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 208008901   4 PILYSLRQCPYAMRARLGIIHAHQIVLLRDVDMNNKPEEMLSISPKGTVPVLLLENGSVIDESIDVMIWAL 74
Cdd:cd03060    1 PILYSFRRCPYAMRARMALLLAGITVELREVELKNKPAEMLAASPKGTVPVLVLGNGTVIEESLDIMRWAL 71

GST_N family, Omega-like subfamily; composed of uncharacterized proteins with similarity to class Omega 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. 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 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. Like Omega enzymes, proteins in this subfamily 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.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 208008901   4 PILYSLRQCPYAMRARLGIIHAHQIVLLRDVDMNNKPEEMLSISPKGTVPVLLLENGSVIDESIDVMIWAL 74
Cdd:cd03060    1 PILYSFRRCPYAMRARMALLLAGITVELREVELKNKPAEMLAASPKGTVPVLVLGNGTVIEESLDIMRWAL 71

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

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 208008901   12 CPYAMRARL-----GIIHAHQIVllrDVDMNNKPEEMLSISPKGTVPVLLLENGSVIDESIDVMIW 72
Cdd:pfam13409   2 SPFSHRVRLaleekGLPYEIELV---DLDPKDKPPELLALNPLGTVPVLVLPDGTVLTDSLVILEY 64

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

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 208008901  134 LMEIEQRLSQHAYIMGEKPSLVDYSILPFIRQFSRVDKKWYAQAPLPYLRAWL 186
Cdd:pfam13410  13 LDALEARLADGPGLLGDRPTLADIALAPVLARLDAAYPGLDLREGYPRLRAWL 65

GST_N family, Omega-like subfamily; composed of uncharacterized proteins with similarity to class Omega 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. 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 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. Like Omega enzymes, proteins in this subfamily 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.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 208008901   4 PILYSLRQCPYAMRARLGIIHAHQIVLLRDVDMNNKPEEMLSISPKGTVPVLLLENGSVIDESIDVMIWAL 74
Cdd:cd03060    1 PILYSFRRCPYAMRARMALLLAGITVELREVELKNKPAEMLAASPKGTVPVLVLGNGTVIEESLDIMRWAL 71

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

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 208008901   12 CPYAMRARL-----GIIHAHQIVllrDVDMNNKPEEMLSISPKGTVPVLLLENGSVIDESIDVMIW 72
Cdd:pfam13409   2 SPFSHRVRLaleekGLPYEIELV---DLDPKDKPPELLALNPLGTVPVLVLPDGTVLTDSLVILEY 64

glutathione dehydrogenase (ascorbate)

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 208008901   9 LRQCPYAMRARLGIIHAHQIVLLRDVDMNNKPEEMLSISPKGTVPVLLLENGSVIDEsiDVMIWALNQSDPNNLLyshdk 88
Cdd:PLN02817  70 LGDCPFCQRVLLTLEEKHLPYDMKLVDLTNKPEWFLKISPEGKVPVVKLDEKWVADS--DVITQALEEKYPDPPL----- 142

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 208008901  89 ALLPVMLELINRSDTEFVNALQKYRAAsryhDDNETACRDMccgwLMEIEQRLSQHA-YIMGEKPSLVDYSILPFIRQFS 167
Cdd:PLN02817 143 ATPPEKASVGSKIFSTFIGFLKSKDPG----DGTEQALLDE----LTSFDDYIKENGpFINGEKISAADLSLGPKLYHLE 214

                        170       180       190
                 ....*....|....*....|....*....|...
gi 208008901 168 RV---DKKWYAQAPLPYLRAWLVNHYNDPLFSK 197
Cdd:PLN02817 215 IAlghYKNWSVPDSLPFVKSYMKNIFSMESFVK 247

Glutathione S-transferase, N-terminal domain;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 208008901    6 LYSLRQCPYAMRARLGIIHAHQIVLLRDVDMNNKPEEMLSISPKGTVPVLLLENGSVID 64
Cdd:pfam13417   1 LYGFPGSPYARRVRIALNEKGLPYEFVPIPPGDHPPELLAKNPLGKVPVLEDDGGILCE 59

