Glutaredoxin (GRX) family, GRX bacterial class 1 and 3 (b_1_3)-like subfamily; composed of bacterial GRXs, approximately 10 kDa in size, and proteins containing a GRX or GRX-like domain. GRX is a glutathione (GSH) dependent reductase, catalyzing the disulfide reduction of target proteins such as ribonucleotide reductase. It contains a redox active CXXC motif in a TRX fold and uses a similar dithiol mechanism employed by TRXs for intramolecular disulfide bond reduction of protein substrates. Unlike TRX, GRX has preference for mixed GSH disulfide substrates, in which it uses a monothiol mechanism where only the N-terminal cysteine is required. The flow of reducing equivalents in the GRX system goes from NADPH -> GSH reductase -> GSH -> GRX -> protein substrates. By altering the redox state of target proteins, GRX is involved in many cellular functions including DNA synthesis, signal transduction and the defense against oxidative stress. Different classes are known including E. coli GRX1 and GRX3, which are members of this subfamily.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 2083972840  3 PVTIYTRQFCGYCSRAKSLLEHKGVDYVEHDATYSPDLRQEMIGKANGRTTFPQIFIGAEHVGGCDDLFALDRAG 77
Cdd:cd03418    1 KVEIYTKPNCPYCVRAKALLDKKGVDYEEIDVDGDPALREEMINRSGGRRTVPQIFIGDVHIGGCDDLYALERKG 75

Glutaredoxin [Posttranslational modification, protein turnover, chaperones];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2083972840  3 PVTIYTRQFCGYCSRAKSLLEHKGVDYVEHDATYSPDLRQEMIgKANGRTTFPQIFIGAEHVGGCDDlfaldraGKLDPM 82
Cdd:COG0695    1 KVTLYTTPGCPYCARAKRLLDEKGIPYEEIDVDEDPEAREELR-ERSGRRTVPVIFIGGEHLGGFDE-------GELDAL 72

                 ..
gi 2083972840 83 LA 84
Cdd:COG0695   73 LA 74

Uxx-star family glutaredoxin-like (seleno)protein; A number of proteins with glutaredoxin-like folds, a length of about 75 amino acids, and a CxxC, C/UxxT, or CxxS motif near the N-terminus end with a UXX-COOH motif. That final motif typically is missed during coding region feature prediction by genome annotation pipelines. This HMM covers proteins from several distinctive families with this feature. The seed alignment illustrates the final selenocysteine or aligned Cys or Ser residues, but the HMM also hits proteins that lack an equivalent motif at the C-terminus. This C-terminal selenocysteine-containing motif has not yet been described in the literature.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 2083972840  4 VTIYTRQFCGYCSRAKSLLEHKGVDYVEHDATYSPDLRQEMIGKANGRTTFPQIFIGAE-HVG 65
Cdd:NF041212   1 VVIYTKPGCPYCAAAKEDLARRGIPFEEIDVSKDPEALEEMLRLTGGERIVPVIVEGGEvTVG 63

Glutaredoxin (GRX) family, GRX bacterial class 1 and 3 (b_1_3)-like subfamily; composed of bacterial GRXs, approximately 10 kDa in size, and proteins containing a GRX or GRX-like domain. GRX is a glutathione (GSH) dependent reductase, catalyzing the disulfide reduction of target proteins such as ribonucleotide reductase. It contains a redox active CXXC motif in a TRX fold and uses a similar dithiol mechanism employed by TRXs for intramolecular disulfide bond reduction of protein substrates. Unlike TRX, GRX has preference for mixed GSH disulfide substrates, in which it uses a monothiol mechanism where only the N-terminal cysteine is required. The flow of reducing equivalents in the GRX system goes from NADPH -> GSH reductase -> GSH -> GRX -> protein substrates. By altering the redox state of target proteins, GRX is involved in many cellular functions including DNA synthesis, signal transduction and the defense against oxidative stress. Different classes are known including E. coli GRX1 and GRX3, which are members of this subfamily.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 2083972840  3 PVTIYTRQFCGYCSRAKSLLEHKGVDYVEHDATYSPDLRQEMIGKANGRTTFPQIFIGAEHVGGCDDLFALDRAG 77
Cdd:cd03418    1 KVEIYTKPNCPYCVRAKALLDKKGVDYEEIDVDGDPALREEMINRSGGRRTVPQIFIGDVHIGGCDDLYALERKG 75

