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)

The DtxR protein from Corynebacterium diphtheriae is an iron-dependent repressor that regulates transcription from the tox, IRP1, and IRP2 promoters. A gene from virulent Mycobacterium tuberculosis H37Rv was recently shown to encode a protein, here designated iron-dependent regulator (IdeR), that is almost 60% homologous to DtxR from C. diphtheriae. A 750-bp PCR-derived DNA fragment carrying the M. tuberculosis ideR allele was subcloned to both high- and low-copy-number vectors. In Escherichia coli, transcription from the C. diphtheriae tox, IRP1, and IRP2 promoters was strongly repressed by ideR under high-iron conditions, and ideR restored normal iron-dependent expression of the corynebacterial siderophore in the C. diphtheriae dtxR mutant C7(beta)hm723. The M. tuberculosis IdeR protein was overexpressed in E. coli and purified to near homogeneity by nickel affinity chromatography. Gel mobility shift experiments revealed that IdeR bound to a DNA fragment that carried the C. diphtheriae tox promoter/operator sequence. DNAse I footprint analysis demonstrated that IdeR, in the presence of Cd2+, Co2+, Fe2+, Mn2+, Ni2+, or Zn2+, protected an approximately 30-bp region on DNA fragments carrying the tox, IRP1, or IRP2 promoter/operator sequences. IdeR reacted very weakly in Western blots (immunoblots) with antiserum against the C. diphtheriae DtxR protein, suggesting that the immunodominant epitopes of DtxR may be located in its poorly conserved carboxyl-terminal domain.
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PMID:Characterization of an iron-dependent regulatory protein (IdeR) of Mycobacterium tuberculosis as a functional homolog of the diphtheria toxin repressor (DtxR) from Corynebacterium diphtheriae. 759 Oct 59

The present study has provided information on the biometal contents of killed and dried Mycobacterium leprae as well as dermal granulomas induced by the invading mycobacteria in various histological types of leprosy patients. For comparison, the biometal contents of the contralateral leprosy-unaffected skin of the same patients also were measured. The study also reports changes of serum levels of the biometals in these patients which were compared with those in healthy control subjects and patients with skin tuberculosis. These data show that M. leprae is rich in zinc. During the course of the evolution of the disease there is gross alteration of the dynamics of the inflammatory cell population that infiltrates into leprosy granulomas, resulting in the alterations of trace element contents of the disease-affected skin lesions. Interestingly, the changes of the biometal contents in the granulomas of the patients with skin tuberculosis are similar to those in leprosy patients. It is postulated that the significant decrease of the contents of copper, zinc, iron, calcium and magnesium in the disease-affected skin in comparison to that of the contralateral healthy skin is a local effect, perhaps due to erosion or influx of biometal-deficient inflammatory cells into the affected skin with eventual loss of connective tissue of skin and mobilization of tissue-bound microelements into the vascular compartment. On the contrary, the changes in biometal levels in the sera of leprosy patients appear to be a general effect perhaps due to the release of interleukin-1, a product of inflammatory cells, causing hypercupremic, hypozincemic and hypoferremic responses in the hosts. Moreover, growth and multiplication of M. leprae, especially in polar lepromatous leprosy patients with a high bacillary load, demand essential biometals which may be mobilized into the bacterial bodies from the hosts. This perhaps results in the change in the homeostasis of the essential biometals in the hosts.
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PMID:Biometals in skin and sera of leprosy patients and their correlation to trace element contents of M. leprae and histological types of the disease; a comparative study with cutaneous tuberculosis. 760 20

Superoxide dismutase (SOD), purified from Mycobacterium smegmatis, was found to contain both manganese and iron. Since the Fe and Mn-reconstituted enzymes had specific activities of 190 and 2810 units/mg protein/g atom of metal/mol of subunit, respectively, the Mycobacterial SOD can be classified with SODs showing activity with either iron or manganese as the active-site metal (a cambialistic SOD). Mn-reconstituted enzyme showed an enzymatic reaction rate constant of 1.4 x 10(8) M-1 s-1 at pH 7.8. This rate only slightly increased with decreasing pH. Fe-reconstituted enzyme showed a rate constant of 2.7 x 10(7) M-1 s-1 at pH 7.8, but this rate increased with decreasing pH to become 1.7 x 10(8) M-1 s-1 at pH 5.7 with two pK values of 6.6 and 9.0. These results show that the metal specificity of the enzymatic activity of M. smegmatis superoxide dismutase shows manganese predominance at pH 7.8, but changes to be equal for either metal at acidic pH.
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PMID:pH-dependent activity change of superoxide dismutase from Mycobacterium smegmatis. 766 26

