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)

Six major lineages of Mycobacterium tuberculosis appear preferentially transmitted amongst distinct ethnic groups. We identified a deletion affecting Rv1519 in CH, a strain isolated from a large outbreak in Leicester U.K., that coincidentally defines the East African-Indian lineage matching a major ethnic group in this city. In broth media, CH grew less rapidly and was less acidic and H2O2-tolerant than reference sequenced strains (CDC1551 and H37Rv). Nevertheless, CH was not impaired in its ability to grow in human monocyte-derived macrophages. When compared with CDC1551 and H37Rv, CH induced less protective IL-12p40 and more antiinflammatory IL-10 and IL-6 gene transcription and secretion from monocyte-derived macrophages. It thus appears that CH compensates microbiological attenuation by skewing the innate response toward phagocyte deactivation. Complementation of Rv1519, but none of nine additional genes absent from CH compared with the type strain, H37Rv, reversed the capacity of CH to elicit antiinflammatory IL-10 production by macrophages. The Rv1519 polymorphism in M. tuberculosis confers an immune subverting phenotype that contributes to the persistence and outbreak potential of this lineage.
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PMID:A deletion defining a common Asian lineage of Mycobacterium tuberculosis associates with immune subversion. 1702 73

Despite catalyzing the same reaction (2 H2O2-->2 H2O+O2) heme-containing monofunctional catalases and bifunctional catalase-peroxidases (KatGs) do not share sequence or structural similarities raising the question of whether or not the reaction pathways are similar or different. The production of dioxygen from hydrogen peroxide by monofunctional catalases has been shown to be a two-step process involving the redox intermediate compound I which oxidizes H2O2 directly to O2. In order to investigate the origin of O2 released in KatG mediated H2O2 degradation we performed a gas chromatography-mass spectrometry investigation of the evolved O2 from a 50:50 mixture of H2(18)O2/H2(16)O2 solution containing KatGs from Mycobacterium tuberculosis and Synechocystis PCC 6803. The GC-MS analysis clearly demonstrated the formation of (18)O2 (m/e = 36) and (16)O2 (m/e = 32) but not (16)O(18)O (m/e = 34) in the pH range 5.6-8.5 implying that O2 is formed by two-electron oxidation without breaking the O-O bond. Also active site variants of Synechocystis KatG with very low catalase but normal or even enhanced peroxidase activity (D152S, H123E, W122F, Y249F and R439A) are shown to oxidize H2O2 by a non-scrambling mechanism. The results are discussed with respect to the catalatic mechanism of KatG.
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PMID:Hydrogen peroxide oxidation by catalase-peroxidase follows a non-scrambling mechanism. 1721 49

Monofunctional catalases (EC 1.11.1.6) and catalase-peroxidases (KatGs, EC 1.11.1.7) have neither sequence nor structural homology, but both catalyze the dismutation of hydrogen peroxide (2H2O2 --> 2H2O + O2). In monofunctional catalases, the catalatic mechanism is well-characterized with conventional compound I [oxoiron(IV) porphyrin pi-cation radical intermediate] being responsible for hydrogen peroxide oxidation. The reaction pathway in KatGs is not as clearly defined, and a comprehensive rapid kinetic and spectral analysis of the reactions of KatGs from three different sources (Synechocystis PCC 6803, Burkholderia pseudomallei, and Mycobacterium tuberculosis) with peroxoacetic acid and hydrogen peroxide has focused on the pathway. Independent of KatG, but dependent on pH, two low-spin forms dominated in the catalase cycle with absorbance maxima at 415, 545, and 580 nm at low pH and 418 and 520 nm at high pH. By contrast, oxidation of KatGs with peroxoacetic acid resulted in intermediates with different spectral features that also differed among the three KatGs. Following the rate of H2O2 degradation by stopped-flow allowed the linking of reaction intermediate species with substrate availability to confirm which species were actually present during the catalase cycle. Possible reaction intermediates involved in H2O2 dismutation by KatG are discussed.
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PMID:Redox intermediates in the catalase cycle of catalase-peroxidases from Synechocystis PCC 6803, Burkholderia pseudomallei, and Mycobacterium tuberculosis. 1726 Sep 48

