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 238018082  58 EEKIRVDILENQAMDVSNQLARVCYSPDFEKLKVEYLEQLPGMVKLFSQFLGQRTWFVGEKITFVDFLAYDILDLHLIFE 137
Cdd:cd03209    1 KERIRVDMLEQQAMDLRMGLIRICYSPDFEKLKPDYLEKLPDKLKLFSEFLGDRPWFAGDKITYVDFLLYEALDQHRIFE 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|
gi 238018082 138 PTCLDAFPNLKDFVARFEVLKRISAYMKTSRFLRTPLYTK 177
Cdd:cd03209   81 PDCLDAFPNLKDFLERFEALPKISAYMKSDRFIKWPINGW 120

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 238018082  58 EEKIRVDILENQAMDVSNQLARVCYSPDFEKLKVEYLEQLPGMVKLFSQFLGQRTWFVGEKITFVDFLAYDILDLHLIFE 137
Cdd:cd03209    1 KERIRVDMLEQQAMDLRMGLIRICYSPDFEKLKPDYLEKLPDKLKLFSEFLGDRPWFAGDKITYVDFLLYEALDQHRIFE 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|
gi 238018082 138 PTCLDAFPNLKDFVARFEVLKRISAYMKTSRFLRTPLYTK 177
Cdd:cd03209   81 PDCLDAFPNLKDFLERFEALPKISAYMKSDRFIKWPINGW 120

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 238018082   71 MDVSNQLARVCYSPDFEKLKVEYLEQLPGMVKLFSQF---LGQRTWFVGEKITFVDFLAYDILDLHLIFEPTCL-DAFPN 146
Cdd:pfam00043   2 MDLRMQIALLPYVPPEEKKEPEVDEALEKVARVLSALeevLKGQTYLVGDKLTLADIALAPALLWLYELDPACLrEKFPN 81

                  ....*....
gi 238018082  147 LKDFVARFE 155
Cdd:pfam00043  82 LKAWFERVA 90

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
                  ....*....|....*....|....*....|....*....|....*...
gi 238018082    1 MGDAPDYDrSQWLSEKFklgldFPNLPYLIDGSHKITQSNAILRYIAR 48
Cdd:pfam02798  35 FGAGPEKS-PELLKLNP-----LGKVPALEDGGKKLTESRAILEYIAR 76

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 238018082  58 EEKIRVDILENQAMDVSNQLARVCYSPDFEKLKVEYLEQLPGMVKLFSQFLGQRTWFVGEKITFVDFLAYDILDLHLIFE 137
Cdd:cd03209    1 KERIRVDMLEQQAMDLRMGLIRICYSPDFEKLKPDYLEKLPDKLKLFSEFLGDRPWFAGDKITYVDFLLYEALDQHRIFE 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|
gi 238018082 138 PTCLDAFPNLKDFVARFEVLKRISAYMKTSRFLRTPLYTK 177
Cdd:cd03209   81 PDCLDAFPNLKDFLERFEALPKISAYMKSDRFIKWPINGW 120

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 238018082  58 EEKIRVDILENQAMDVSNQLARVCYSPD----FEKLKVEYLEQLPGMVKLFSQFLGQRT--WFVGEKITFVDFLAYDILD 131
Cdd:cd03192    1 EEEARVDAIVDTIADLRAEFAPYFYEPDgeekKEKKKEFLEEALPKFLGKFEKILKKSGggYFVGDKLTWADLALFDVLD 80

                         90       100
                 ....*....|....*....|....
gi 238018082 132 LHLIFEPTC-LDAFPNLKDFVARF 154
Cdd:cd03192   81 YLLYLLPKDlLEKYPKLKALRERV 104

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 238018082  57 EEEKIRVDILENQAMDVSNQLARVCYsPDFEKLKVEYLEQLPGMVKLFSQFLGQ---RTWFVGEKITFVDFLAYDILDLH 133
Cdd:cd03210    1 EKEAALIDMVNDGVEDLRLKYVRMIY-QNYEAGKDDYIKDLPEQLKPFEKLLAKnngKGFIVGDKISFADYNLFDLLDIH 79

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|
gi 238018082 134 LIFEPTCLDAFPNLKDFVARFEVLKRISAYMKTSRFLRTP 173
Cdd:cd03210   80 LVLAPGCLDAFPLLKAFVERLSARPKLKAYLESDAFKNRP 119

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 238018082  27 PYLIDGSHKITQSNAILRYIARKH---NLCGETEEEKIRVDILENQAM-DVSNQLARV--CYSPDFEKLKVE-YLEQLPG 99
Cdd:COG0625   54 PVLVDDGLVLTESLAILEYLAERYpepPLLPADPAARARVRQWLAWADgDLHPALRNLleRLAPEKDPAAIArARAELAR 133

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 238018082 100 MVKLFSQFLGQRTWFVGEKITFVDFLAYDILDLHLIFEPTcLDAFPNLKDFVARFE 155
Cdd:COG0625  134 LLAVLEARLAGGPYLAGDRFSIADIALAPVLRRLDRLGLD-LADYPNLAAWLARLA 188

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
                  ....*....|....*....|....*....|....*....|....*...
gi 238018082    1 MGDAPDYDrSQWLSEKFklgldFPNLPYLIDGSHKITQSNAILRYIAR 48
Cdd:pfam02798  35 FGAGPEKS-PELLKLNP-----LGKVPALEDGGKKLTESRAILEYIAR 76

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 238018082  84 PDFEKLKVEYLEQLPGMVKLFSQFLGQRTWFVGEKITFVDFLAYDILDLHLIFEPTC--LDAFPNLKDFVAR 153
Cdd:cd00299   28 PKDEAAVEAAREELPALLAALEQLLAGRPYLAGDQFSLADVALAPVLARLEALGPYYdlLDEYPRLKAWYDR 99

glutathione S-transferase

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 238018082  23 FPNLPYLIDGSHKITQSNAILRYIARKH-----NLCGETEEEKIRVDilenQAMDVSNQ--------------LARVCYS 83
Cdd:PLN02395  50 FGVVPVIVDGDYKIFESRAIMRYYAEKYrsqgpDLLGKTIEERGQVE----QWLDVEATsyhppllnltlhilFASKMGF 125

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 238018082  84 PDFEKLKVEYLEQLPGMVKLFSQFLGQRTWFVGE--------KITFVDFLAYDILDLHLIFE 137
Cdd:PLN02395 126 PADEKVIKESEEKLAKVLDVYEARLSKSKYLAGDfvsladlaHLPFTEYLVGPIGKAYLIKD 187

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

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 238018082  85 DFEKLKVEYLE-QLPGMVKLFSQFLGQRTWFVGEKITFVDFLAYDILDLHLIFEPTCLDAFPNL 147
Cdd:cd10295   30 VKEKMFNEALTgPAPHLLKDLDTYLGGREWLVGKSVTWADFYWDTCSTTLLSFKPDLLKNYPRL 93

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 238018082  27 PYLIDGSHKITQSNAILRYIARKH 50
Cdd:cd03046   52 PVLVDGDLVLTESAAIILYLAEKY 75