The unique antitubercular activity of isoniazid requires that the drug be oxidized by the katG-encoded mycobacterial catalase-peroxidase to an activated drug form. In order to quantitatively assess the catalytic capabilities of the enzyme, the native catalase-peroxidase from Mycobacterium smegmatis was purified over 200-fold to homogeneity. The enzyme was shown to exhibit both catalase and peroxidase activities, and in the presence of either hydrogen peroxide or t-butyl peroxide, was found to catalyze the oxidation of the reduced pyridine nucleotides, NADH and NADPH, as well as artificial peroxidase substrates, at rates between 2.7 and 20 s-1. The homogeneous enzyme exhibited a visible absorbance spectrum typical of ferric heme-containing catalase-peroxidases, with a Soret maximum at 406 nm. Low temperature (10 K) electron paramagnetic resonance spectra in the presence of ethylene glycol revealed a high spin Fe(III) signal with g values of 5.9 and 5.6. The enzyme was very slowly (t1/2 = approximately 20 min) reduced by dithionite, and the reduced form showed typical spectral changes when either KCN or CO were subsequently added. The M. smegmatis catalase-peroxidase was found to contain 2 heme molecules per tetramer, which were identified as iron protoporphyrin IX by the pyridine hemochromogen assay. The peroxidatic activity was inhibited by KCN, NaN3, isoniazid (isonicotinic acid hydrazide), and its isomer, nicotinic acid hydrazide, but not by 3-amino-1,2,4-triazole. The role of mycobacterial catalase-peroxidases in the oxidative activation of the antitubercular prodrug isoniazid is discussed.
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PMID:Purification and characterization of the Mycobacterium smegmatis catalase-peroxidase involved in isoniazid activation. 767 10

The effects of 2,3-dimercaptopropane sulphonate (DMPS) and N-(2-mercapto-2-methylpropanoyl)-L-cysteine (bucillamine) against the renal damage induced by gold sodium thiomalate (AuTM) in adjuvant-arthritic rats were studied. Arthritic rats induced by adjuvant using Mycobacterium butyricum were injected intraperitoneally with a chelating agent (0.6 mmol/kg) immediately after intramuscular injection of AuTM (0.066 mmol/kg) every other day for 21 days. Treatment with DMPS and bucillamine prevented increases in the urinary excretion of protein, aspartate aminotransferase, and glucose and blood urea nitrogen level after AuTM injection. AuTM prevented the increase in both adjuvant-injected and uninjected hind-feet volumes. The prevention of these inflamed lesions by AuTM was not affected by DMPS and bucillamine. These chelating agents decreased the gold concentration in the kidney and liver after AuTM administration, but did not affect the hepatic and renal concentrations of copper, zinc, iron, and calcium except the renal copper level after AuTM. These findings suggest that DMPS and bucillamine are very useful antidotes for gold toxicity.
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PMID:The utility of chelating agents as antidotes for nephrotoxicity of gold sodium thiomalate in adjuvant-arthritic rats. 771 81

Mycobacterium tuberculosis, the primary agent of tuberculosis, must acquire iron from the host to cause infection. To do so, it releases high-affinity iron-binding siderophores called exochelins. Exochelins are thought to transfer iron to another type of high-affinity iron-binding molecule in the bacterial cell wall, mycobactins, for subsequent utilization by the bacterium. In this paper, we describe the purification of exochelins of M. tuberculosis and their characterization by mass spectrometry. Exochelins comprise a family of molecules whose most abundant species range in mass from 744 to 800 Da in the neutral Fe(3+)-loaded state. The molecules form two 14-Da-increment series, one saturated and the other unsaturated, with the increments reflecting different numbers of CH2 groups on a side chain. These series further subdivide into serine- or threonine-containing species. The virulent M. tuberculosis Erdman strain and the avirulent M. tuberculosis H37Ra strain produce a similar set of exochelins. Based on a comparison of their tandem mass spectra, exochelins share a common core structure with mycobactins. However, exochelins are smaller than mycobactins due to a shorter alkyl side chain, and the side chain of exochelins terminates in a methyl ester. These differences render exochelins more polar than the lipophilic mycobactins and hence soluble in the aqueous extracellular milieu of the bacterium in which they bind iron in the host.
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PMID:Iron acquisition by Mycobacterium tuberculosis: isolation and characterization of a family of iron-binding exochelins. 776 71

