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 4504183    3 PYTVVYFPVRGRCAALRMLLADQGQSWKEEVVTVETWQEgSLKASCLYGQLPKFQDGDLTLYQSNTILRHLGRT 76
Cdd:cd03076   1 PYTLTYFPVRGRAEAIRLLLADQGISWEEERVTYEEWQE-SLKPKMLFGQLPCFKDGDLTLVQSNAILRHLGRK 73

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 4504183    3 PYTVVYFPVRGRCAALRMLLADQGQSWKEEVVTVETWQEgSLKASCLYGQLPKFQDGDLTLYQSNTILRHLGRT 76
Cdd:cd03076   1 PYTLTYFPVRGRAEAIRLLLADQGISWEEERVTYEEWQE-SLKPKMLFGQLPCFKDGDLTLVQSNAILRHLGRK 73

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4504183    4 YTVVYFPVRGRCAALRMLLADQGQSWkeEVVTVETWQEGSLKASCL----YGQLPKFQDGDLTLYQSNTILRHLGRTLG- 78
Cdd:COG0625   2 MKLYGSPPSPNSRRVRIALEEKGLPY--ELVPVDLAKGEQKSPEFLalnpLGKVPVLVDDGLVLTESLAILEYLAERYPe 79

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4504183   79 --LYGKDQQEAALVDMV----NDGVE-DLRCKYISLIYTNYEAGKDDYVKALPGQLKPFETLLsqnqGGKTFIVGDQISF 151
Cdd:COG0625  80 ppLLPADPAARARVRQWlawaDGDLHpALRNLLERLAPEKDPAAIARARAELARLLAVLEARL----AGGPYLAGDRFSI 155

                       170       180       190       200
                ....*....|....*....|....*....|....*....|....*..
gi 4504183  152 ADYNLLDLLLIHEVLAPGcLDAFPLLSAYVGRLSARPKLKAFLASPE 198
Cdd:COG0625 156 ADIALAPVLRRLDRLGLD-LADYPNLAAWLARLAARPAFQRALAAAE 201

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 4504183      2 PPYTVVYFPVRGRCAALRMLLADQGQSWKEEVVTVETWQEGS--LKASCLYGQLPKFQDGDLTLYQSNTILRHLGR 75
Cdd:pfam02798   1 MVLTLYGIRGSPRAHRIRWLLAEKGVEYEIVPLDFGAGPEKSpeLLKLNPLGKVPALEDGGKKLTESRAILEYIAR 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 4504183    3 PYTVVYFPVRGRCAALRMLLADQGQSWKEEVVTVETWQEgSLKASCLYGQLPKFQDGDLTLYQSNTILRHLGRT 76
Cdd:cd03076   1 PYTLTYFPVRGRAEAIRLLLADQGISWEEERVTYEEWQE-SLKPKMLFGQLPCFKDGDLTLVQSNAILRHLGRK 73

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 4504183    4 YTVVYFPVRGRCAALRMLLADQGQSWKEEVVTVETWQEGSLKASCLYGQLPKFQDGDLTLYQSNTILRHLGR 75
Cdd:cd03039   1 YKLTYFNIRGRGEPIRLLLADAGVEYEDVRITYEEWPELDLKPTLPFGQLPVLEIDGKKLTQSNAILRYLAR 72

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 4504183   85 QEAALVDMVNDGVEDLRCKYISLIYT-----NYEAGKDDYVKALPGQLKPFETLLSQNQGGktFIVGDQISFADYNLLDL 159
Cdd:cd03192   1 EEEARVDAIVDTIADLRAEFAPYFYEpdgeeKKEKKKEFLEEALPKFLGKFEKILKKSGGG--YFVGDKLTWADLALFDV 78

                        90       100
                ....*....|....*....|....*
gi 4504183  160 LLIHEVLAPGC-LDAFPLLSAYVGR 183
Cdd:cd03192  79 LDYLLYLLPKDlLEKYPKLKALRER 103

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4504183    4 YTVVYFPVRGRCAALRMLLADQGQSWkeEVVTVETWQEGSLKASCL----YGQLPKFQDGDLTLYQSNTILRHLGRTLG- 78
Cdd:COG0625   2 MKLYGSPPSPNSRRVRIALEEKGLPY--ELVPVDLAKGEQKSPEFLalnpLGKVPVLVDDGLVLTESLAILEYLAERYPe 79

