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 1292374456   3 LELYMDLLSAPCRAVYIFSKKHDIQFNFQFVDLLKGHHHSKGYIDINPLRKLPSLKDGKFILSESAAILYYLCRKY 78
Cdd:cd03050     1 LKLYYDLMSQPSRAVYIFLKLNKIPFEECPIDLRKGEQLTPEFKKINPFGKVPAIVDGDFTLAESVAILRYLARKF 76

GST_N 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 TRX-fold domain and a C-terminal alpha helical domain, with an active site located in a cleft between the two domains. 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 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 aryl or alkyl sulfate esters.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1292374456   3 LELYMDLLSAPCRAVYIFSKKHDIQFNFQFVDLLKGHHHSKGYIDINPLRKLPSLKDGKFILSESAAILYYLCRKY 78
Cdd:cd03050     1 LKLYYDLMSQPSRAVYIFLKLNKIPFEECPIDLRKGEQLTPEFKKINPFGKVPAIVDGDFTLAESVAILRYLARKF 76

glutathione transferase;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1292374456   2 ALELYMD--LLSAPCRAVYIFSKKHDIQFNFQFVDLLKGHHHSKGYIDINPLRKLPSLKDGKFILSESAAILYYLCRKYS 79
Cdd:PRK15113    5 AITLYSDahFFSPYVMSAFVALQEKGLPFELKTVDLDAGEHLQPTYQGYSLTRRVPTLQHDDFELSESSAIAEYLEERFA 84

                          90       100
                  ....*....|....*....|....
gi 1292374456  80 APSHWC--PPDPHARARVDEFVAW 101
Cdd:PRK15113   85 PPAWERiyPADLQARARARQIQAW 108

Glutathione S-transferase, N-terminal domain;

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1292374456   5 LYMDLLSAPCRAVYIFSKKHDIQFnfQFVDLLKGHHhSKGYIDINPLRKLPSLKDGKFILSESAAILYYLCRKYSAPS 82
Cdd:pfam13417   1 LYGFPGSPYARRVRIALNEKGLPY--EFVPIPPGDH-PPELLAKNPLGKVPVLEDDGGILCESLAIIDYLEELYPGPP 75

GST_N 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 TRX-fold domain and a C-terminal alpha helical domain, with an active site located in a cleft between the two domains. 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 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 aryl or alkyl sulfate esters.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1292374456   3 LELYMDLLSAPCRAVYIFSKKHDIQFNFQFVDLLKGHHHSKGYIDINPLRKLPSLKDGKFILSESAAILYYLCRKY 78
Cdd:cd03050     1 LKLYYDLMSQPSRAVYIFLKLNKIPFEECPIDLRKGEQLTPEFKKINPFGKVPAIVDGDFTLAESVAILRYLARKF 76

GST_N family, Class Delta and Epsilon 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. 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. The class Delta and Epsilon subfamily is made up primarily of insect GSTs, which play major roles in insecticide resistance by facilitating reductive dehydrochlorination of insecticides or conjugating them with GSH to produce water-soluble metabolites that are easily excreted. They are also implicated in protection against cellular damage by oxidative stress.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1292374456   3 LELYMDLLSAPCRAVYIFSKKHDIQFNFQFVDLLKGHHHSKGYIDINPLRKLPSLKDGKFILSESAAILYYLC 75
Cdd:cd03045     1 IDLYYLPGSPPCRAVLLTAKALGLELNLKEVNLMKGEHLKPEFLKLNPQHTVPTLVDNGFVLWESHAILIYLV 73

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 1292374456   3 LELYMDLLSAPCRAVYIFSKKHDIQFNFQFVDLLKGHHhsKGYIDINPLRKLPSLKDGKFILSESAAILYYLC 75
Cdd:cd00570     1 LKLYYFPGSPRSLRVRLALEEKGLPYELVPVDLGEGEQ--EEFLALNPLGKVPVLEDGGLVLTESLAILEYLA 71

GST_N family, Class Phi subfamily; composed of plant-specific class Phi GSTs and related fungal and bacterial proteins. 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 Phi GST subfamily has experience extensive gene duplication. The Arabidopsis and Oryza genomes contain 13 and 16 Phi GSTs, respectively. They are primarily responsible for herbicide detoxification together with class Tau GSTs, showing class specificity in substrate preference. Phi enzymes are highly reactive toward chloroacetanilide and thiocarbamate herbicides. Some Phi GSTs have other functions including transport of flavonoid pigments to the vacuole, shoot regeneration and GSH peroxidase activity.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1292374456   2 ALELYMDLLSAPCRAVYIFSKKHDIQFNFQFVDLLKGHHHSKGYIDINPLRKLPSLKDGKFILSESAAILYYLCRK 77
Cdd:cd03053     1 VLKLYGAAMSTCVRRVLLCLEEKGVDYELVPVDLTKGEHKSPEHLARNPFGQIPALEDGDLKLFESRAITRYLAEK 76

