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)

Growth of Mycobacterium phlei under low oxygen tension resulted in specific activities two to twenty times lower for formate dehydrogenase, malate dehydrogenase, beta-hydroxybutyrate dehydrogenase, lactate oxidase and NADH dehydrogenase than when cultures were grown under high aeration. An increase in fumarate reductase and succinate dehydrogenase occurred with M. phlei grown under low oxygen tension. Malate: vitamin K dehydrogenase and glucose-6-phosphate dehydrogenase activity were not significantly affected by the oxygen tension used to grow the bacteria, and neither culture contained a lactate dehydrogenase. With growth of M. phlei in conditions of low oxygen tension, cytochrome a was not detected, but cytochrome b was prominent in membranes and cytochrome c was present in the soluble fraction.
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PMID:Influence of oxygen tension on the respiratory activity of Mycobacterium phlei. 318 14

A variety of Mycobacterium species contained the 5-deazaflavin coenzyme known as F420. Mycobacterium smegmatis was found to have a glucose-6-phosphate dehydrogenase that was dependent on F420 as an electron acceptor and which did not utilize NAD or NADP. The enzyme was purified by ammonium sulfate fractionation, phenyl-Sepharose column chromatography, F420-ether-linked aminohexyl-Sepharose 4B affinity chromatography, and quaternary aminoethyl-Sephadex column chromatography, and the sequence of the first 26 N-terminal amino acids has been determined. The response of enzyme activity to a range of pHs revealed a two-peak pattern, with maxima at pH 5.5 and 8.0. The apparent Km values for F420 and glucose-6-phosphate were, respectively, 0.004 and 1.6 mM. The apparent native and subunit molecular masses were 78,000 and approximately 40,000 Da, respectively.
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PMID:Purification of a novel coenzyme F420-dependent glucose-6-phosphate dehydrogenase from Mycobacterium smegmatis. 863 74

Coenzyme F420 is a 5-deazaflavin. Upon reduction, 1,5-dihydro-coenzyme F420 is formed with a prochiral center at C5. In this study we report that the F420-dependent glucose-6-phosphate dehydrogenase from Mycobacterium smegmatis and the F420-dependent alcohol dehydrogenase from Methanoculleus thermophilicus are Si-face stereospecific with respect to C5 of the 5-deazaflavin. These results were obtained by following the stereochemical course of the reversible incorporation of 3H into F420 from tritium-labeled substrates. Our findings bring to eight the number of coenzyme-F420-dependent enzymes shown to be Si-face stereospecific. No F420-dependent enzyme with Re-face stereospecificity is known. This is noteworthy since coenzyme F420 is functionally similar to pyridine nucleotides for which both Si-face and Re-face specific enzymes have been found.
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PMID:Si-face stereospecificity at C5 of coenzyme F420 for F420-dependent glucose-6-phosphate dehydrogenase from Mycobacterium smegmatis and F420-dependent alcohol dehydrogenase from Methanoculleus thermophilicus. 870 24

A range of organisms known to contain F420 or to be relatives of mycobacteria were examined for F420-dependent glucose-6-phosphate dehydrogenase (FGD) and NADP-dependent glucose-6-phosphate dehydrogenase (NADP-G6PD) activities. All free-growing Mycobacterium species examined (including a virulent Mycobacterium tuberculosis strain) had FGD activities of 0.014-0.418 mumol min-1 mg protein-1, and NADP-G6PD activities of 0.013-0.636 mumol min-1 mg-1. Armadillo-grown Mycobacterium leprae had FGD activity of 0.008 mumol min-1 mg-1, but no detectable NADP-G6PD activity. Nocardia species also had FGD activity (0.088-0.154 mumol min-1 mg-1). Streptomyces and Corynebacterium species had no FGD, but had NADP-G6PD. Methanogenic Archaea had neither activity.
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PMID:Presence of F420-dependent glucose-6-phosphate dehydrogenase in Mycobacterium and Nocardia species, but absence from Streptomyces and Corynebacterium species and methanogenic Archaea. 899 17

