Characterization ofMycobacterium smegmatisMutants Defective in 1-d-myo-Inosityl-2-amino-2-deoxy-α-d-glucopyranoside and Mycothiol Biosynthesis

Newton, Gerald L.; Unson, M. D.; Anderberg, Sara J.; Aguilera, Joseph; Oh, Nancy N.; delCardayré, Stephen B.; Av‐Gay, Yossef; Fahey, Robert C.

doi:10.1006/bbrc.1999.0156

Cited by 94 publications

(123 citation statements)

References 28 publications

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“…1B) (32)(33)(34). Using exact mass measurements (m͞z 485.1437, within 2 ppm of calculated mass) and MS͞MS experiments (data not shown), we showed that the mycothiol ion was present in both M. tuberculosis and M. smegmatis extracts.…”

Section: Identification Of R-sulfur and Sulfatedmentioning

confidence: 74%

Discovery of sulfated metabolites in mycobacteria with a genetic and mass spectrometric approach

Mougous

Leavell

Senaratne

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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The study of the metabolome presents numerous challenges, first among them being the cataloging of its constituents. A step in this direction will be the development of tools to identify metabolites that share common structural features. The importance of sulfated molecules in cell-cell communication motivated us to develop a rapid two-step method for identifying these metabolites in microorganisms, particularly in pathogenic mycobacteria. Sulfurcontaining molecules were initially identified by mass spectral analysis of cell extracts from bacteria labeled metabolically with a stable sulfur isotope ( 34 SO 4 2؊ ). To differentiate sulfated from reduced-sulfur-containing molecules, we employed a mutant lacking the reductive branch of the sulfate assimilation pathway. In these sulfur auxotrophs, heavy sulfate is channeled exclusively into sulfated metabolites. The method was applied to the discovery of several new sulfated molecules in Mycobacterium tuberculosis and Mycobacterium smegmatis. Because a sulfur auxotrophic strain is the only requirement of the approach, many microorganisms can be studied in this manner. Such genetic engineering in combination with stable isotopic labeling can be applied to various metabolic pathways and their products.T he modification of primary and secondary metabolites by the addition or removal of sulfate can have a profound influence on their biological properties (1-5). Typically, sulfated molecules are directed outside the cell, where they serve as modulators of cell-cell interactions. As a notable example pertinent to human health, sulfation of the glycans of endothelial CD34 engenders high-affinity binding with the leukocyte adhesion molecule L-selectin, facilitating an interaction that eventually leads to the recruitment of lymphocytes into peripheral lymph nodes (6). Similarly, sulfation of tyrosyl residues found on the chemokine receptor CCR5 is a modification required for binding of HIV gp120 and therefore efficient viral entry (7).The roles of sulfated compounds in prokaryotes and other microbes are less clear. In one well-characterized case, however, sulfation acts as a modulator of cell-cell communication, similar to its role in eukaryotes. The nitrogen-fixing bacterium Sinorhizobium meliloti utilizes a sulfated glycolipid as a secondary messenger to induce root nodulation in its plant host alfalfa (4,8). Mutants lacking the sulfotransferase that installs this sulfate ester are unable to induce root nodulation in alfalfa but gain the ability to colonize the roots of vetch. That sulfation of a single glycolipid plays such a vital role in nitrogen fixation has far-reaching implications for the agricultural community and presents a possible target for chemical or genetic engineering.Sulfation may also be relevant to the process of bacterial pathogenesis (9). Several mycobacteria, including the human pathogens Mycobacterium tuberculosis and Mycobacterium avium, are known to produce sulfated compounds. One example is Sulfatide-1 (SL-1, Fig. 1A), a sulfated glycolipid from M....

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Section: Identification Of R-sulfur and Sulfatedmentioning

confidence: 74%

Discovery of sulfated metabolites in mycobacteria with a genetic and mass spectrometric approach

Mougous

Leavell

Senaratne

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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“…The NADPH-dependent enzyme mycothiol disulfide reductase (Mtr) 30 helps to maintain an intracellular reducing environment by reducing MSSM back to MSH. MSH is essential for the growth of M. tuberculosis 31 and MSH-deficient mycobacteria exhibit increased sensitivity to oxidative stress, [32] and [33] making this redox pathway a potential biological target for novel antitubercular chemotherapies. The catalytic properties of Mtr were originally reported using both MSSM and some commercial naphthoquinones (e.g.…”

Section: Mycobacterium Tuberculosis Lacks Glutathione Instead It Maimentioning

confidence: 99%

Activity of 7-methyljuglone derivatives against Mycobacterium tuberculosis and as subversive substrates for mycothiol disulfide reductase

Mahapatra

Mativandlela

Binneman

et al. 2007

Bioorganic & Medicinal Chemistry

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The naphthoquinone 7-methyljuglone (5-hydroxy-7-methyl-1,4-naphthoquinone) has previously been isolated and identified as an active component of root extracts of Euclea natalensis which displays antitubercular activity. Herein, a series of synthetic and plantderived naphthoquinone derivates of the 7-methyljuglone scaffold have been prepared and evaluated for antibacterial activity against Mycobacterium tuberculosis. Several of these compounds have been shown to operate as subversive substrates with mycothiol disulfide reductase. The absence of a direct correlation between antitubercular activity and subversive substrate efficiency with mycothiol disulfide reductase, might be a consequence of their non-specific reactivity with multiple biological targets (e.g. other disulfide reductases). openUP (December 2007) Graphical abstractArticle Outline

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“…Several studies have demonstrated the role of MSH in detoxifying reactive species by either (i) donating a reducing equivalent (4) or (ii) forming an S-conjugate composed of MSH and the respective agent (5). Consistent with these findings, mycobacterial species deficient in MSH are found to have varying but increased sensitivity to H 2 O 2 (3,4,6), nitric oxide (NO) (7), and other redox cycling agents (3,4,8,9). Despite the importance of MSH in protecting mycobacteria against oxidative and nitrosative stressors, M. tuberculosis strains lacking MSH remain viable in vivo, suggesting a compensatory mechanism (10).…”

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confidence: 78%

Regulation of Ergothioneine Biosynthesis and Its Effect on Mycobacterium tuberculosis Growth and Infectivity

Richard-Greenblatt

Bach

Adamson³

et al. 2015

Journal of Biological Chemistry

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Background: Mycobacterium tuberculosis synthesizes ergothioneine, a sulfur-containing molecule with unknown function. Results: egtD encodes for a histidine methyltransferase that is essential for ergothioneine biosynthesis and is negatively regulated through M. tuberculosis serine/threonine protein kinase D. Conclusion: M. tuberculosis modulates intracellular ergothioneine levels in response to starvation. Significance: Mechanisms by which M. tuberculosis senses and adapts to nutrient starvation is essential for understanding persistence and disease latency.

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Characterization ofMycobacterium smegmatisMutants Defective in 1-d-myo-Inosityl-2-amino-2-deoxy-α-d-glucopyranoside and Mycothiol Biosynthesis

Cited by 94 publications

References 28 publications

Discovery of sulfated metabolites in mycobacteria with a genetic and mass spectrometric approach

Discovery of sulfated metabolites in mycobacteria with a genetic and mass spectrometric approach

Activity of 7-methyljuglone derivatives against Mycobacterium tuberculosis and as subversive substrates for mycothiol disulfide reductase

Regulation of Ergothioneine Biosynthesis and Its Effect on Mycobacterium tuberculosis Growth and Infectivity

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