1.8.4.2	evolution	DsbA is a periplasmic thiol-disulfide oxidoreductase that belongs to the thioredoxin family of proteins with a CxxC conserved domain	-, 764747	
1.8.4.2	evolution	homologues of SdbA appear to be present in a range of Gram-positive bacteria that lack DsbA. SdbA is able to introduce a disulfide bond into its natural substrate, the major autolysin AtlS. This can be achieved with a single C-terminal cysteine in its CPDC active site, further suggesting SdbA is quite different from DsbA	-, 765006	
1.8.4.2	evolution	the oxidoreductase MdbA identified from Corynebacterium matruchotii is highly homologous to the Corynebacterium diphtheriae thiol-disulfide oxidoreductase MdbA (MdbACd). The disulfide oxidoreductase activity requires the catalytic motif CXXC. MdbACm is a major thiol-disulfide oxidoreductase, which likely mediates posttranslocational protein folding in Corynebacterium matruchotii by a mechanism that is conserved in Actinobacteria, the enzyme is essential in the organism. Corynebacterium matruchotii MdbA can replace Corynebacterium diphtheriae MdbA in mutants to maintain normal cell growth and morphology, toxin production, and pilus assembly. The protein active site closely resembles active sites of other MdbA/DsbA enzymes. The superposition of Corynebacterium matruchotii and Corynebacterium diphtheriae MdbA active sites does not show notable changes of active-site arrangement, overview	-, 765004	
1.8.4.2	malfunction	gene sdbA mutants are defective in autolysis, extracellular DNA (eDNA) release, bacteriocin production, and genetic competence but form more biofilm. Inactivation of sdbA upregulates the CiaRH two-component regulatory system in Streptococcus gordonii, leading to the repression of the ComDE quorum sensing system, which results in the enhanced biofilm formation and the lack of bacteriocin production. The sdbB-ccdA2 mutant produces all of the phenotypes displayed by the sdbA mutant. The sdbB-sgo_1177 mutant is defective in eDNA release and bacteriocin production but not autolysis or genetic competence. The sdbB-ccdA1 mutant is defective in autolysis but not eDNA release, bacteriocin production, or genetic competence. The sgo_1177-ccdA2 mutant is partially defective in autolysis but not in other phenotypes. The ccdA1-ccdA2 mutant is defective only in bacteriocin production. AtlS, the natural substrate of SdbA, in the sdbB-ccdA2 mutant lacks activity and a disulfide bond. The lack of autolysis in the sdbB-ccdA2 mutant is due to a defect in the activity of AtlS. Enzyme mutant SdbAC89A variant forms mixed disulfide with SdbB in vivo	-, 765006	
1.8.4.2	malfunction	SpeA in the culture supernatant remains reduced when gene sdbA is inactivated and restored to the oxidized state when a functional copy of sdbA is returned to the sdbA-knockout mutant. Complementation of sdbA deletion restores SpeA to an oxidized state. The enzyme mutant SdbAC49A forms a mixed disulfide with substrate mutant SpeAC87A. No reactions between SdbAC49A and SpeAC98A, SdbAC46A and SpeAC87A, or SdbAC46A and SpeAC98A	765010	
1.8.4.2	malfunction	the purple non-sulfur bacterium Rhodobacter capsulatus mutants lacking DsbA show severe temperature-sensitive and medium-dependent respiratory growth defects. Absence of thiol-disulfide oxidoreductase DsbA impairs cbb3-type cytochrome c oxidase (cbb3-Cox) biogenesis in Rhodobacter capsulatus. Absence of DsbA, besides impairing the maturation of the c-type cytochrome subunits, also affects the incorporation of Cu into the catalytic subunit of cbb3-Cox. Defective high affinity Cu acquisition pathway, which includes the MFS-type Cu importer CcoA, and lower production of the c-type cytochrome subunits lead together to improper assembly and degradation of cbb3-Cox. DsbA- and several cbb3-Cox biogenesis mutants exhibit similar phenotypes. Mutational analysis of enzyme function, overview	-, 764747	
