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 21450105  84 QQEAALVDMVNDGLEDL----FRRIARQYrhilKEGKDQYQKELPGHLKPFETLLAQNrGGQSFIVGDQISFADYRLLDV 159
Cdd:cd03210   1 EKEAALIDMVNDGVEDLrlkyVRMIYQNY----EAGKDDYIKDLPEQLKPFEKLLAKN-NGKGFIVGDKISFADYNLFDL 75

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....
gi 21450105 160 LLNLELLFPGYLNDFPLFSAYVARLKSRPKLKAFLESPEHVNRP 203
Cdd:cd03210  76 LDIHLVLAPGCLDAFPLLKAFVERLSARPKLKAYLESDAFKNRP 119

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 21450105  84 QQEAALVDMVNDGLEDL----FRRIARQYrhilKEGKDQYQKELPGHLKPFETLLAQNrGGQSFIVGDQISFADYRLLDV 159
Cdd:cd03210   1 EKEAALIDMVNDGVEDLrlkyVRMIYQNY----EAGKDDYIKDLPEQLKPFEKLLAKN-NGKGFIVGDKISFADYNLFDL 75

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....
gi 21450105 160 LLNLELLFPGYLNDFPLFSAYVARLKSRPKLKAFLESPEHVNRP 203
Cdd:cd03210  76 LDIHLVLAPGCLDAFPLLKAFVERLSARPKLKAYLESDAFKNRP 119

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21450105   4 YTIVYFPSRGRCEVMRMLLADQGQSWKEEVVTLDVWEQGT--FKASCLFGQIPKFQDGELTLYQSNTILRHLGRSFG--- 78
Cdd:COG0625   2 MKLYGSPPSPNSRRVRIALEEKGLPYELVPVDLAKGEQKSpeFLALNPLGKVPVLVDDGLVLTESLAILEYLAERYPepp 81

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21450105  79 LYGKDQQEAALVDMV----NDGLEDLFRRIARQYRHIL-KEGKDQYQKELPGHLKPFETLLAqnrgGQSFIVGDQISFAD 153
Cdd:COG0625  82 LLPADPAARARVRQWlawaDGDLHPALRNLLERLAPEKdPAAIARARAELARLLAVLEARLA----GGPYLAGDRFSIAD 157

                       170       180       190       200       210
                ....*....|....*....|....*....|....*....|....*....|..
gi 21450105 154 -------YRlldvllnlELLFPGYLNDFPLFSAYVARLKSRPKLKAFLESPE 198
Cdd:COG0625 158 ialapvlRR--------LDRLGLDLADYPNLAAWLARLAARPAFQRALAAAE 201

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21450105   113 KEGKDQYQKELPGHLKPFETLLAQNRGGqsFIVGDQISFADYRL-LDVLLNLELLFPGYLNDFPLFSAYVARLKSRPKLK 191
Cdd:pfam14497  21 KRRKEFREERLPKFLGYFEKVLNKNGGG--YLVGDKLTYADLALfQVLDGLLYPKAPDALDKYPKLKALHERVAARPNIK 98

                  ....*.
gi 21450105   192 AFLESP 197
Cdd:pfam14497  99 AYLASR 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 21450105  84 QQEAALVDMVNDGLEDL----FRRIARQYrhilKEGKDQYQKELPGHLKPFETLLAQNrGGQSFIVGDQISFADYRLLDV 159
Cdd:cd03210   1 EKEAALIDMVNDGVEDLrlkyVRMIYQNY----EAGKDDYIKDLPEQLKPFEKLLAKN-NGKGFIVGDKISFADYNLFDL 75

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....
gi 21450105 160 LLNLELLFPGYLNDFPLFSAYVARLKSRPKLKAFLESPEHVNRP 203
Cdd:cd03210  76 LDIHLVLAPGCLDAFPLLKAFVERLSARPKLKAYLESDAFKNRP 119

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 21450105   4 YTIVYFPSRGRCEVMRMLLADQGQSWKEEVVTLDVWEQGTFKASCLFGQIPKFQDGELTLYQSNTILRHLGR 75
Cdd:cd03039   1 YKLTYFNIRGRGEPIRLLLADAGVEYEDVRITYEEWPELDLKPTLPFGQLPVLEIDGKKLTQSNAILRYLAR 72

