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        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958752368  13 EKQKPEFLKSIPEKMKIYSEFLGKRPWFAGDKVTYVDFLAYDILDQYRMFEPECLDAFPNLKDFLARFEGLKKISAYMKS 92
Cdd:cd03209    30 EKLKPDYLEKLPDKLKLFSEFLGDRPWFAGDKITYVDFLLYEALDQHRIFEPDCLDAFPNLKDFLERFEALPKISAYMKS 109

                          90
                  ....*....|..
gi 1958752368  93 SSFLPRPVFTKI 104
Cdd:cd03209   110 DRFIKWPINGWK 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 1958752368  13 EKQKPEFLKSIPEKMKIYSEFLGKRPWFAGDKVTYVDFLAYDILDQYRMFEPECLDAFPNLKDFLARFEGLKKISAYMKS 92
Cdd:cd03209    30 EKLKPDYLEKLPDKLKLFSEFLGDRPWFAGDKITYVDFLLYEALDQHRIFEPDCLDAFPNLKDFLERFEALPKISAYMKS 109

                          90
                  ....*....|..
gi 1958752368  93 SSFLPRPVFTKI 104
Cdd:cd03209   110 DRFIKWPINGWK 121

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

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1958752368  13 EKQKPEFLKSIPEKMKIYSEFLGKRPWFAGDKVTYVDFLAYDILDQYRMFEPEcLDAFPNLKDFLARFE 81
Cdd:COG0625   121 PAAIARARAELARLLAVLEARLAGGPYLAGDRFSIADIALAPVLRRLDRLGLD-LADYPNLAAWLARLA 188

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 1958752368  13 EKQKPEFLKSIPEKMKIYSEFLGKRPWFAGDKVTYVDFLAYDILDQYRMFEPECLDAFPNLKDFLARFEGLKKISAYMKS 92
Cdd:cd03209    30 EKLKPDYLEKLPDKLKLFSEFLGDRPWFAGDKITYVDFLLYEALDQHRIFEPDCLDAFPNLKDFLERFEALPKISAYMKS 109

                          90
                  ....*....|..
gi 1958752368  93 SSFLPRPVFTKI 104
Cdd:cd03209   110 DRFIKWPINGWK 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.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958752368   3 MIlgYWNVRGEKQKpeFLKSIPEKMKIYSEFL---GKRPWFAGDKVTYVDFLAYDILDQYRMFEPECLDAFPNLKDFLAR 79
Cdd:cd03210    24 MI--YQNYEAGKDD--YIKDLPEQLKPFEKLLaknNGKGFIVGDKISFADYNLFDLLDIHLVLAPGCLDAFPLLKAFVER 99

                          90       100
                  ....*....|....*....|.
gi 1958752368  80 FEGLKKISAYMKSSSFLPRPV 100
Cdd:cd03210   100 LSARPKLKAYLESDAFKNRPI 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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1958752368  13 EKQKPEFLKSIPEKMKIYSEFLGK--RPWFAGDKVTYVDFLAYDILDQYRMFEPEC-LDAFPNLKDFLARF 80
Cdd:cd03192    34 EKKKEFLEEALPKFLGKFEKILKKsgGGYFVGDKLTWADLALFDVLDYLLYLLPKDlLEKYPKLKALRERV 104

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

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1958752368  13 EKQKPEFLKSIPEKMKIYSEFLGKRPWFAGDKVTYVDFLAYDILDQYRMFEPEcLDAFPNLKDFLARFE 81
Cdd:COG0625   121 PAAIARARAELARLLAVLEARLAGGPYLAGDRFSIADIALAPVLRRLDRLGLD-LADYPNLAAWLARLA 188

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 1958752368   1 MAMILGYWNVRGEKQKpEFLKSIPEKMK-IYSEFLGKRPWFAGDKVTYVDFLAYDILDQ-----YRMFEPecldaFPNLK 74
Cdd:cd03183    29 LLPLFGGTPVSPEKVK-KAEENLEESLDlLENKFLKDKPFLAGDEISIADLSAICEIMQpeaagYDVFEG-----RPKLA 102

                  ....*
gi 1958752368  75 DFLAR 79
Cdd:cd03183   103 AWRKR 107

C-terminal, alpha helical domain of GTT1-like Glutathione S-transferases; Glutathione S-transferase (GST) C-terminal domain 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 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. 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        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 1958752368  34 LGKRPWFAGDKVTYVDFLAYDILDQYRMFEPEcLDAFPNLKDFLARFEG 82
Cdd:cd03189    74 LAKHPYFAGDELTAADIMMSFPLEAALARGPL-LEQYPNIAAYLERIEA 121

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 1958752368  34 LGKRPWFAGDKVTYVDFLAYDILDQYRMFePECLDAFPNLKDFLAR 79
Cdd:cd03188    58 LAGGPYLLGDQFSVADAYLFVVLRWARAV-GLDLSDWPHLAAYLAR 102

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

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1958752368  18 EFLKSIPEKMKIYSEFLGKRPWFAGDKVTYVDFLAYDILDQYRMFEPEC--LDAFPNLKDFLAR 79
Cdd:pfam13410   4 RAREQLRAALDALEARLADGPGLLGDRPTLADIALAPVLARLDAAYPGLdlREGYPRLRAWLER 67