Glutaredoxin [Posttranslational modification, protein turnover, chaperones];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2083972840  3 PVTIYTRQFCGYCSRAKSLLEHKGVDYVEHDATYSPDLRQEMIgKANGRTTFPQIFIGAEHVGGCDDlfaldraGKLDPM 82
Cdd:COG0695    1 KVTLYTTPGCPYCARAKRLLDEKGIPYEEIDVDEDPEAREELR-ERSGRRTVPVIFIGGEHLGGFDE-------GELDAL 72

                 ..
gi 2083972840 83 LA 84
Cdd:COG0695   73 LA 74

Glutaredoxin (GRX) family, GRX human class 1 and 2 (h_1_2)-like subfamily; composed of proteins similar to human GRXs, approximately 10 kDa in size, and proteins containing a GRX or GRX-like domain. GRX is a glutathione (GSH) dependent reductase, catalyzing the disulfide reduction of target proteins such as ribonucleotide reductase. It contains a redox active CXXC motif in a TRX fold and uses a similar dithiol mechanism employed by TRXs for intramolecular disulfide bond reduction of protein substrates. Unlike TRX, GRX has preference for mixed GSH disulfide substrates, in which it uses a monothiol mechanism where only the N-terminal cysteine is required. The flow of reducing equivalents in the GRX system goes from NADPH -> GSH reductase -> GSH -> GRX -> protein substrates. By altering the redox state of target proteins, GRX is involved in many cellular functions including DNA synthesis, signal transduction and the defense against oxidative stress. Different classes are known including human GRX1 and GRX2, which are members of this subfamily. Also included in this subfamily are the N-terminal GRX domains of proteins similar to human thioredoxin reductase 1 and 3.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2083972840  3 PVTIYTRQFCGYCSRAKSLLEHKGVDY--VEHDATYSPDLRQEMIGKANGRTTFPQIFIGAEHVGGCDDLFALDRAGKLD 80
Cdd:cd03419    1 PVVVFSKSYCPYCKRAKSLLKELGVKPavVELDQHEDGSEIQDYLQELTGQRTVPNVFIGGKFIGGCDDLMALHKSGKLV 80

                 ..
gi 2083972840 81 PM 82
Cdd:cd03419   81 KL 82

Glutaredoxin (GRX) family, PRX5 hybrid subfamily; composed of hybrid proteins containing peroxiredoxin (PRX) and GRX domains, which is found in some pathogenic bacteria and cyanobacteria. PRXs are thiol-specific antioxidant (TSA) proteins that confer a protective antioxidant role in cells through their peroxidase activity in which hydrogen peroxide, peroxynitrate, and organic hydroperoxides are reduced and detoxified using reducing equivalents derived from either thioredoxin, glutathione, trypanothione and AhpF. GRX is a glutathione (GSH) dependent reductase, catalyzing the disulfide reduction of target proteins. PRX-GRX hybrid proteins from Haemophilus influenza and Neisseria meningitis exhibit GSH-dependent peroxidase activity. The flow of reducing equivalents in the catalytic cycle of the hybrid protein goes from NADPH -> GSH reductase -> GSH -> GRX domain of hybrid -> PRX domain of hybrid -> peroxide substrate.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 2083972840  4 VTIYTRQFCGYCSRAKSLLEHKGVDYVEhdATYSPDLRQEMIGKANGRTTFPQIFIGAEHVGGCDDL 70
Cdd:cd03029    3 VSLFTKPGCPFCARAKAALQENGISYEE--IPLGKDITGRSLRAVTGAMTVPQVFIDGELIGGSDDL 67

NrdH-redoxin (NrdH) family; NrdH is a small monomeric protein with a conserved redox active CXXC motif within a TRX fold, characterized by a glutaredoxin (GRX)-like sequence and TRX-like activity profile. In vitro, it displays protein disulfide reductase activity that is dependent on TRX reductase, not glutathione (GSH). It is part of the NrdHIEF operon, where NrdEF codes for class Ib ribonucleotide reductase (RNR-Ib), an efficient enzyme at low oxygen levels. Under these conditions when GSH is mostly conjugated to spermidine, NrdH can still function and act as a hydrogen donor for RNR-Ib. It has been suggested that the NrdHEF system may be the oldest RNR reducing system, capable of functioning in a microaerophilic environment, where GSH was not yet available. NrdH from Corynebacterium ammoniagenes can form domain-swapped dimers, although it is unknown if this happens in vivo. Domain-swapped dimerization, which results in the blocking of the TRX reductase binding site, could be a mechanism for regulating the oxidation state of the protein.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 2083972840  3 PVTIYTRQFCGYCSRAKSLLEHKGVDYVEHDATYSPDLRQEMiGKANGRTTFPQIFIGAEHVGG 66
Cdd:cd02976    1 EVTVYTKPDCPYCKATKRFLDERGIPFEEVDVDEDPEALEEL-KKLNGYRSVPVVVIGDEHLSG 63