Immune suppression and disturbances of normal leukocyte populations are side effects attributed to many antimalarial drugs and were concerns during a recent year-long placebo-controlled trial that compared daily primaquine (0.5 mg of base per kg of body weight per day) with weekly chloroquine (300 mg of base one time per week) for malaria prophylaxis. The study took place in Irian Jaya, Indonesia, from July 1994 to August 1995 and enrolled 129 Javanese men with normal glucose-6-phosphate dehydrogenase function. Tests for lymphocyte function and subset composition were conducted blindly on a cross-section of subjects during weeks 10 (n = 42) and 48 (n = 72) of supervised prophylaxis. Lymphocyte function, measured as the proliferative response of peripheral blood mononuclear cells to a panel of mitogens (pokeweed mitogen, phytohemagglutinin, and concanavalin A) and antigens (purified protein derivative of Mycobacterium tuberculosis and Clostridium tetani toxoid) and expressed as a stimulation index, allowed for statistical comparison between groups and sampling times. The lymphocyte subset composition for each group and time point was based on flow cytometry profiling, and the results were expressed as the mean percentages of CD3 (total T cells), CD19 (total B cells), CD4+ (T-helper and inducer cells), and CD8+ (T suppressor and cytotoxic cells), CD3/CD16+ CD56 (natural killer cells), CD3/anti-HLA-DR (activated T cells) cells and the CD4+/CD8+ ratios. Lymphocyte stimulation indices were statistically comparable among the placebo, primaquine, and chloroquine groups at both time points, although the primaquine group was distinguished by having repeatedly greater proportions of subjects with high ( > 3.0) stimulation indices. The lymphocyte subset profiles of these groups at both time points were also similar and undistorted relative to those of healthy reference populations matched for age, sex, and ethnicity. The results provide quantitative support for the safety of daily primaquine prophylaxis.
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PMID:Lymphocyte proliferative response and subset profiles during extended periods of chloroquine or primaquine prophylaxis. 912 32

The gene fgd, which codes for F420-dependent glucose-6-phosphate dehydrogenase (FGD), was cloned from Mycobacterium smegmatis, and its sequence was determined and analyzed. A homolog of FGD which has a very high similarity to the M. smegmatis FGD-derived amino acid sequence was identified in Mycobacterium tuberculosis. FGD showed significant homology with F420-dependent N5,N10-methylene-tetrahydromethanopterin reductase (MER) from methanogenic archaea and with several hypothetical proteins from M. tuberculosis and Archaeoglobus fulgidus, but FGD showed no significant homology with NADP-dependent glucose-6-phosphate dehydrogenases. Multiple alignment of FGD and MER proteins revealed four conserved consensus sequences. Multiple alignment of FGD with the hypothetical proteins also revealed portions of the same conserved sequences. Moderately high levels of FGD were expressed in Escherichia coli BL21(DE3) carrying fgd in pBluescript.
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PMID:Molecular analysis of the gene encoding F420-dependent glucose-6-phosphate dehydrogenase from Mycobacterium smegmatis. 955 6

FGD1 is an F(420)-dependent glucose-6-phosphate dehydrogenase from Mycobacterium tuberculosis that has been shown to be essential for activation of the anti-TB compound PA-824. Initial attempts to produce recombinant FGD1 using Escherichia coli as a host was unsuccessful, but when the alternative host Mycobacterium smegmatis was used, soluble protein yields of 7 mg/L of culture were achieved. Both native and selenomethionine-substituted FGD1 were obtained by culturing M. smegmatis in autoinduction media protocols originally developed for E. coli. Using these media afforded the advantages of decreased handling, as cultures did not require monitoring of optical density and induction, and reduced cost by removing the need for expensive ADC enrichment normally used in mycobacterial cultures. Selenomethionine was efficiently incorporated at levels required for multiwavelength anomalous diffraction experiments used in crystal structure determination. As far as we are aware this is the first protocol for preparation of selenomethionine-substituted protein in mycobacteria. Native and selenomethionine-labeled FGD1 were successfully crystallized by vapor diffusion, with the crystals diffracting to 2.1 Angstrom resolution.
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PMID:Expression, purification and crystallization of native and selenomethionine labeled Mycobacterium tuberculosis FGD1 (Rv0407) using a Mycobacterium smegmatis expression system. 1737 2

