Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026918 (Mycobacterium)
 52,428 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Methionine sulfoxide reductases (Msr) reduce methionine sulfoxide (MetSO)-containing proteins, back to methionine (Met). MsrAs are stereospecific for the S epimer whereas MsrBs reduce the R epimer of MetSO. Although structurally unrelated, the Msrs characterized so far display a similar catalytic mechanism with formation of a sulfenic intermediate on the catalytic cysteine and a concomitant release of Met, followed by formation of at least one intramolecular disulfide bond (between the catalytic and a recycling cysteine), which is then reduced by thioredoxin. In the case of the MsrA from Escherichia coli, two disulfide bonds are formed, i.e. first between the catalytic Cys51 and the recycling Cys198 and then between Cys198 and the second recycling Cys206. Three crystal structures including E. coli and Mycobacterium tuberculosis MsrAs, which, for the latter, possesses only the unique recycling Cys198, have been solved so far. In these structures, the distances between the cysteine residues involved in the catalytic mechanism are too large to allow formation of the intramolecular disulfide bonds. Here structural and dynamical NMR studies of the reduced wild-type and the oxidized (Cys51-Cys198) forms of C86S/C206S MsrA from E. coli have been carried out. The mapping of MetSO substrate-bound C51A MsrA has also been performed. The data support (1) a conformational switch occurring subsequently to sulfenic acid formation and/or Met release that would be a prerequisite to form the Cys51-Cys198 bond and, (2) a high mobility of the C-terminal part of the Cys51-Cys198 oxidized form that would favor formation of the second Cys198-Cys206 disulfide bond.
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PMID:Solution structure and backbone dynamics of the reduced form and an oxidized form of E. coli methionine sulfoxide reductase A (MsrA): structural insight of the MsrA catalytic cycle. 1715 15

The genome sequence of Mycobacterium tuberculosis H37Rv revealed the presence of seven whiB-like open reading frames. In spite of several genetic studies on whiB genes, the biochemical properties of WhiB proteins are poorly understood. All WhiB-like proteins have four conserved cysteine residues, out of which two are present in a CXXC motif. We report for the first time the detailed biochemical and biophysical properties of M. tuberculosis WhiB4/Rv3681c and demonstrate the functional relevance of four conserved cysteines and the CXXC motif. UV-visible absorption spectra of freshly purified mWhiB4 showed the presence of a [2Fe-2S] cluster, whereas the electron paramagnetic resonance (EPR) spectra of reconstituted protein showed the presence of a [4Fe-4S] cluster. The iron-sulphur cluster was redox sensitive but stably co-ordinated to the protein even in the presence of high concentration of chaotropic agents. Despite primary sequence divergence from thioredoxin family proteins, the apo mWhiB4 has properties similar to thioredoxins and functions as a protein disulphide reductase, whereas holo mWhiB4 is enzymatically inactive. Apart from the cysteine thiol of CXXC motif the distantly placed thiol pair also contributes equally to the enzymatic activity of mWhiB4. A functional model of mWhiB4 in redox signaling during oxidative stress in M. tuberculosis has been presented.
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PMID:Molecular function of WhiB4/Rv3681c of Mycobacterium tuberculosis H37Rv: a [4Fe-4S] cluster co-ordinating protein disulphide reductase. 1730 17

Cellular iron levels are closely monitored by iron regulatory and sensor proteins of Mycobacterium tuberculosis for survival inside macrophages. One such class of proteins systematically studied in eukaryotes and reported in a few prokaryotes are the iron-responsive proteins (IRPs). These IRPs bind to iron-responsive elements (IREs) present at untranslated regions (UTRs) of mRNAs and are responsible for posttranscriptional regulation of the expression of proteins involved in iron homeostasis. Amino acid sequence analysis of M. tuberculosis aconitase (Acn), a tricarboxylic acid (TCA) cycle enzyme, showed the presence of the conserved residues of the IRP class of proteins. We demonstrate that M. tuberculosis Acn is bifunctional. It is a monomeric protein that is enzymatically active in converting isocitrate to cis-aconitate at a broad pH range of 7 to 10 (optimum, pH 8). As evident from gel retardation assays, M. tuberculosis Acn also behaves like an IRP by binding to known mammalian IRE-like sequences and to predicted IRE-like sequences present at the 3' UTR of thioredoxin (trxC) and the 5' UTR of the iron-dependent repressor and activator (ideR) of M. tuberculosis. M. tuberculosis Acn when reactivated with Fe(2+) functions as a TCA cycle enzyme, but upon iron depletion by a specific iron chelator, it behaves like an IRP, binding to the selected IREs in vitro. Since iron is required for the Acn activity and inhibits the RNA-binding activity of Acn, the two activities of M. tuberculosis Acn are mutually exclusive. Our results demonstrate the bifunctional nature of M. tuberculosis Acn, pointing to its likely role in iron homeostasis.
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PMID:Iron-dependent RNA-binding activity of Mycobacterium tuberculosis aconitase. 1738 88

