Protein Disulfide Oxidoreductases and Other Proteins with a Thioredoxin fold; The thioredoxin (TRX)-like superfamily is a large, diverse group of proteins containing a TRX fold. Many members contain a classic TRX domain with a redox active CXXC motif. They function as protein disulfide oxidoreductases (PDOs), altering the redox state of target proteins via the reversible oxidation of their active site dithiol. The PDO members of this superfamily include the families of TRX, protein disulfide isomerase (PDI), tlpA, glutaredoxin, NrdH redoxin, and bacterial Dsb proteins (DsbA, DsbC, DsbG, DsbE, DsbDgamma). Members of the superfamily that do not function as PDOs but contain a TRX-fold domain include phosducins, peroxiredoxins, glutathione (GSH) peroxidases, SCO proteins, GSH transferases (GST, N-terminal domain), arsenic reductases, TRX-like ferredoxins and calsequestrin, among others.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 49169814   4 KPKLHYTRGRGKMESIRWLLAAAGVEFEEEFIEKKEDLEKLRNDGSLLFQQVPMVEIDGMKMVQSRAILCYIAGKYNLY 82
Cdd:cd03077   1 KPVLHYFNGRGRMESIRWLLAAAGVEFEEKFIESAEDLEKLKKDGSLMFQQVPMVEIDGMKLVQTRAILNYIAGKYNLY 79

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 49169814   4 KPKLHYTRGRGKMESIRWLLAAAGVEFEEEFIEKKEDLEKLRNDGSLLFQQVPMVEIDGMKMVQSRAILCYIAGKYNLY 82
Cdd:cd03077   1 KPVLHYFNGRGRMESIRWLLAAAGVEFEEKFIESAEDLEKLKKDGSLMFQQVPMVEIDGMKLVQTRAILNYIAGKYNLY 79

glutathione s-transferase; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 49169814    1 MAGKPKLHYTRGRGKMESIRWLLAAAGVEFEEEFIEKKED----LEKLRNDGSLLFQQVPMVEIDGMKMVQSRAILCYIA 76
Cdd:PTZ00057   1 MAEEIVLYYFDARGKAELIRLIFAYLGIEYTDKRFGENGDafieFKNFKKEKDTPFEQVPILEMDNIIFAQSQAIVRYLS 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 49169814   77 GKYNLYGKDLKERAWIDMYVEGTTDLMgmimaLPFQAADVKEKNIALITERATTRYFPVYEKALKDHGQDYLVGNKLSWA 156
Cdd:PTZ00057  81 KKYKICGESELNEFYADMIFCGVQDIH-----YKFNNTNLFKQNETTFLNEELPKWSGYFENILKKNHCNYFVGDNLTYA 155

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|....*....
gi 49169814  157 DIHLLEAILMTEELKSDILSAFPLLQAFKGRMSNVPTIKKFLqpgSQRK 205
Cdd:PTZ00057 156 DLAVFNLYDDIETKYPNSLKNFPLLKAHNEFISNLPNIKNYI---SNRK 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 49169814    11 RGRGKMESIRWLLAAAGVEFEEEFIekkeDLEKLRNDGSLL-----FQQVPMVEIDGMKMVQSRAILCYIA 76
Cdd:pfam02798   9 RGSPRAHRIRWLLAEKGVEYEIVPL----DFGAGPEKSPELlklnpLGKVPALEDGGKKLTESRAILEYIA 75

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 49169814   4 KPKLHYTRGRGKMESIRWLLAAAGVEFEEEFIEKKEDLEKLRNDGSLLFQQVPMVEIDGMKMVQSRAILCYIAGKYNLY 82
Cdd:cd03077   1 KPVLHYFNGRGRMESIRWLLAAAGVEFEEKFIESAEDLEKLKKDGSLMFQQVPMVEIDGMKLVQTRAILNYIAGKYNLY 79

glutathione s-transferase; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 49169814    1 MAGKPKLHYTRGRGKMESIRWLLAAAGVEFEEEFIEKKED----LEKLRNDGSLLFQQVPMVEIDGMKMVQSRAILCYIA 76
Cdd:PTZ00057   1 MAEEIVLYYFDARGKAELIRLIFAYLGIEYTDKRFGENGDafieFKNFKKEKDTPFEQVPILEMDNIIFAQSQAIVRYLS 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 49169814   77 GKYNLYGKDLKERAWIDMYVEGTTDLMgmimaLPFQAADVKEKNIALITERATTRYFPVYEKALKDHGQDYLVGNKLSWA 156
Cdd:PTZ00057  81 KKYKICGESELNEFYADMIFCGVQDIH-----YKFNNTNLFKQNETTFLNEELPKWSGYFENILKKNHCNYFVGDNLTYA 155