1.8.4.2	malfunction	the truncation mutation (E87X) clearly disrupts the CHCH domain by removing a large portion of the protein from helix 2 onward. The other two mutations, W59C and W66R, are found within the first helix of COA6, where the side chains of each tryptophan face the bulk solvent, suggesting that these residues may facilitate interactions with their client proteins. Overexpression of the wild-type and mutant alleles of COA6 in control and COA6 patient fibroblasts shows that the W66R variant fails to rescue CcO activity. In contrast, expression of the W59C mutant leads to a partial recovery of CcO activity and COX2 levels. It seems that in most cell types residual levels of the partially functional W59C allele are not sufficient to support CcO assembly and mitochondrial respiration because coa6DELTA cells expressing the W59C variant do not exhibit respiratory growth. The human patient with the W59C mutation exhibits a severe CcO deficiency in cardiac tissue	764441	
1.8.4.2	metabolism	enzyme reacts with glutathionylated substrates in a GSH-dependent ping pong mechanism. The pKa of GrxS12 catalytic Cys29 is very low (3.9) and makes GrxS12 itself sensitive to oxidation by H2O2 and to direct glutathionylation by nitrosoglutathione. Glutathionylated-GrxS12 is temporarily inactive until it is deglutathionylated by GSH	762613	
1.8.4.2	metabolism	identification and characterization of the SdbA redox partners SdbB and CcdA2 (encoded by gene ccdA2) in Streptococcus gordonii. CcdA2 is annotated as cytochrome c biogenesis protein A. Thiol-disulfide oxidoreductase-associated lipoprotein SdbB, encoded by gene sgo_1177, constitutes the main pathway for SdbA reoxidation. SdbA has multiple redox partners, e.g. SdbB and CcdA2, forming a complex oxidative protein-folding pathway. This pathway is essential for autolysis, bacteriocin production, genetic competence, and extracellular DNA (eDNA) release in Streptococcus gordonii	-, 765006	
1.8.4.2	metabolism	posttranslocational protein folding in the Gram-positive biofilm-forming actinobacterium Actinomyces oris is mediated by membrane-bound thiol-disulfide oxidoreductase, MdbA, which catalyzes oxidative folding of nascent polypeptides transported by the Sec translocon. Reoxidation of MdbA involves a bacterial vitamin K epoxide reductase (VKOR)-like protein that contains four cysteine residues, C93/C101 and C175/C178, with the latter forming a canonical CXXC thioredoxin-like motif. Topological view of the Actinomyces oris membrane-spanning protein VKOR with these four exoplasmic cysteine residues that participate in MdbA reoxidation. Like deletion of the VKOR gene, alanine replacement of individual cysteine residues abrogates polymicrobial interactions and biofilm formation, concomitant with the failure to form adhesive pili on the bacterial surface. Mutational analysis of VKOR function, overview. The C93 residue of VKOR is postulated to form a mixed disulfide bond with MdbA	745224	
1.8.4.2	metabolism	the actinobacterium Corynebacterium matruchotii has been implicated in nucleation of oral microbial consortia leading to biofilm formation	-, 765004	
1.8.4.2	metabolism	the enzyme affects multiple phenotypes in Streptococcus gordonii and is required for production of disulfide-bonded proteins like Anti-CR1 scFv	725524	
1.8.4.2	additional information	the enzyme structure of MdbACm possesses two conserved features found in actinobacterial MdbA enzymes, a thioredoxin-like fold and an extended alpha-helical domain. The MdbA alpha-helical domain comprises 7 alpha-helices. The conserved catalytic CHYC motif (residues 91 to 94) forms the active site together with a conserved cis-Pro loop (residues S221 and P222). Structure modeling and structure comparisons, overview	-, 765004	
1.8.4.2	additional information	the solution structure of COA6 reveals a coiled-coil-helix-coiled-coil-helix domain typical of redox-active proteins found in the mitochondrial inter-membrane space. COA6 structure analysis by NMR spectroscopy, overview	-, 764441	
1.8.4.2	additional information	the solution structure of COA6 reveals a coiled-coil-helix-coiled-coil-helix domain typical of redox-active proteins found in the mitochondrial inter-membrane space. COA6 structure analysis by NMR spectroscopy, overview. The conserved tryptophans W59 and W66 are critical for COA6 stability and possibly for their interactions with client proteins	764441	
1.8.4.2	additional information	VKOR-mediated reactivation of MdbA appears to be conserved in the Actinobacteria. Formation of the MdbA-VKOR mixed disulfide complex requires C93. The signal of this MdbA-VKOR complex is greatly diminished when the sample is treated with 2-mercaptoethanol. The complex is not found when both C93 and C101 are mutated to alanine. The results suggest that when C101 is mutated, VKOR forms a complex with MdbA via the VKOR C93 residue	745224	