A superoxide dismutase was purified 62-fold in seven steps to homogeneity from Methylobacillus sp. strain SK1, an obligate methanol-oxidizing bacterium, with a yield of 9.6%. The final specific activity was 4,831 units per milligram protein as determined by an assay based on a 50% decrease in the rate of cytochrome c reduction. The molecular weight of the native enzyme was estimated to be 44,000. Sodium dodecyl sulfate gel electrophoresis revealed two identical subunits of molecular weight 23,100. The isoelectric point of the purified enzyme was found to be 4.4. Maximum activity of the enzyme was measured at pH 8. The enzyme was stable at pH range from 6 to 8 and at high temperature. The enzyme showed an absorption peak at 280 nm with a shoulder at 292 nm. Hydrogen peroxide and sodium azide, but not sodium cyanide, was found to inhibit the purified enzyme. The enzyme activity in cell-free extracts prepared from cells grown in manganese-rich medium, however, was not inhibited by hydrogen peroxide but inhibited by sodium azide. The activity in cell extracts from cells grown in iron-rich medium was found to be highly sensitive to hydrogen peroxide and sodium azide. One mol of native enzyme was found to contain 1.1 g-atom of iron and 0.7 g-atom of manganese. The N-terminal amino acid sequence of the purified enzyme was Ala-Tyr-Thr-Leu-Pro-Pro-Leu-Asn-Tyr-Ala-Tyr. The superoxide dismutase of Methylobacillus sp. strain SK1 was found to have antigenic sites identical to those of Methylobacillus glycogenes enzyme. The enzyme, however, shared no antigenic sites with Mycobacterium sp. strain JC1, Methylovorus sp. strain SS1, Methylobacterium sp. strain SY1, and Methylosinus trichosproium enzymes.
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PMID:Characterization of an iron- and manganese-containing superoxide dismutase from Methylobacillus sp. strain SK1 DSM 8269. 1764 12

Mycobacterium tuberculosis is responsible for over 8 million cases of tuberculosis (TB) annually. Natural products may play important roles in the chemotherapy of TB. The immunological activity of Davilla elliptica chloroform extract (DECE) was evaluated in vitro by the determination of hydrogen peroxide (H2O2), nitric oxide (NO), and tumor necrosis factor-alpha (TNF-alpha) release in peritoneal macrophages cultures. DECE was also tested for its antimycobacterial activity against M. tuberculosis using the microplate alamar blue assay. DECE (50, 150, 250 microg/ml) stimulated the production of H2O2 (from 1,79 +/- 0,23 to 7,27 +/- 2,54; 15,02 +/- 2,86; 20,5 +/- 2,1 nmols) (means +/- SD), NO (from 2,64 +/- 1,02 to 25,59 +/- 2,29; 26,68 +/- 2,41; 29,45 +/- 5,87 micromols) (means +/- SD) and TNF-alpha (from 2,44 +/- 1,46 to 30,37 +/- 8,13; 38,68 +/- 1,59; 41,6 +/- 0,90 units/ml) (means +/- SD) in a dose-dependent manner and also showed a promising antimycobacterial activity with a minimum inhibitory concentration of 62,5 microg/ml. This plant may have therapeutic potential in the immunological and microbiological control of TB.
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PMID:Immunological and microbiological activity of Davilla elliptica St. Hill. (Dilleniaceae) against Mycobacterium tuberculosis. 1792 9

Mycobacterium tuberculosis is a very important global pathogen. One quarter of the world's TB cases occur in India. The tuberculosis strains isolated from south Indian patients exhibit certain phenotypic characteristics like low virulence in guinea-pigs, resistance to isoniazid, thiophene-2-carboxylic acid hydrazide (TCH) and para-amino salicylic acid (PAS), and enhanced susceptibility to H2O2. Besides this, a large percentage of the isolates harbor only a single copy of IS 6110 which makes these strains distinct. Hence, we have studied the genotypic characteristics of these strains by using advanced techniques like Deletion Micro array, deletion PCR, allelic discrimination RT-PCR using several lineage specific markers and KatG G1388T (non-synonymous) polymorphism along with spoligotyping. The analysis of 1215 tuberculosis patient isolates from south India revealed that 85.2% belonged to the ancestral lineage of M. tuberculosis. Comparative whole-genome hybridization identified six new genomic regions within this lineage that were variably deleted.
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PMID:Genomic interrogation of ancestral Mycobacterium tuberculosis from south India. 1802 33

Catalase-peroxidases or KatGs from seven different organisms, including Archaeoglobus fulgidus,Bacillus stearothermophilus, Burkholderia pseudomallei, Escherichia coli, Mycobacterium tuberculosis, Rhodobacter capsulatus and Synechocystis PCC 6803, have been characterized to provide a comparative picture of their respective properties. Collectively, the enzymes exhibit similar turnover rates with the catalase and peroxidase reactions varying between 4900 and 15,900s(-1) and 8-25s(-1), respectively. The seven enzymes also exhibited similar pH optima for the peroxidase (4.25-5.0) and catalase reactions (5.75), and high sensitivity to azide and cyanide with IC50 values of 0.2-20muM and 50-170muM, respectively. The K(M)s of the enzymes for H2O2 in the catalase reaction were relatively invariant between 3 and 5mM at pH 7.0, but increased to values ranging from 20 to 225mM at pH 5, consistent with protonation of the distal histidine (pKa approximately 6.2) interfering with H2O2 binding to Cpd I. The catalatic k(cat) was 2- to 3-fold higher at pH 5 compared to pH 7, consistent with the uptake of a proton being involved in the reduction of Cpd I. The turnover rates for the INH lyase and isonicotinoyl-NAD synthase reactions, responsible for the activation of isoniazid as an anti-tubercular drug, were also similar across the seven enzymes, but considerably slower, at 0.5 and 0.002s(-1), respectively. Only the NADH oxidase reaction varied more widely between 10(-4) and 10(-2)s(-1) with the fastest rate being exhibited by the enzyme from B. pseudomallei.
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PMID:Comparative study of catalase-peroxidases (KatGs). 1817 43