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|....*....
gi 49169814  157 DIHLLEAILMTEELKSDILSAFPLLQAFKGRMSNVPTIKKFLqpgSQRK 205
Cdd:PTZ00057 156 DLAVFNLYDDIETKYPNSLKNFPLLKAHNEFISNLPNIKNYI---SNRK 201

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 49169814  87 KERAWIDMYVEGTTDLMGMIMALPFQAADV-KEKNIALITERattryFPVYEKALKDH-GQDYLVGNKLSWADIHLLEAI 164
Cdd:cd03210   2 KEAALIDMVNDGVEDLRLKYVRMIYQNYEAgKDDYIKDLPEQ-----LKPFEKLLAKNnGKGFIVGDKISFADYNLFDLL 76

                        90       100       110       120
                ....*....|....*....|....*....|....*....|...
gi 49169814 165 LMTEELKSDILSAFPLLQAFKGRMSNVPTIKKFLQPGSQRKPP 207
Cdd:cd03210  77 DIHLVLAPGCLDAFPLLKAFVERLSARPKLKAYLESDAFKNRP 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 49169814   5 PKLHYTRGRGKMESIRWLLAAAGVeFEEEFIEKKEDLEKLRNDGSLLFQQVPMVEIDGMKMVQSRAILCYIA 76
Cdd:cd03039   1 YKLTYFNIRGRGEPIRLLLADAGV-EYEDVRITYEEWPELDLKPTLPFGQLPVLEIDGKKLTQSNAILRYLA 71

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 49169814    11 RGRGKMESIRWLLAAAGVEFEEEFIekkeDLEKLRNDGSLL-----FQQVPMVEIDGMKMVQSRAILCYIA 76
Cdd:pfam02798   9 RGSPRAHRIRWLLAEKGVEYEIVPL----DFGAGPEKSPELlklnpLGKVPALEDGGKKLTESRAILEYIA 75

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 49169814  87 KERAWIDMYVEGTTDL-MGMIM---------ALPFQAADVKEKnialiterattryFPVYEKALKDHgqDYLVGNKLSWA 156
Cdd:cd03209   1 KERIRVDMLEQQAMDLrMGLIRicyspdfekLKPDYLEKLPDK-------------LKLFSEFLGDR--PWFAGDKITYV 65

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*...
gi 49169814 157 DIHLLEAILMTEELKSDILSAFPLLQAFKGRMSNVPTIKKFLQpgSQR 204
Cdd:cd03209  66 DFLLYEALDQHRIFEPDCLDAFPNLKDFLERFEALPKISAYMK--SDR 111

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 49169814   5 PKLHYTRGRGKMESIRWLLAAAGVEFEEEFIEKKEDLEKLRNDGSLlFQQVPMVEIDGMKMVQSRAILCYIA 76
Cdd:cd00570   1 LKLYYFPGSPRSLRVRLALEEKGLPYELVPVDLGEGEQEEFLALNP-LGKVPVLEDGGLVLTESLAILEYLA 71

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 49169814   4 KPKLHYTRGRGKMESIRWLLAAAGVEFEEEFIEKKEDLEKLRNdgSLLFQQVPMVEIDGMKMVQSRAILCYIAGK 78
Cdd:cd03076   1 PYTLTYFPVRGRAEAIRLLLADQGISWEEERVTYEEWQESLKP--KMLFGQLPCFKDGDLTLVQSNAILRHLGRK 73

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
                ....*....|....*....|....*
gi 49169814  52 FQQVPMVEIDGMKMVQSRAILCYIA 76
Cdd:cd03056  49 NGEVPVLELDGRVLAESNAILVYLA 73