The extracellular siderophore from Mycobacterium smegmatis, exochelin MS, was isolated from iron-deficiently grown cultures and purified to > 98% by a combination of ion-exchange chromatography and h.p.l.c. The material is unextractable into organic solvents, is basic (pI = 9.3-9.5), has a lambda max at 420 nm and a probable Ks for Fe3+ of between 10(25) and 10(30). Its structure has been determined by examination of desferri- and ferri-exochelin and its gallium complex. The methods used were electrospray-m.s. and one- and two-dimensional (NOESY, DQF-COSY and TOCSY) 1H n.m.r. The constituent amino acids were examined by chiral g.l.c analysis of N-trifluoroacetyl isopropyl and N-pentafluoropropionyl methyl esters after hydrolysis, and reductive HI hydrolysis, of the siderophore. The exochelin is a formylated pentapeptide: N-(delta-N-formyl,delta N-hydroxy-R-ornithyl) -beta-alaninyl-delta N-hydroxy-R-ornithinyl-R-allo-threoninyl-delta N-hydroxy-S-ornithine. The linkages involving the three ornithine residues are via their delta N(OH) and alpha-CO groups leaving three free alpha-NH2 groups. Although there are two peptide bonds, these involve the three R (D)-amino acids. Thus the molecule has no conventional peptide bond, and this suggests that it will be resistant to peptidase hydrolysis. The co-ordination centre with Fe3+ is hexadenate in an octahedral structure involving the three hydroxamic acid groups. Molecular modelling shows it to have similar features to other ferric trihydroxamate siderophores whose three-dimensional structures have been established. The molecule is shown to have little flexibility around the iron chelation centre, although the terminal (Orn-3) residue, which is not involved in iron binding except at its delta N atom, has more motional freedom.
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PMID:Isolation, purification and structure of exochelin MS, the extracellular siderophore from Mycobacterium smegmatis. 782 28

The X-ray structure of the tetrameric iron-dependent superoxide dismutase from Mycobacterium tuberculosis has been refined to an R-factor of 0.167 and a correlation coefficient of 0.954 at 2.0 A resolution. The crystals are monoclinic P2(1) and have four subunits related by strong non-crystallographic 222 (or D2) symmetry in the asymmetric unit. 198 of the 207 amino acids of each subunit are defined by the electron density which shows that they adopt the conserved fold of other iron- or manganese-dependent SODs. The structure can be divided into two domains, the N-terminal domain involving an extended region followed by two projecting antiparallel alpha-helices, and the C-terminal domain containing four more helical segments with a three-stranded antiparallel beta-sheet inserted sequentially between the fourth and fifth helices. The catalytic iron is co-ordinated by five ligands: three histidines (residues 28, 76 and 164), one aspartate (160) and a solvent molecule. The inferred positions of protons at the active site are consistent with the solvent ligand being a hydroxide ion. This ligand interacts with His145 in the Mycobacterium tuberculosis SOD. In the highly homologous Mycobacterium leprae Mn-SOD, the histidine is replaced by glutamine, this being the only significant residue difference within 10 A of the Fe3+. The nature of the amino acid at this position may influence the metal ion specificity of these enzymes. The subunits of the Mycobacterium tuberculosis SOD associate by polar contacts to form dimers, which closely resemble those of other dimeric or tetrameric Fe- or Mn-SODs. However, the dimer-dimer interactions within the tetramer are novel, being dominated by dimerisation of the 144 to 152 loop regions which connect the outer two beta-strands of the three-membered beta-sheet. This contrasts strongly with the other tetrameric Fe- or Mn-SODs where the dimer-dimer association is dominated by the projecting alpha alpha-turn in the N-terminal domain.
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PMID:X-ray structure analysis of the iron-dependent superoxide dismutase from Mycobacterium tuberculosis at 2.0 Angstroms resolution reveals novel dimer-dimer interactions. 787 74