GST_N family, Stringent starvation protein A (SspA) subfamily; SspA is a RNA polymerase (RNAP)-associated protein required for the lytic development of phage P1 and for stationary phase-induced acid tolerance of E. coli. It is implicated in survival during nutrient starvation. SspA adopts the GST fold with an N-terminal TRX-fold domain and a C-terminal alpha helical domain, but it does not bind glutathione (GSH) and lacks GST activity. SspA is highly conserved among gram-negative bacteria. Related proteins found in Neisseria (called RegF), Francisella and Vibrio regulate the expression of virulence factors necessary for pathogenesis.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 208008901   6 LYSLRQCPYAMRARLgIIHAHQI-VLLRDVDMNNKPEEMLSISPKGTVPVLL-----LENGSVIDESID 68
Cdd:cd03059    3 LYSGPDDVYSHRVRI-VLAEKGVsVEIIDVDPDNPPEDLAELNPYGTVPTLVdrdlvLYESRIIMEYLD 70

GST_N family, Saccharomyces cerevisiae GTT2-like subfamily; composed of predominantly uncharacterized proteins with similarity to the S. cerevisiae GST protein, GTT2. 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. GTT2, a homodimer, exhibits GST activity with standard substrates. Strains with deleted GTT2 genes are viable but exhibit increased sensitivity to heat shock.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 208008901   6 LYSLRQCPYAMRARLgIIHAHQIVL-LRDVDM---NNKPEEMLSISPKGTVPVLLLENGSVIDES 66
Cdd:cd03051    3 LYDSPTAPNPRRVRI-FLAEKGIDVpLVTVDLaagEQRSPEFLAKNPAGTVPVLELDDGTVITES 66

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
                 ....*....|....*....|....*....|....*....|....*....|.
gi 208008901 136 EIEQRLSQHAYIMGEKPSLVDYSILPFIRQFSRVDKKWYAQAPLPYLRAWL 186
Cdd:cd00299   47 ALEQLLAGRPYLAGDQFSLADVALAPVLARLEALGPYYDLLDEYPRLKAWY 97

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 208008901    5 ILYSLRQCPYAMRARLGIIHA---HQIVLLRDVDMNNKPEEMLSISPKGTVPVlLLENGSVIDES 66
Cdd:pfam02798   4 TLYGIRGSPRAHRIRWLLAEKgveYEIVPLDFGAGPEKSPELLKLNPLGKVPA-LEDGGKKLTES 67

C-terminal, alpha helical domain of Ure2p and related Glutathione S-transferase-like proteins; Glutathione S-transferase (GST) C-terminal domain family, Ure2p-like subfamily; composed of the Saccharomyces cerevisiae Ure2p, YfcG and YghU from Escherichia coli, and related GST-like 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. YfcG and YghU are two of the nine GST homologs in the genome of Escherichia coli. They display very low or no GSH transferase, but show very good disulfide bond oxidoreductase activity. YghU also shows modest organic hydroperoxide reductase 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
                 ....*....|....*....|....*....|....*....|....*....|
gi 208008901 137 IEQRLSQHAYIMGEKPSLVDYSILPFIRQFSRVDKKWYAQapLPYLRAWL 186
Cdd:cd03178   52 LDKRLSDRPYLAGEEYSIADIALYPWTHYADLGGFADLSE--YPNVKRWL 99

GST_N family, Glutaredoxin 2 (GRX2) subfamily; composed of bacterial proteins similar to E. coli GRX2, an atypical GRX with a molecular mass of about 24kD, compared with other GRXs which are 9-12kD in size. GRX2 adopts a GST fold containing an N-terminal thioredoxin-fold domain and a C-terminal alpha helical domain. It contains a redox active CXXC motif located in the N-terminal domain but is not able to reduce ribonucleotide reductase like other GRXs. However, it catalyzes GSH-dependent protein disulfide reduction of other substrates efficiently. GRX2 is thought to function primarily in catalyzing the reversible glutathionylation of proteins in cellular redox regulation including stress responses.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 208008901   5 ILYSLRQCPYAMRARL--GI--IHAHQIVLLRDVDmnNKPEEMLSispKGTVPVLLLENGSVIDESIDV 69
Cdd:cd03037    2 KLYIYEHCPFCVKARMiaGLknIPVEQIILQNDDE--ATPIRMIG---AKQVPILEKDDGSFMAESLDI 65