Glutaredoxin-like protein, YruB-family; This glutaredoxin-like protein family contains the conserved CxxC motif and includes the Clostridium pasteurianum protein YruB which has been cloned from a rubredoxin operon. Somewhat related to NrdH, it is unknown whether this protein actually interacts with glutathione/glutathione reducatase, or, like NrdH, some other reductant system.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 2083972840  3 PVTIYTRQFCGYCSRAKSLLEHKGVDYVEHDATYSPDLRQEMIGKANGRTTfPQIFIGAEHVGGCD 68
Cdd:TIGR02196  1 KVKVYTTPWCPPCVKAKEYLTSKGVAFEEIDVEKDAAAREELLKVYGQRGV-PVIVIGHKIVVGFD 65

Uxx-star family glutaredoxin-like (seleno)protein; A number of proteins with glutaredoxin-like folds, a length of about 75 amino acids, and a CxxC, C/UxxT, or CxxS motif near the N-terminus end with a UXX-COOH motif. That final motif typically is missed during coding region feature prediction by genome annotation pipelines. This HMM covers proteins from several distinctive families with this feature. The seed alignment illustrates the final selenocysteine or aligned Cys or Ser residues, but the HMM also hits proteins that lack an equivalent motif at the C-terminus. This C-terminal selenocysteine-containing motif has not yet been described in the literature.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 2083972840  4 VTIYTRQFCGYCSRAKSLLEHKGVDYVEHDATYSPDLRQEMIGKANGRTTFPQIFIGAE-HVG 65
Cdd:NF041212   1 VVIYTKPGCPYCAAAKEDLARRGIPFEEIDVSKDPEALEEMLRLTGGERIVPVIVEGGEvTVG 63

Glutaredoxin (GRX) family, PKC-interacting cousin of TRX (PICOT)-like subfamily; composed of PICOT and GRX-PICOT-like proteins. The non-PICOT members of this family contain only the GRX-like domain, whereas PICOT contains an N-terminal TRX-like domain followed by one to three GRX-like domains. It is interesting to note that PICOT from plants contain three repeats of the GRX-like domain, metazoan proteins (except for insect) have two repeats, while fungal sequences contain only one copy of the domain. PICOT is a protein that interacts with protein kinase C (PKC) theta, a calcium independent PKC isoform selectively expressed in skeletal muscle and T lymphocytes. PICOT inhibits the activation of c-Jun N-terminal kinase and the transcription factors, AP-1 and NF-kB, induced by PKC theta or T-cell activating stimuli. Both GRX and TRX domains of PICOT are required for its activity. Characterized non-PICOT members of this family include CXIP1, a CAX-interacting protein in Arabidopsis thaliana, and PfGLP-1, a GRX-like protein from Plasmodium falciparum.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2083972840  3 PVTIY---TRQF--CGYCSRAKSLLEHKGVDYVEHDATYSPDLRQEmIGKANGRTTFPQIFIGAEHVGGCDDLFALDRAG 77
Cdd:cd03028    9 PVVLFmkgTPEEprCGFSRKVVQILNQLGVDFGTFDILEDEEVRQG-LKEYSNWPTFPQLYVNGELVGGCDIVKEMHESG 87

                 ..
gi 2083972840 78 KL 79
Cdd:cd03028   88 EL 89

Glutaredoxin-like family; This family of glutaredoxin-like proteins is aparrently limited to plants. Multiple isoforms are found in A. thaliana and O.sativa.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2083972840  3 PVTIYTRQFCGYCSRAKSLLEHKGVDYVEHDATYSPDLR--QEMIGKANGRTTFPQIFIGAEHVGGCDDLFALDRAGKLD 80
Cdd:TIGR02189  9 AVVIFSRSSCCMCHVVKRLLLTLGVNPAVHEIDKEPAGKdiENALSRLGCSPAVPAVFVGGKLVGGLENVMALHISGSLV 88