The modified flavin coenzyme F(420) is found in a restricted number of microorganisms. It is widely distributed in mycobacteria, however, where it is important in energy metabolism, and in Mycobacterium tuberculosis (Mtb) is implicated in redox processes related to non-replicating persistence. In Mtb, the F(420)-dependent glucose-6-phosphate dehydrogenase FGD1 provides reduced F(420) for the in vivo activation of the nitroimidazopyran prodrug PA-824, currently being developed for anti-tuberculosis therapy against both replicating and persistent bacteria. The structure of M. tuberculosis FGD1 has been determined by x-ray crystallography both in its apo state and in complex with F(420) and citrate at resolutions of 1.90 and 1.95 A(,) respectively. The structure reveals a highly specific F(420) binding mode, which is shared with several other F(420)-dependent enzymes. Citrate occupies the substrate binding pocket adjacent to F(420) and is shown to be a competitive inhibitor (IC(50) 43 microm). Modeling of the binding of the glucose 6-phosphate (G6P) substrate identifies a positively charged phosphate binding pocket and shows that G6P, like citrate, packs against the isoalloxazine moiety of F(420) and helps promote a butterfly bend conformation that facilitates F(420) reduction and catalysis.
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PMID:Crystal structures of F420-dependent glucose-6-phosphate dehydrogenase FGD1 involved in the activation of the anti-tuberculosis drug candidate PA-824 reveal the basis of coenzyme and substrate binding. 1843 8

In mycobacteria, F(420), a deazaflavin derivative, acts as a hydride transfer coenzyme for an F(420)-specific glucose-6-phosphate dehydrogenase (Fgd). Physiologically relevant reactions in the mycobacteria that use Fgd-generated reduced F(420) (F(420)H(2)) are unknown. In this work, F(420)H(2) was found to be oxidized by NO only in the presence of oxygen. Further analysis demonstrated that NO(2), produced from NO and O(2), was the oxidant. UV-visible spectroscopic and NO-sensor-based analyses proved that F(420)H(2) reduced NO(2) to NO. This reaction could serve as a defense system for Mycobacterium tuberculosis, which is more sensitive to NO(2) than NO under aerobic conditions. Activated macrophages produce NO, which in acidified phagosomes is converted to NO(2). Hence, by converting NO(2) back to NO with F(420)H(2), M. tuberculosis could decrease the effectiveness of antibacterial action of macrophages; such defense would correspond to active tuberculosis conditions where the bacterium grows aerobically. This hypothesis was consistent with the observation that a mutant strain of Mycobacterium smegmatis, a nonpathogenic relative of M. tuberculosis, which either did not produce or could not reduce F(420), was approximately 4-fold more sensitive to NO(2) than the wild-type strain. The phenomenon is reminiscent of the anticancer activity of gamma-tocopherol, which reduces NO(2) to NO and protects human cells from NO(2)-induced carcinogenesis.
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PMID:Conversion of NO2 to NO by reduced coenzyme F420 protects mycobacteria from nitrosative damage. 1932 22

Glucose 6-phosphate (G6P) is a metabolic intermediate with many possible cellular fates. In mycobacteria, G6P is a substrate for an enzyme, F(420)-dependent glucose-6-phosphate dehydrogenase (Fgd), found in few bacterial genera. Intracellular G6P levels in six Mycobacterium sp. were remarkably higher ( approximately 17-130-fold) than Escherichia coli and Bacillus megaterium. The high G6P level in Mycobacterium smegmatis may result from 10-25-fold higher activity of the gluconeogenic enzyme fructose-1,6-bisphosphatase when grown on glucose, glycerol, or acetate compared with B. megaterium and E. coli. In M. smegmatis this coincided with up-regulation of the first gluconeogenic enzyme, phosphoenolpyruvate carboxykinase, when acetate was the carbon source, suggesting a cellular program for maintaining high G6P levels. G6P was depleted in cells under oxidative stress induced by redox cycling agents plumbagin and menadione, whereas an fgd mutant of M. smegmatis used G6P less well under such conditions. The fgd mutant was more sensitive to these agents and, in contrast to wild type, was defective in its ability to reduce extracellular plumbagin and menadione. These data suggest that intracellular G6P in mycobacteria serves as a source of reducing power and, with the mycobacteria-specific Fgd-F(420) system, plays a protective role against oxidative stress.
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PMID:Glucose 6-phosphate accumulation in mycobacteria: implications for a novel F420-dependent anti-oxidant defense system. 2007 70


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