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
                 ....*....|....*....|....*....|..
gi 559098434   1 MFEQVPMVEIDGMKLVQTKAILNYIATKYNLY 32
Cdd:cd03077   48 MFQQVPMVEIDGMKLVQTRAILNYIAGKYNLY 79

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 559098434   49 VADLELMVLYYPYMPPGEKEASLAKIKDKARNRYFPAYEKVLKshGQDYLVGNKLSRADVSLVELLYHVEEMDPGIV-DN 127
Cdd:pfam00043   1 LMDLRMQIALLPYVPPEEKKEPEVDEALEKVARVLSALEEVLK--GQTYLVGDKLTLADIALAPALLWLYELDPACLrEK 78

                          90
                  ....*....|....*
gi 559098434  128 FPLLKALRTRVSNLP 142
Cdd:pfam00043  79 FPNLKAWFERVAARP 93

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
                 ....*....|....*....|....*....|..
gi 559098434   1 MFEQVPMVEIDGMKLVQTKAILNYIATKYNLY 32
Cdd:cd03077   48 MFQQVPMVEIDGMKLVQTRAILNYIAGKYNLY 79

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
                  ....*....|....*....|....*
gi 559098434    2 FEQVPMVEIDGMKLVQTKAILNYIA 26
Cdd:pfam02798  51 LGKVPALEDGGKKLTESRAILEYIA 75

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 559098434  38 ERALIDMYAEGVADLELMVLYYPYMP-PGEKEASLAKIKDKARNRYFPAYEKVLKSHGQDYLVGNKLSRADVSLVELLYH 116
Cdd:cd03192    2 EEARVDAIVDTIADLRAEFAPYFYEPdGEEKKEKKKEFLEEALPKFLGKFEKILKKSGGGYFVGDKLTWADLALFDVLDY 81

                         90       100
                 ....*....|....*....|...
gi 559098434 117 VEEMDPG-IVDNFPLLKALRTRV 138
Cdd:cd03192   82 LLYLLPKdLLEKYPKLKALRERV 104

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 559098434   51 DLELMVLYYPYMPPGEKEASLAK-IKDKARNRYFPAYEKVLKSHGQDYLVGNKLSRADVSLVELLYHVEE-MDPGIVDNF 128
Cdd:pfam14497   2 DLHHPIASSLYYEDEKKKAKRRKeFREERLPKFLGYFEKVLNKNGGGYLVGDKLTYADLALFQVLDGLLYpKAPDALDKY 81

                          90       100
                  ....*....|....*....|.
gi 559098434  129 PLLKALRTRVSNLPTVKKFLQ 149
Cdd:pfam14497  82 PKLKALHERVAARPNIKAYLA 102

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 559098434  37 KERALIDMYAEGVADLELMVLYYPYMppgEKEASLAK-IKDKARNryFPAYEKVLKSH-GQDYLVGNKLSRADVSLVELL 114
Cdd:cd03210    2 KEAALIDMVNDGVEDLRLKYVRMIYQ---NYEAGKDDyIKDLPEQ--LKPFEKLLAKNnGKGFIVGDKISFADYNLFDLL 76

                         90       100       110
                 ....*....|....*....|....*....|....*
gi 559098434 115 YHVEEMDPGIVDNFPLLKALRTRVSNLPTVKKFLQ 149
Cdd:cd03210   77 DIHLVLAPGCLDAFPLLKAFVERLSARPKLKAYLE 111

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 559098434   4 QVPMVEIDGMKLVQTKAILNYIATKY---NLYGKDMKERALIDM---YAEGVADLELMVLYYPYMPPGEKEAsLAKIKDK 77
Cdd:COG0625   52 KVPVLVDDGLVLTESLAILEYLAERYpepPLLPADPAARARVRQwlaWADGDLHPALRNLLERLAPEKDPAA-IARARAE 130

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 559098434  78 ARnRYFPAYEKVLKshGQDYLVGNKLSRADVSLVELLYHVEEMDPGIvDNFPLLKALRTRVSNLPTVKKFLQPG 151
Cdd:COG0625  131 LA-RLLAVLEARLA--GGPYLAGDRFSIADIALAPVLRRLDRLGLDL-ADYPNLAAWLARLAARPAFQRALAAA 200

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 559098434  39 RALIDMYAEGVADLELMVLYYPYMPPGEKEASLAKIKDKARnRYFPAYEKVLKshGQDYLVGNKLSRADVSLVELLYHVE 118
Cdd:cd00299    2 RALEDWADATLAPPLVRLLYLEKVPLPKDEAAVEAAREELP-ALLAALEQLLA--GRPYLAGDQFSLADVALAPVLARLE 78