                 ...
gi 2083972840 81 PML 83
Cdd:TIGR02189 89 PML 91

Glutaredoxin, GrxA family; Glutaredoxins are thioltransferases (disulfide reductases) which utilize glutathione and NADPH as cofactors. Oxidized glutathione is regenerated by glutathione reductase. Together these components compose the glutathione system. Glutaredoxins utilize the CXXC motif common to thioredoxins and are involved in multiple cellular processes including protection from redox stress, reduction of critical enzymes such as ribonucleotide reductase and the generation of reduced sulfur for iron sulfur cluster formation. Glutaredoxins are capable of reduction of mixed disulfides of glutathione as well as the formation of glutathione mixed disulfides. This model includes the E. coli glyutaredoxin GrxA which appears to have primary responsibility for the reduction of ribonucleotide reductase.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 2083972840  4 VTIYTRQFCGYCSRAKSLLEHKGVDYVEHDATYSpDLRQEMIGKAN-----GRT--TFPQIFIGAEHVGGCDDLFALDR 75
Cdd:TIGR02183  2 VVIFGRPGCPYCVRAKQLAEKLAIERADFEFRYI-DIHAEGISKADlektvGKPveTVPQIFVDEKHVGGCTDFEQLVK 79

bifunctional gluaredoxin/ribonucleoside-diphosphate reductase subunit beta; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2083972840   1 MVPVTIYTRQFCGYCSRAKSLLEHKGVDYVE-------HDATYSPDLRQEMIGKANGRTTFPQIFIGAEHVGGCDDLFAl 73
Cdd:PRK12759    1 MVEVRIYTKTNCPFCDLAKSWFGANDIPFTQisldddvKRAEFYAEVNKNILLVEEHIRTVPQIFVGDVHIGGYDNLMA- 79

                  ....*.
gi 2083972840  74 dRAGKL 79
Cdd:PRK12759   80 -RAGEV 84

Thioredoxin (TRX) superfamily; 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 TRX, protein disulfide isomerase (PDI), tlpA-like, glutaredoxin, NrdH redoxin, and the bacterial Dsb (DsbA, DsbC, DsbG, DsbE, DsbDgamma) protein families. Members of the superfamily that do not function as PDOs but contain a TRX-fold domain include phosducins, peroxiredoxins and 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
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 2083972840  4 VTIYTRQFCGYCSRAKSLL-----EHKGVDYVEHDATYSPDLRQEMigKANGRTTFPQIFIG 60
Cdd:cd01659    1 LVLFYAPWCPFCQALRPVLaelalLNKGVKFEAVDVDEDPALEKEL--KRYGVGGVPTLVVF 60

Arsenate Reductase (ArsC) family; composed of TRX-fold arsenic reductases and similar proteins including the transcriptional regulator, Spx. ArsC catalyzes the reduction of arsenate [As(V)] to arsenite [As(III)], using reducing equivalents derived from glutathione (GSH) via glutaredoxin (GRX), through a single catalytic cysteine. This family of predominantly bacterial enzymes is unrelated to two other families of arsenate reductases which show similarity to low-molecular-weight acid phosphatases and phosphotyrosyl phosphatases. Spx is a general regulator that exerts negative and positive control over transcription initiation by binding to the C-terminal domain of the alpha subunit of RNA polymerase.

                          10        20        30
                  ....*....|....*....|....*....|
gi 2083972840   4 VTIYTRQFCGYCSRAKSLLEHKGVDYVEHD 33
Cdd:cd02977     1 ITIYGNPNCSTSRKALAWLEEHGIEYEFID 30

glutaredoxin; Provisional

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 2083972840  11 FCGYCSRAKSLLEHKGVDYVEHDATYSPDLRQEMIGKANGrTTFPQIFIGAEHVGGCD 68
Cdd:PTZ00062  127 FCRFSNAVVNMLNSSGVKYETYNIFEDPDLREELKVYSNW-PTYPQLYVNGELIGGHD 183

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
                 ....*....|....*....|....*....|....*....|....*....|..
gi 2083972840  4 VTIYTRQFCGYCSRAKSLLEHKGVDYVEHDATYsPDLRQEMIGKANGRTTFP 55
Cdd:cd00570    1 LKLYYFPGSPRSLRVRLALEEKGLPYELVPVDL-GEGEQEEFLALNPLGKVP 51