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4504183   79 --LYGKDQQEAALVDMV----NDGVE-DLRCKYISLIYTNYEAGKDDYVKALPGQLKPFETLLsqnqGGKTFIVGDQISF 151
Cdd:COG0625  80 ppLLPADPAARARVRQWlawaDGDLHpALRNLLERLAPEKDPAAIARARAELARLLAVLEARL----AGGPYLAGDRFSI 155

                       170       180       190       200
                ....*....|....*....|....*....|....*....|....*..
gi 4504183  152 ADYNLLDLLLIHEVLAPGcLDAFPLLSAYVGRLSARPKLKAFLASPE 198
Cdd:COG0625 156 ADIALAPVLRRLDRLGLD-LADYPNLAAWLARLAARPAFQRALAAAE 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 4504183    4 YTVVYFPVRGRCAALRMLLADQGQSWKEEVVTVETWQEGSLKASCLYGQLPKFQDGDLTLYQSNTILRHL 73
Cdd:cd00570   1 LKLYYFPGSPRSLRVRLALEEKGLPYELVPVDLGEGEQEEFLALNPLGKVPVLEDGGLVLTESLAILEYL 70

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
                ....*....|....*....|....*....|....*....|....*....|....*.
gi 4504183  134 LSQNQGGKTFIVGDQISFADYNLLDLLLIheVLAPGCLDAFPLLSAYVGRLSARPK 189
Cdd:cd03207  48 LEAALAGRPYLVGERFSAADLLLASVLRW--ARAFGLLPEYPALRAYVARCTARPA 101

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 4504183   88 ALVDMVNDGVEDLRCKYISLIYTN---YEAGKDDYVKALPGQLKPFETLLSQNQggktFIVGDQISFADYNLLDLLLIHE 164
Cdd:cd00299   3 ALEDWADATLAPPLVRLLYLEKVPlpkDEAAVEAAREELPALLAALEQLLAGRP----YLAGDQFSLADVALAPVLARLE 78

                        90       100
                ....*....|....*....|..
gi 4504183  165 VL--APGCLDAFPLLSAYVGRL 184
Cdd:cd00299  79 ALgpYYDLLDEYPRLKAWYDRL 100

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 4504183  117 DDYVKALPGQLKPFETLLSQNqggKTFIVGDQISFAdynllDLLLIHEVLAP---GC--LDAFPLLSAYVGRLSAR 187
Cdd:cd03183  44 KKAEENLEESLDLLENKFLKD---KPFLAGDEISIA-----DLSAICEIMQPeaaGYdvFEGRPKLAAWRKRVKEA 111

C-terminal, alpha helical domain of Class Omega Glutathione S-transferases; Glutathione S-transferase (GST) C-terminal domain family, Class Omega 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 Omega GSTs show little or no GSH-conjugating activity towards standard GST substrates. Instead, they catalyze the GSH dependent reduction of protein disulfides, dehydroascorbate and monomethylarsonate, activities which are more characteristic of glutaredoxins. They contain a conserved cysteine equivalent to the first cysteine in the CXXC motif of glutaredoxins, which is a redox active residue capable of reducing GSH mixed disulfides in a monothiol mechanism. Polymorphisms of the class Omega GST genes may be associated with the development of some types of cancer and the age-at-onset of both Alzheimer's and Parkinson's diseases.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4504183  102 CKYISLIYTNYEAGKDDyvkalPGQLKPFETLLSQ-----NQGGKTFIVGDQISFADY---------NLLDLLLIHEvla 167
Cdd:cd03184  14 SKVPSAFYKFLRSGEDR-----KGLKEELRSALENleeelAKRGTPFFGGNSPGMVDYmiwpwferlEALKLLDGYE--- 85

                        90       100       110
                ....*....|....*....|....*....|.
gi 4504183  168 pGCLDAFPLLSAYVGRLSARPKLKAFLASPE 198
Cdd:cd03184  86 -LCLDRFPKLKKWMAAMKQDPAVKAFYTDPE 115

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 4504183    8 YFPVRGRCAALRMLLADQGQSWKEEVV-TVETWQEGSLKASCLYGQLPKFQDGDLTLYQSNTILRHLGRTLGLY 80
Cdd:cd03077   6 YFNGRGRMESIRWLLAAAGVEFEEKFIeSAEDLEKLKKDGSLMFQQVPMVEIDGMKLVQTRAILNYIAGKYNLY 79