Cytoplasmic protein reduction via generalized thiol/disulfide exchange reactions and maintenance of cellular redox homeostasis is mediated by the thioredoxin superfamily of proteins. Here, we describe the characterization of the thioredoxin system from Mycobacterium tuberculosis, whose genome bears the potential to encode three putative thioredoxins from the open reading frames designated trxAMtb, trxBMtb, and trxCMtb. We show that all three thioredoxins, overproduced in Escherichia coli, are able to reduce insulin, a model substrate, in the presence of dithiothreitol. However, we observe that thioredoxin reductase is not capable of reducing TrxAMtb in an NADPH-dependent manner, indicating that only TrxBMtb and TrxCMtb are the biologically active disulfide reductases. The absence of detectable mRNA transcripts of trxAMtb observed when M. tuberculosis strain H37Rv was cultivated under different growth conditions suggests that trxAMtb expression may be cryptic. The measured redox potentials of TrxBMtb and TrxCMtb (-262+/-2 mV and -269+/-2 mV, respectively) render these proteins somewhat more oxidizing than E. coli thioredoxin 1 (TrxA). In E. coli strains lacking components of cytoplasmic protein reduction pathways, heterologous expression of the mycobacterial thioredoxins was able to effectively substitute for their function.
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PMID:Functional studies of multiple thioredoxins from Mycobacterium tuberculosis. 1872 12

From Allium stipitatum, three pyridine-N-oxide alkaloids (1-3) possessing disulfide functional groups were isolated. The structures of these natural products were elucidated by spectroscopic means as 2-(methyldithio)pyridine-N-oxide (1), 2-[(methylthiomethyl)dithio]pyridine-N-oxide (2), and 2,2'-dithio-bis-pyridine-N-oxide (3). The proposed structure of 1 was confirmed by synthetic S-methylthiolation of commercial 2-thiopyridine-N-oxide. Compounds 1 and 2 are new natural products, and 3 is reported for the first time from an Allium species. All compounds were evaluated for activity against fast-growing species of Mycobacterium, methicillin-resistant Staphylococcus aureus, and a multidrug-resistant (MDR) variants of S. aureus. Compounds 1 and 2 exhibited minimum inhibitory concentrations (MICs) of 0.5-8 microg/mL against these strains. A small series of analogues of 1 were synthesized in an attempt to optimize antibacterial activity, although the natural product had the most potent in vitro activity. In a whole-cell assay at 30 microg/mL, 1 was shown to give complete inhibition of the incorporation of (14)C-labeled acetate into soluble fatty acids, indicating that it is potentially an inhibitor of fatty acid biosynthesis. In a human cancer cell line antiproliferative assay, 1 and 2 displayed IC(50) values ranging from 0.3 to 1.8 microM with a selectivity index of 2.3 when compared to a human somatic cell line. Compound 1 was evaluated in a microarray analysis that indicated a similar mode of action to menadione and 8-quinolinol by interfering with the thioredoxin system and up-regulating the production of various heat shock proteins. This compound was also assessed in a mouse model for in vivo toxicity.
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PMID:Bioactive pyridine-N-oxide disulfides from Allium stipitatum. 1909 48

Mycobacterium tuberculosis is one of the most successful pathogens of humankind. During infection, M. tuberculosis must cope with and survive against a variety of different environmental conditions. Sigma factors likely facilitate the modulation of the pathogen's gene expression in response to changes in its extracellular milieu during infection. sigma(H), an alternate sigma factor encoded by the M. tuberculosis genome, is induced by thiol-oxidative stress, heat shock, and phagocytosis. In response to these conditions, sigma(H) induces the expression of sigma(B), sigma(E), and the thioredoxin regulon. In order to more effectively characterize the transcriptome controlled by sigma(H), we studied the long-term effects of the induction of sigma(H) on global transcription in M. tuberculosis. The M. tuberculosis isogenic mutant of sigma(H) (Delta-sigma(H)) is more susceptible to diamide stress than wild-type M. tuberculosis. To study the long-term effects of sigma(H) induction, we exposed both strains to diamide, rapidly washed it away, and resumed culturing in diamide-free medium (post-diamide stress culturing). Analysis of the effects of sigma(H) induction in this experiment revealed a massive temporal programming of the M. tuberculosis transcriptome. Immediately after the induction of sigma(H), genes belonging to the functional categories "virulence/detoxification" and "regulatory proteins" were induced in large numbers. Fewer genes belonging to the "lipid metabolism" category were induced, while a larger number of genes belonging to this category were downregulated. sigma(H) caused the induction of the ATP-dependent clp proteolysis regulon, likely mediated by a transcription factor encoded by Rv2745c, several members of the mce1 virulence regulon, and the sulfate acquisition/transport network.
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PMID:Functional genomics reveals extended roles of the Mycobacterium tuberculosis stress response factor sigmaH. 1937 62