We aimed to delineate factors operating at the interface of macrophage-mycobacterium interaction which could determine the fate of a 'subclinical' infection in healthy people of a tuberculosis-endemic region. Ten study subjects (blood donors) were classified as 'high' or 'low' responders based on the ability of their monocyte-derived macrophages to restrict or promote an infection with Mycobacterium tuberculosis. Bacterial multiplication between days 4 and 8 in high responder macrophages was significantly lower (P < 0.02) than low responders. All donor sera were positive for antibodies against cell-membrane antigens of M. tuberculosis and bacilli opsonized with heat-inactivated sera were coated with IgG. In low responder macrophages, multiplication of opsonized bacilli was significantly less (P < 0.04) than that of unopsonized bacilli. The levels of tumour necrosis factor (TNF)-alpha and interleukin (IL)-12 produced by infected high responder macrophages was significantly higher (P < 0.05) than low responders. However, infection with opsonized bacilli enhanced the production of IL-12 in low responders to its level in high responders. The antibody level against membrane antigens was also significantly higher (P < 0.05) in high responders, although the antigens recognized by two categories of sera were not remarkably different. Production of certain other cytokines (IL-1beta, IL-4, IL-6 and IL-10) or reactive oxygen species (H2O2 and NO) by macrophages of high and low responders did not differ significantly. The study highlights the heterogeneity of Indian subjects with respect to their capability in handling subclinical infection with M. tuberculosis and the prominent role that TNF-alpha, opsonizing antibodies and, to a certain extent, IL-12 may play in containing it.
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PMID:Determinants of natural immunity against tuberculosis in an endemic setting: factors operating at the level of macrophage-Mycobacterium tuberculosis interaction. 1823 54

Kinetics of ferric Mycobacterium leprae truncated hemoglobin O (trHbOFe(III)) oxidation by H2O2 and of trHbOFe(IV)O reduction by (.)NO and NO2- are reported. The value of the second-order rate constant for H2O2-mediated oxidation of trHbOFe(III) is 2.4 x 10(3) M(-1) s(-1). The value of the second-order rate constant for (.)NO-mediated reduction of trHbOFe(IV)O is 7.8 x 10(6) M(-1) s(-1). The value of the first-order rate constant for trHbOFe(III)ONO decay to the resting form trHbOFe(III) is 2.1 x 10(1) s(-1). The value of the second-order rate constant for NO2--mediated reduction of trHbOFe(IV)=O is 3.1 x 10(3) M(-1) s(-1). As a whole, trHbOFe(IV)O, generated upon reaction with H2O2, catalyzes (.)NO reduction to NO2-. In turn, (.)NO and NO2- act as antioxidants of trHbOFe(IV)O, which could be responsible for the oxidative damage of the mycobacterium. Therefore, Mycobacterium leprae trHbO could be involved in both H2O2 and (.)NO scavenging, protecting from nitrosative and oxidative stress, and sustaining mycobacterial respiration.
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PMID:H2O2 and (.)NO scavenging by Mycobacterium leprae truncated hemoglobin O. 1854 37

A mechanism accounting for the robust catalase activity in catalase-peroxidases (KatG) presents a new challenge in heme protein enzymology. In Mycobacterium tuberculosis, KatG is the sole catalase and is also responsible for peroxidative activation of isoniazid, an anti-tuberculosis pro-drug. Here, optical stopped-flow spectrophotometry, rapid freeze-quench EPR spectroscopy both at the X-band and at the D-band, and mutagenesis are used to identify catalase reaction intermediates in M. tuberculosis KatG. In the presence of millimolar H2O2 at neutral pH, oxyferrous heme is formed within milliseconds from ferric (resting) KatG, whereas at pH 8.5, low spin ferric heme is formed. Using rapid freeze-quench EPR at X-band under both of these conditions, a narrow doublet radical signal with an 11 G principal hyperfine splitting was detected within the first milliseconds of turnover. The radical and the unique heme intermediates persist in wild-type KatG only during the time course of turnover of excess H2O2 (1000-fold or more). Mutation of Met255, Tyr229, or Trp107, which have covalently linked side chains in a unique distal side adduct (MYW) in wild-type KatG, abolishes this radical and the catalase activity. The D-band EPR spectrum of the radical exhibits a rhombic g tensor with dual gx values (2.00550 and 2.00606) and unique gy (2.00344) and gz values (2.00186) similar to but not typical of native tyrosyl radicals. Density functional theory calculations based on a model of an MYW adduct radical built from x-ray coordinates predict experimentally observed hyperfine interactions and a shift in g values away from the native tyrosyl radical. A catalytic role for an MYW adduct radical in the catalase mechanism of KatG is proposed.
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PMID:An oxyferrous heme/protein-based radical intermediate is catalytically competent in the catalase reaction of Mycobacterium tuberculosis catalase-peroxidase (KatG). 1913 99


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