1.8.4.2	physiological function	a significant portion of protein HP_0377 is present in the oxidized form in an HP_0231 mutant	-, 742200	
1.8.4.2	physiological function	CGFS-type GRX is not reduced by GSH and has an atypically low redox potential (-323 mV at pH 7.9). GRX3 can be reduced in the light by photoreduced ferredoxin and ferredoxin-thioredoxin reductase	763241	
1.8.4.2	physiological function	gene deletion results in a severe growth defect at 37°C. By electron microscopy, the MdbA mutant is indistinguishable from wild-type at 30°C. At 37°C, the mutant becomes chained, clumped and coccoid in appearance. The mutant also fails to assemble pilus structures and is greatly defective in toxin production	-, 743311	
1.8.4.2	physiological function	in eukaryotes, cellular respiration is driven by mitochondrial cytochrome c oxidase (CcO), an enzyme complex that requires copper cofactors for its catalytic activity. Insertion of copper into its catalytically active subunits, including COX2, is a complex process that requires metallochaperones and redox proteins including SCO1, SCO2, and COA6. COA6 is structurally tuned to function as a thiol-disulfide oxidoreductase in copper delivery to mitochondrial cytochrome c oxidase. COA6 can reduce the copper-coordinating disulfides of its client proteins, SCO1 and COX2, allowing for copper binding. Determination of the interaction surfaces and reduction potentials of COA6 and its client proteins provides a mechanism of how metallochaperone and disulfide reductase activities are coordinated to deliver copper to CcO, overview. COA6 acts as a disulfide reductase of SCO and COX2 proteins	-, 764441	
1.8.4.2	physiological function	in eukaryotes, cellular respiration is driven by mitochondrial cytochrome c oxidase (CcO), an enzyme complex that requires copper cofactors for its catalytic activity. Insertion of copper into its catalytically active subunits, including COX2, is a complex process that requires metallochaperones and redox proteins including SCO1, SCO2, and COA6. COA6 is structurally tuned to function as a thiol-disulfide oxidoreductase in copper delivery to mitochondrial cytochrome c oxidase. COA6 can reduce the copper-coordinating disulfides of its client proteins, SCO1 and COX2, allowing for copper binding. Determination of the interaction surfaces and reduction potentials of COA6 and its client proteins provides a mechanism of how metallochaperone and disulfide reductase activities are coordinated to deliver copper to CcO, overview. COA6 function can be bypassed in a reducing environment. Coa6 has a redox as opposed to a metallochaperone function in Cu delivery to Cox2. COA6 acts as a disulfide reductase of SCO and COX2 proteins. COA6 can reduce the disulfides of SCO proteins, generating free sulfhydryl groups. COA6 can also reduce the cysteines of COX2	764441	
1.8.4.2	physiological function	inactivation of SdbA results in enhanced biofilm formation. Biofilm formation is mediated by the interaction between the CiaRH and ComDE two-component signalling systems. CiaRH is upregulated in the SdbA mutant and is essential for the enhanced biofilm phenotype. The enhanced biofilm phenotype also corresponds to increased oral colonization in mice	-, 742794	
1.8.4.2	physiological function	isoform DsbA1 is essential for the motility and autoagglutination phenotypes, and plays a critical role in the oxidative folding of alkaline phosphatase PhoX	743646	
1.8.4.2	physiological function	isoform GRX5 is not an efficient catalyst of protein deglutathionylation nor exhibits distinct substrate specificities	763028	
1.8.4.2	physiological function	isoform GRX6 is not an efficient catalyst of protein deglutathionylation nor exhibits distinct substrate specificities	763028	
1.8.4.2	physiological function	loss of isoform DsbA2 has no impact on motility and autoagglutination phenotypes. DsbA2 is crucial for the activity of arylsulfotransferase AstA	743646	
1.8.4.2	physiological function	posttranslocational protein folding in the Gram-positive biofilm-forming actinobacterium Actinomyces oris is mediated by membrane-bound thiol-disulfide oxidoreductase, MdbA, which catalyzes oxidative folding of nascent polypeptides transported by the Sec translocon	745224	