Mycobacterium tuberculosis resides within alveolar macrophages. These phagocytes produce reactive nitrogen and oxygen intermediates to combat the invading pathogens. The macrophage glutathione (GSH) pool reduces nitric oxide (NO) to S-nitrosoglutathione (GSNO). Both glutathione disulfide (GSSG) and GSNO possess mycobactericidal activities in vitro. In this study we demonstrate that M. tuberculosis thioredoxin system, comprises of thioredoxin reductase B2 and thioredoxin C reduces the oxidized form of the intracellular mycothiol (MSSM) and is able to efficiently reduce GSSG and GSNO in vitro. Our study suggests that the thioredoxin system provide a general reduction mechanism to cope with oxidative stress associated with the microbe's metabolism as well as to detoxify xenobiotics produced by the host.
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PMID:Glutathione disulfide and S-nitrosoglutathione detoxification by Mycobacterium tuberculosis thioredoxin system. 1973 61

Disulfide bond forming (Dsb) proteins ensure correct folding and disulfide bond formation of secreted proteins. Previously, we showed that Mycobacterium tuberculosis DsbE (Mtb DsbE, Rv2878c) aids in vitro oxidative folding of proteins. Here, we present structural, biochemical, and gene expression analyses of another putative Mtb secreted disulfide bond isomerase protein homologous to Mtb DsbE, Mtb DsbF (Rv1677). The X-ray crystal structure of Mtb DsbF reveals a conserved thioredoxin fold although the active-site cysteines may be modeled in both oxidized and reduced forms, in contrast to the solely reduced form in Mtb DsbE. Furthermore, the shorter loop region in Mtb DsbF results in a more solvent-exposed active site. Biochemical analyses show that, similar to Mtb DsbE, Mtb DsbF can oxidatively refold reduced, unfolded hirudin and has a comparable pK(a) for the active-site solvent-exposed cysteine. However, contrary to Mtb DsbE, the Mtb DsbF redox potential is more oxidizing and its reduced state is more stable. From computational genomics analysis of the M. tuberculosis genome, we identified a potential Mtb DsbF interaction partner, Rv1676, a predicted peroxiredoxin. Complex formation is supported by protein coexpression studies and inferred by gene expression profiles, whereby Mtb DsbF and Rv1676 are upregulated under similar environments. Additionally, comparison of Mtb DsbF and Mtb DsbE gene expression data indicates anticorrelated gene expression patterns, suggesting that these two proteins and their functionally linked partners constitute analogous pathways that may function under different conditions.
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PMID:An extracellular disulfide bond forming protein (DsbF) from Mycobacterium tuberculosis: structural, biochemical, and gene expression analysis. 2006 Aug 36

NrdH is one of the intracellular redoxins exist in Mycobacterium and other microorganisms lacking the common glutathione system. NrdH seems a chimeric protein of glutaredoxin amino acid sequence and thioredoxin activity. It serves as a hydrogen donor for ribonucleotide reductase. Mycobacterium tuberculosis might take advantage of this enzyme to persist in the highly oxidized host mononuclear phagocytes and maintain the balance of intracellular redox potential. Physiological role of NrdH and comparison of its genomic context organization were summarized here. The most intriguing feature might be its new drug targets potential.
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PMID:Comparative genomics analysis of Mycobacterium NrdH-redoxins. 2009 72

Steady exposure to environmental arsenic has led to the evolution of vital cellular detoxification mechanisms. Under aerobic conditions, a two-step process appears most common among microorganisms involving reduction of predominant, oxidized arsenate (H(2)As(V)O(4)(-)/HAs(V)O(4)(2-)) to arsenite (As(III)(OH)(3)) by a cytosolic enzyme (ArsC; Escherichia coli type arsenate reductase) and subsequent extrusion via ArsB (E. coli type arsenite transporter)/ACR3 (yeast type arsenite transporter). Here, we describe novel fusion proteins consisting of an aquaglyceroporin-derived arsenite channel with a C-terminal arsenate reductase domain of phosphotyrosine-phosphatase origin, providing transposable, single gene-encoded arsenate resistance. The fusion occurred in actinobacteria from soil, Frankia alni, and marine environments, Salinispora tropica; Mycobacterium tuberculosis encodes an analogous ACR3-ArsC fusion. Mutations rendered the aquaglyceroporin channel more polar resulting in lower glycerol permeability and enhanced arsenite selectivity. The arsenate reductase domain couples to thioredoxin and can complement arsenate-sensitive yeast strains. A second isoform with a nonfunctional channel may use the mycothiol/mycoredoxin cofactor pool. These channel enzymes constitute prototypes of a novel concept in metabolism in which a substrate is generated and compartmentalized by the same molecule. Immediate diffusion maintains the dynamic equilibrium and prevents toxic accumulation of metabolites in an energy-saving fashion.
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PMID:Novel channel enzyme fusion proteins confer arsenate resistance. 2094 11


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