Recognition of the central role of iron in the generation of toxic, oxygen-derived species through the Haber-Weiss reaction, the ability of desferrioxamine (DFX) to prevent the damage associated with free radical generation in reperfusion injury, and its inhibitory effect on cell proliferation by inactivation of the iron dependent enzyme ribonucleotide reductase, resulted in an increasing number of studies exploring the novel therapeutic applications of iron chelating drugs: (a) Animal models of reperfusion injury have shown that DFX is able to decrease post-anoxic damage to the brain and heart as manifested in decreased infarct size and improved functional recovery. Iron chelators may be particularly useful in improving the preservation of organs intended for transplantation such as the heart, lung or kidney. (b) Anthracycline cardiotoxicity is aggravated by iron and inhibited by iron chelators. Because the mechanism of its antineoplastic effect differs from its cardiotoxic effect, it is possible to inhibit anthracycline cardiotoxicity without interfering with therapeutic efficacy. In vivo and in vitro animal studies have yielded encouraging results but much additional experimental work is still required before iron chelating therapy may be advocated for use in patients on anthracycline therapy. (c) Cell proliferation can be inhibited by iron chelators through the reversible inhibition of ribonucleotide reductase, a rate-limiting enzyme in DNA synthesis. This may be exploited for the treatment of malignant disease, and preliminary studies have already shown that DFX in combination with multidrug chemotherapy is effective in controlling neuroblastoma and other tumours. However, the contribution of DF to the overall clinical effect is unclear. Prospective controlled clinical studies are required in order to establish whether the antiproliferative, or cell synchronizing properties of DFX may be of practical usefulness in the control of malignant disease. (d) Control of protozoal infection: Experimental in vivo and in vitro models have shown that malarial infection may be inhibited by iron chelating therapy. This useful effect of DFX and other iron chelators is most probably related to ribonucleotide reductase inhibition. Clinical studies of asymptomatic P. falciparum malaria and of cerebral malaria have shown both an accelerated rate of parasite clearance and earlier recovery from coma. These observations lend new meaning to the term 'nutritional immunity' and open new channels for exploring the possibility of controlling infection by means of selective intracellular iron deprivation. Experimental models for studying the effect of iron chelators on other intracellular pathogens such as Toxoplasma gondii, Chlamydia psittaci, or Mycobacterium tuberculosis should be established.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Control of disease by selective iron depletion: a novel therapeutic strategy utilizing iron chelators. 788 Nov 62

Mycobacteria produce two siderophores, mycobactin and exochelin. Mycobacterium smegmatis mutants defective in the production of exochelin were isolated using agar medium containing chrome azural S for the sensitive detection of siderophores. Cosmids of genomic libraries from M. smegmatis and Mycobacterium bovis BCG were screened for complementation of the mutation. Subcloning of the complementing M. smegmatis cosmid identified a 4.3 kb fragment required for restoring exochelin biosynthesis. Sequencing of the DNA revealed four open reading frames whose genes were named fxuA, fxuB, fxuC, and fxbA. FxuA, FxuB, and FxuC share amino acid sequence homology with the iron permeases FepG, FepC, and FepD from Escherichia coli, respectively. Deletion analysis identified fxbA as the gene required to restore exochelin biosynthesis in our mutant. Although fxbA does not share amino acid sequence homology with any of the published sequences for siderophore biosynthetic genes, it does show limited homology with the phosphoribosylglycineamide formyltransferases (GAR enzymes) and methionyl-tRNA formyltransferase over a limited region of the sequence, suggesting that fxbA may code for an enzyme which adds a formyl group in the synthesis of exochelin. A fusion of fxbA with the E. coli lacZ gene demonstrated regulation of gene expression by iron. The ability of M. smegmatis mutants to produce mycobactin in the absence of exochelin supports the hypothesis that exochelin is not a precursor of mycobactin and suggests that the siderophores have independent biosynthetic pathways. In addition, complementation of the M. smegmatis mutant with the BCG cosmid restored the synthesis of the M. smegmatis exochelin, demonstrating the use of M. smegmatis as a surrogate host for analysis of exochelins from slow-growing mycobacteria.
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PMID:Identification of genes involved in the sequestration of iron in mycobacteria: the ferric exochelin biosynthetic and uptake pathways. 788 34


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