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 21450105   4 YTIVYFPSRGRCEVMRMLLADQGQSWKEEVVTLDVWEQGTFKASCLFGQIPKFQDGELTLYQSNTILRHL 73
Cdd:cd00570   1 LKLYYFPGSPRSLRVRLALEEKGLPYELVPVDLGEGEQEEFLALNPLGKVPVLEDGGLVLTESLAILEYL 70

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21450105   113 KEGKDQYQKELPGHLKPFETLLAQNRGGqsFIVGDQISFADYRL-LDVLLNLELLFPGYLNDFPLFSAYVARLKSRPKLK 191
Cdd:pfam14497  21 KRRKEFREERLPKFLGYFEKVLNKNGGG--YLVGDKLTYADLALfQVLDGLLYPKAPDALDKYPKLKALHERVAARPNIK 98

                  ....*.
gi 21450105   192 AFLESP 197
Cdd:pfam14497  99 AYLASR 104

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 21450105  85 QEAALVDMVNDGLEDLFRRIAR-QYRHILKEGKDQYQKELPGHLKPFETLLaqnrGGQSFIVGDQISFADYRLLDVLLNL 163
Cdd:cd03209   1 KERIRVDMLEQQAMDLRMGLIRiCYSPDFEKLKPDYLEKLPDKLKLFSEFL----GDRPWFAGDKITYVDFLLYEALDQH 76

                        90       100       110       120
                ....*....|....*....|....*....|....*....|.
gi 21450105 164 ELLFPGYLNDFPLFSAYVARLKSRPKLKAFLESPEHVNRPL 204
Cdd:cd03209  77 RIFEPDCLDAFPNLKDFLERFEALPKISAYMKSDRFIKWPI 117

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 21450105     2 PPYTIVYFPSRGRCEVMRMLLADQGQSWkeEVVTLDVWEQGT----FKASCLFGQIPKFQDGELTLYQSNTILRHLGR 75
Cdd:pfam02798   1 MVLTLYGIRGSPRAHRIRWLLAEKGVEY--EIVPLDFGAGPEkspeLLKLNPLGKVPALEDGGKKLTESRAILEYIAR 76

GST_N family, unknown subfamily 4; composed of 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 TRX-fold domain and a C-terminal alpha helical domain, with an active site located in a cleft between the two domains.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 21450105   4 YTIVYFPSRGRCEVMRMLLADQGQSWkeEVVTLDVWEQGT----FKASCLFGQIPKFQDGELTLYQSNTILRHL 73
Cdd:cd03056   1 MKLYGFPLSGNCYKVRLLLALLGIPY--EWVEVDILKGETrtpeFLALNPNGEVPVLELDGRVLAESNAILVYL 72

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 21450105   5 TIVYFPSRGRCEVMRMLLADQGQSWKEEVVTLD--------VWEQGTFKASCLFGQIPKFQDGELTLYQSNTILRHLGR 75
Cdd:cd03075   2 TLGYWDIRGLAQPIRLLLEYTGEKYEEKRYELGdapdydrsQWLNEKFKLGLDFPNLPYYIDGDVKLTQSNAILRYIAR 80

glutathione S-transferase

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21450105   50 FGQIPKFQDGELTLYQSNTILRHLGRSFG-----LYGKDQQEAALVDMVNDGLEDLFRRIARQYRHIL----KEGK---- 116
Cdd:PLN02473  51 FGQVPAIEDGDLKLFESRAIARYYATKYAdqgtdLLGKTLEHRAIVDQWVEVENNYFYAVALPLVINLvfkpRLGEpcdv 130

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|
gi 21450105  117 ---DQYQKELPGHLKPFETLLAQNRggqsFIVGDQISFAD 153
Cdd:PLN02473 131 alvEELKVKFDKVLDVYENRLATNR----YLGGDEFTLAD 166

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 21450105   108 YRHILKEGKDQYQKELPGHLKPFETLLAQNRGgQSFIVGDQISFADYRLLDVLLNLELLFPGYLND-FPLFSAYVARLKS 186
Cdd:pfam00043  13 YVPPEEKKEPEVDEALEKVARVLSALEEVLKG-QTYLVGDKLTLADIALAPALLWLYELDPACLREkFPNLKAWFERVAA 91

                  ..
gi 21450105   187 RP 188
Cdd:pfam00043  92 RP 93