1.8.4.2	physiological function	reoxidation of MdbA involves bacterial vitamin K epoxide reductase-like protein that contains four cysteine residues, C93/C101 and C175/C178. Mutation C101A in this protein results in a high molecular weight complex of MdbA and bacterial vitamin K epoxide reductase-like protein	742796	
1.8.4.2	physiological function	SdbA mutants lack bacteriocin activity due to strong repression of bacteriocin gene. The Com pathway is functional but not activated in the SdbA mutant. Repression of bacteriocin production is mediated by the CiaRH two-component system, which is strongly upregulated in the sdbA mutant. The CiaRH-induced protease DegP is also upregulated in the SdbA mutant	-, 742794	
1.8.4.2	physiological function	SpyM18_2037, named SdbA, is the catalyst that introduces the disulfide bond in SpeA. Enzyme SdbA has a typical C46XXC49 active site motif commonly found in TDORs. The cysteines in the CXXC motif are required for the disulfide bond in SpeA to form. Interactions between SdbA and SpeA are examined using cysteine variant proteins. The results show that SdbAC49A forms a mixed disulfide with SpeAC87A, suggesting that the N-terminal Cys46 of SdbA and the C-terminal Cys98 of SpeA participate in the initial reaction. SpeA oxidized by SdbA displays biological activities suggesting that SpeA is properly folded following oxidation by SdbA. The enzyme substrate superantigen exotoxin A, SpeA (25 kDa) contains three cysteine residues (Cys87, Cys90, and Cys98). In the crystal structure of SpeA, Cys87 and Cys98 are linked by a disulfide bond. The disulfide bond and neighboring amino acids form a socalled disulfide loop, which is a conserved feature in all staphylococcal enterotoxins except the toxic shock syndrome toxin 1 (TSST-1). The importance of the disulfide bond in SpeA and staphylococcal enterotoxins (e.g. SEC2). SpeA and other streptococcal and staphylococcal superantigens are able to bind simultaneously to the major histocompatibility complex (MHC) class II molecules and the T-cell receptors, resulting in T cell activation and massive cytokine production	765010	
1.8.4.2	physiological function	the organism encodes a large number of exported proteins containing paired cysteine residues. Proteins possessing 2 or more cysteine residues made up 58.4% of the Corynabacterium matruchotii proteome (1530 of 2619 proteins). In the Gram-positive actinobacteria, oxidative protein folding via disulfide bond formation appears to be the major pathway for posttranslocational folding of these unfolded proteins. The oxidoreductase MdbA identified from Corynebacterium matruchotii, MdbACm, catalyzes disulfide bond formation within the actinobacterial pilin FimA	-, 765004	
1.8.4.2	physiological function	the thiol-disulfide oxidoreductase DsbA carries out oxidative folding of extra-cytoplasmic proteins by catalyzing the formation of intramolecular disulfide bonds. It has an important role in various cellular functions, including cell division. DsbA activity is required for full respiratory capability of Rhodobacter capsulatus, and in particular, for proper biogenesis of its cbb3-type cytochrome c oxidase (cbb3-Cox). Enzyme DsbA facilitates oxidative folding of extra-cytoplasmic proteins by catalyzing the formation of intramolecular disulfide bonds between two reactive Cys residues of its substrates, which include the c-type apocyts with their conserved CxxCH heme-binding sites. Reduced DsbA is re-oxidized by its recycling partner DsbB, which then transfers the reducing equivalents to the Q pool, and eventually to the electron transport chain	-, 764747	
1.8.4.2	physiological function	thiol-disulfide oxidoreductase, SdbA, in Streptococcus gordonii forms disulfide bonds in substrate proteins and plays a role in multiple phenotypes. SdbA has multiple redox partners, e.g. SdbB and CcdA2, forming a complex oxidative protein-folding pathway. This pathway is essential for autolysis, bacteriocin production, genetic competence, and extracellular DNA (eDNA) release in Streptococcus gordonii. These cellular processes are considered to be important for the success of Streptococcus gordonii as a dental plaque organism. Homologues of SdbA appear to be present in a range of Gram-positive bacteria that lack DsbA. SdbA is able to introduce a disulfide bond into its natural substrate, the major autolysin AtlS. This can be achieved with a single C-terminal cysteine in its CPDC active site, further suggesting SdbA is quite different from DsbA	-, 765006