                         90       100
                 ....*....|....*....|..
gi 559098434 119 EMDP--GIVDNFPLLKALRTRV 138
Cdd:cd00299   79 ALGPyyDLLDEYPRLKAWYDRL 100

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
                 ....*....|....*....|....*.
gi 559098434   1 MFEQVPMVEIDGMKLVQTKAILNYIA 26
Cdd:cd03039   46 PFGQLPVLEIDGKKLTQSNAILRYLA 71

C-terminal, alpha helical domain of Class Zeta Glutathione S-transferases; Glutathione S-transferase (GST) C-terminal domain family, Class Zeta 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 Zeta GSTs, also known as maleylacetoacetate (MAA) isomerases, catalyze the isomerization of MAA to fumarylacetoacetate, the penultimate step in tyrosine/phenylalanine catabolism, using GSH as a cofactor. They show little GSH-conjugating activity towards traditional GST substrates, but display modest GSH peroxidase activity. They are also implicated in the detoxification of the carcinogen dichloroacetic acid by catalyzing its dechlorination to glyoxylic acid.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 559098434  83 FPAYEKVLKSHGQDYLVGNKLSRADVSLVELLYHVEEMDpgiVD--NFPLLKALRTRVSNLPTVKK 146
Cdd:cd03191   53 FQALEKLLASTAGKYCVGDEPTLADICLVPQVYNARRFG---VDlsPYPTIVRINEACLELPAFQA 115

C-terminal, alpha helical domain of fungal Ure2p Glutathione S-transferases; Glutathione S-transferase (GST) C-terminal domain family, Ure2p subfamily; composed of the Saccharomyces cerevisiae Ure2p and related fungal proteins. 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 thioredoxin-fold domain and a C-terminal alpha helical domain. The N-terminal thioredoxin-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. 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. The GST active site is located in a cleft between the N- and C-terminal domains. GSH binds to the N-terminal domain while the hydrophobic substrate occupies a pocket in the C-terminal domain.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 559098434  80 NRYFPAYEKVLKSHGQDYLVGNKLSRADVSLVELLYHVE----EMDPGIVDNFPLLKALRTRVSNLPTVKK 146
Cdd:cd10293   46 RRVLGVLETALAERYRVWLVGDKFTIADLAFVPWNNVVDmifiDPELDIKKEFPHVYKWLKRMLARPAVKK 116

Glutathione S-transferase C-terminal-like, alpha helical domain of the Gamma subunit of Elongation Factor 1B and similar proteins; Glutathione S-transferase (GST) C-terminal domain family, Gamma subunit of Elongation Factor 1B (EF1Bgamma) 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 thioredoxin-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 to 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. Also included in this subfamily is the GST_C-like domain at the N-terminus of human valyl-tRNA synthetase (ValRS) and its homologs. Metazoan ValRS forms a stable complex with Elongation Factor-1H (EF-1H), and together, they catalyze consecutive steps in protein biosynthesis, tRNA aminoacylation and its transfer to EF.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 559098434  38 ERALIDMYAeGVADLELM------VL----YYPYMPPGEKEAslakiKDKArNRYFPAYEKVLKSHGqdYLVGNKLSRAD 107
Cdd:cd03181    1 EAAQVLQWI-SFANSELLpaaatwVLpllgIAPYNKKAVDKA-----KEDL-KRALGVLEEHLLTRT--YLVGERITLAD 71

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|...
gi 559098434 108 VSLVELLYHVEE--MDPGIVDNFPLLKALRTRVSNLPTVKKFL 148
Cdd:cd03181   72 IFVASALLRGFEtvLDPEFRKKYPNVTRWFNTVVNQPKFKAVF 114

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 559098434  38 ERALIDMYAE--------GVADLELMVLYYPYMppGEKEASLAKIKdKARNRYFPAY----EKVLKshGQDYLVGNKLSR 105
Cdd:cd03183    1 KRARVDEYLAwqhtnlrlGCAAYFWQKVLLPLF--GGTPVSPEKVK-KAEENLEESLdlleNKFLK--DKPFLAGDEISI 75

                         90       100       110
                 ....*....|....*....|....*....|....*
gi 559098434 106 ADVSLVELLYHVEEMDPGIVDNFPLLKALRTRVSN 140
Cdd:cd03183   76 ADLSAICEIMQPEAAGYDVFEGRPKLAAWRKRVKE 110