GST_N family, Ure2p-like subfamily; composed of the Saccharomyces cerevisiae Ure2p and related GSTs. Ure2p is a regulator for nitrogen catabolism in yeast. It represses the expression of several gene products involved in the use of poor nitrogen sources when rich sources are available. A transmissible conformational change of Ure2p results in a prion called [Ure3], an inactive, self-propagating and infectious amyloid. Ure2p displays a GST fold containing 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 N-terminal TRX-fold domain is sufficient to induce the [Ure3] phenotype and is also called the prion domain of Ure2p. In addition to its role in nitrogen regulation, Ure2p confers protection to cells against heavy metal ion and oxidant toxicity, and shows glutathione (GSH) peroxidase activity. Characterized GSTs in this subfamily include Aspergillus fumigatus GSTs 1 and 2, and Schizosaccharomyces pombe GST-I. GSTs are cytosolic dimeric proteins involved in cellular detoxification by catalyzing the conjugation of 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.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1292374456  17 VYIFSKKHDIQFNFQFVDLLKGHHHSKGYIDINPLRKLPSLKD---GKFILSESAAILYYLCRKY 78
Cdd:cd03048    15 VSIMLEELGLPYEIHPVDISKGEQKKPEFLKINPNGRIPAIVDhngTPLTVFESGAILLYLAEKY 79

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        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1292374456  25 DIQFNFQFVDLLKGHHHSKGYIDINPLRKLPSLKDGKFILSESAAILYYLCRKY 78
Cdd:cd03046    22 GLPYELVLYDRGPGEQAPPEYLAINPLGKVPVLVDGDLVLTESAAIILYLAEKY 75

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
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1292374456  25 DIQFNFQFVDLLKGHHHSKGYIDINPLRKLPSLKDGKFILSESAAILYYLCR 76
Cdd:pfam02798  25 GVEYEIVPLDFGAGPEKSPELLKLNPLGKVPALEDGGKKLTESRAILEYIAR 76

GST_N 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 TRX-fold domain and a C-terminal alpha helical domain, with an active site located in a cleft between the two domains. Unlike mammalian GSTs which detoxify a broad range of compounds, the bacterial class Beta GSTs exhibit limited GSH conjugating activity with a narrow range of substrates. In addition to GSH conjugation, they also bind antibiotics and reduce the antimicrobial activity of beta-lactam drugs. The structure of the Proteus mirabilis enzyme reveals that the cysteine in the active site forms a covalent bond with GSH.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 1292374456  25 DIQFNFQFVDLLKGHHHSKGYIDINPLRKLPSL--KDGKfILSESAAILYYLCRKY 78
Cdd:cd03057    22 GLPFELVRVDLRTKTQKGADYLAINPKGQVPALvlDDGE-VLTESAAILQYLADLH 76

glutathione S-transferase

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1292374456   1 MALELYMDLLSA-PCRAVYIFSKKhDIQFNFQFVDLLKGHHHSKGYIDINPLRKLPSLKDGKFILSESAAILYYLCRKYS 79
Cdd:PLN02473    1 MVVKVYGQIKAAnPQRVLLCFLEK-GIEFEVIHVDLDKLEQKKPEHLLRQPFGQVPAIEDGDLKLFESRAIARYYATKYA 79

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1292374456  80 -APSHWCPPDPHARARVDEFVAWQHTAFQLPMKKIVwLKLLIPKITGEEVSAEKMEHAVEEVKNSLQLFEEYfLQDKMFI 158
Cdd:PLN02473   80 dQGTDLLGKTLEHRAIVDQWVEVENNYFYAVALPLV-INLVFKPRLGEPCDVALVEELKVKFDKVLDVYENR-LATNRYL 157

                         170
                  ....*....|
gi 1292374456 159 TGNQISLADL 168
Cdd:PLN02473  158 GGDEFTLADL 167

Glutathione S-transferase, N-terminal domain; This family is closely related to pfam02798.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 1292374456  26 IQFNFQFVDLlKGHHHSKGYIDINPLRKLPSLKDGK-FILSESAAILYYLCRK 77
Cdd:pfam13409  17 LPYEIELVDL-DPKDKPPELLALNPLGTVPVLVLPDgTVLTDSLVILEYLEEL 68

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1292374456 112 KIVWLkLLIPKITGEEVSAEKmehAVEEVKNSLQLFEEYfLQDKMFITGNQISLADLVAV 171
Cdd:pfam00043   7 QIALL-PYVPPEEKKEPEVDE---ALEKVARVLSALEEV-LKGQTYLVGDKLTLADIALA 61

GST_N family, Gamma subunit of Elongation Factor 1B (EFB1gamma) subfamily; EF1Bgamma is part of the eukaryotic translation elongation factor-1 (EF1) complex which plays a central role in the elongation cycle during protein biosynthesis. EF1 consists of two functionally distinct units, EF1A and EF1B. EF1A catalyzes the GTP-dependent binding of aminoacyl-tRNA to the ribosomal A site concomitant with the hydrolysis of GTP. The resulting inactive EF1A:GDP complex is recycled to the active GTP form by the guanine-nucleotide exchange factor EF1B, a complex composed of at least two subunits, alpha and gamma. Metazoan EFB1 contain a third subunit, beta. The EF1B gamma subunit contains a GST fold consisting of an N-terminal TRX-fold domain and a C-terminal alpha helical domain. The GST-like domain of EF1Bgamma is believed to mediate the dimerization of the EF1 complex, which in yeast is a dimer of the heterotrimer EF1A:EF1Balpha:EF1Bgamma. In addition to its role in protein biosynthesis, EF1Bgamma may also display other functions. The recombinant rice protein has been shown to possess GSH conjugating activity. The yeast EF1Bgamma binds membranes in a calcium dependent manner and is also part of a complex that binds to the msrA (methionine sulfoxide reductase) promoter suggesting a function in the regulation of its gene expression.

                          10        20        30
                  ....*....|....*....|....*....|....*
gi 1292374456  45 YIDINPLRKLPSLK--DGkFILSESAAILYYLCRK 77
Cdd:cd03044    42 FLKKFPLGKVPAFEgaDG-FCLFESNAIAYYVANL 75