALDVVLYMDPM-CLDAF 173
Cdd:pfam14497   2 DLHHPIASSLYYEDekkKAKRRKEFREErLPKFLGYFEKVLNKNggGYLVGDKLTYADLALFQVLDGLLYPKAPdALDKY 81

                          90       100
                  ....*....|....*....|..
gi 28948614   174 PKLVCFKKRIEAIPQIDKYLKS 195
Cdd:pfam14497  82 PKLKALHERVAARPNIKAYLAS 103

glutathione s-transferase; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 28948614   40 KWRNKKFELGLEFPNLPYYIDGDVKLTQSMAIIRYIADKHNMLGGCPKERAEISMLEGAVLDIRYGVSRIAYSKDFETlk 119
Cdd:PTZ00057  44 EFKNFKKEKDTPFEQVPILEMDNIIFAQSQAIVRYLSKKYKICGESELNEFYADMIFCGVQDIHYKFNNTNLFKQNET-- 121

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 28948614  120 vDFLSK-LPEMLKMFEDRL--CHKTYLNGDHVTHPDFMLYDALDVVLYMDPMCLDAFPKLVCFKKRIEAIPQIDKYLKSS 196
Cdd:PTZ00057 122 -TFLNEeLPKWSGYFENILkkNHCNYFVGDNLTYADLAVFNLYDDIETKYPNSLKNFPLLKAHNEFISNLPNIKNYISNR 200

                 .
gi 28948614  197 K 197
Cdd:PTZ00057 201 K 201

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 28948614  87 KERAEISMLEGAVLDIRYGVSRIAYSKDFETLKVDFLSKLPEMLKMFEDRLCHKTYLNGDHVTHPDFMLYDALDVVLYMD 166
Cdd:cd03209   1 KERIRVDMLEQQAMDLRMGLIRICYSPDFEKLKPDYLEKLPDKLKLFSEFLGDRPWFAGDKITYVDFLLYEALDQHRIFE 80

                        90       100       110       120
                ....*....|....*....|....*....|....*....|.
gi 28948614 167 PMCLDAFPKLVCFKKRIEAIPQIDKYLKSSKYIAWPLQGWQ 207
Cdd:cd03209  81 PDCLDAFPNLKDFLERFEALPKISAYMKSDRFIKWPINGWK 121

C-terminal, alpha helical domain of Class Pi Glutathione S-transferases; Glutathione S-transferase (GST) C-terminal domain 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 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 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 tumors.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 28948614  86 PKERAEISMLEGAVLDIRYGVSRIAYsKDFETLKVDFLSKLPEMLKMFEDRL---CHKTYLNGDHVTHPDFMLYDALDVV 162
Cdd:cd03210   1 EKEAALIDMVNDGVEDLRLKYVRMIY-QNYEAGKDDYIKDLPEQLKPFEKLLaknNGKGFIVGDKISFADYNLFDLLDIH 79

                        90       100       110       120
                ....*....|....*....|....*....|....*....|...
gi 28948614 163 LYMDPMCLDAFPKLVCFKKRIEAIPQIDKYLKSSKYIAWPLQG 205
Cdd:cd03210  80 LVLAPGCLDAFPLLKAFVERLSARPKLKAYLESDAFKNRPING 122

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 28948614   3 PILGYWKIKGLVQPTRLLLEYLEEKYEEHLYERDEgdkWRNKKFELGLEFPNLPYYIDGDVKLTQSMAIIRYIAD 77
Cdd:cd03039   1 YKLTYFNIRGRGEPIRLLLADAGVEYEDVRITYEE---WPELDLKPTLPFGQLPVLEIDGKKLTQSNAILRYLAR 72

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 28948614  56 PYYIDGDVKLTQSMAIIRYIADKH---NMLGGCPKERAEISMLEG-AVLDIRYGVSRIAY---SKDFETLKVDFLSKLPE 128
Cdd:COG0625  54 PVLVDDGLVLTESLAILEYLAERYpepPLLPADPAARARVRQWLAwADGDLHPALRNLLErlaPEKDPAAIARARAELAR 133

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*....
gi 28948614 129 MLKMFEDRLCHKTYLNGDHVTHPDFMLYDALDVVLYMDpMCLDAFPKLVCFKKRIEAIP 187
Cdd:COG0625 134 LLAVLEARLAGGPYLAGDRFSIADIALAPVLRRLDRLG-LDLADYPNLAAWLARLAARP 191

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 28948614   111 YSKDFETLKVDFLSKLP---EMLKMFEDRLCHKTYLNGDHVTHPDFMLYDALDVVLYMDPMCL-DAFPKLVCFKKRIEAI 186
Cdd:pfam00043  13 YVPPEEKKEPEVDEALEkvaRVLSALEEVLKGQTYLVGDKLTLADIALAPALLWLYELDPACLrEKFPNLKAWFERVAAR 92

                  .
gi 28948614   187 P 187
Cdd:pfam00043  93 P 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
                  ....*....|....*....|....*.
gi 28948614    52 FPNLPYYIDGDVKLTQSMAIIRYIAD 77
Cdd:pfam02798  51 LGKVPALEDGGKKLTESRAILEYIAR 76

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        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 28948614 116 ETLKVDFLSKLPEMLKMFEDRLCHKTYLNGDHVTHPDFMLYdaldVVL---YMDPMCLDAFPKLVCFKKRIEAIPQI 189
Cdd:cd03188  37 EEVKAAARERLERRLAYLDAQLAGGPYLLGDQFSVADAYLF----VVLrwaRAVGLDLSDWPHLAAYLARVAARPAV 109

GST_N 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 TRX-fold domain and a C-terminal alpha helical domain, with an active site located in a cleft between the two domains. 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
                ....*....|....*....|....
gi 28948614  56 PYYIDGDVKLTQSMAIIRYIADKH 79
Cdd:cd03046  52 PVLVDGDLVLTESAAIILYLAEKY 75

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
                ....*....|....*....|....*..
gi 28948614  52 FPNLPYYIDGDVKLTQSMAIIRYIADK 78
Cdd:cd03053  50 FGQIPALEDGDLKLFESRAITRYLAEK 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 28948614   2 SPILGYWKIKGLVQPTRLLLEYLEEKYEEHLYERDEGDKWRNKKFELGlefpNLPYYIDGDVKLTQSMAIIRYIADK 78
Cdd:cd03076   1 PYTLTYFPVRGRAEAIRLLLADQGISWEEERVTYEEWQESLKPKMLFG----QLPCFKDGDLTLVQSNAILRHLGRK 73