Sulfate Metabolism in Mycobacteria

Schelle, Michael W.; Bertozzi, Carolyn R.

doi:10.1002/cbic.200600224

Cited by 82 publications

(55 citation statements)

References 77 publications

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“…Another role of sulfate is in the synthesis of sulfated lipids. (See reference [101] for a review of sulfate metabolism in M. tuberculosis .) Sulfated lipids are synthesized from PAPS and known targets to date are cysC (kinase domain) and Rv1373 [100].…”

Section: Discussionmentioning

confidence: 99%

Identification of gene targets against dormant phase Mycobacterium tuberculosis infections

2007

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Background: Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), infects approximately 2 billion people worldwide and is the leading cause of mortality due to infectious disease. Current TB therapy involves a regimen of four antibiotics taken over a six month period. Patient compliance, cost of drugs and increasing incidence of drug resistant M. tuberculosis strains have added urgency to the development of novel TB therapies. Eradication of TB is affected by the ability of the bacterium to survive up to decades in a dormant state primarily in hypoxic granulomas in the lung and to cause recurrent infections.

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Section: Discussionmentioning

confidence: 99%

Identification of gene targets against dormant phase Mycobacterium tuberculosis infections

2007

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“…The identification of new antibacterial targets is essential to address MDR- and latent-TB infection [63, 64]. Toward this end, mycobacterial sulfur metabolism represents a promising new area for anti-TB therapy [62, 65, 66]. Numerous studies have validated amino acid biosynthetic pathways and downstream metabolites as antimicrobial targets [67–70] and sulfur metabolic pathways are required for the expression of virulence in many pathogenic bacteria [71–74].…”

Section: Sulfur and Mycobacterial Survivalmentioning

confidence: 99%

“…However, an important question raised from the findings of this study is whether the sulfur requirements for an attenuated M. bovis strain reflect those of M. tuberculosis known to elicit a more potent host immune response [22, 29, 40]. It is also possible that the mycobacterial genome encodes for an additional sulfate transporter which is not expressed under culture conditions, but is specifically up-regulated during infection [88, 89]. In support of this hypothesis, mRNA array analysis has shown significant up-regulation of hypothetical proteins from Rv1739c and Rv1707 [51, 78] 24 h post infection of activated macrophages in response to nitric oxide [46] or hypoxia [52].…”

Section: Sulfate Import and Activationmentioning

confidence: 99%

New Targets and Inhibitors of Mycobacterial Sulfur Metabolism

Paritala¹,

Carroll²

2013

IDDT

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The identification of new antibacterial targets is urgently needed to address multidrug resistant and latent tuberculosis infection. Sulfur metabolic pathways are essential for survival and the expression of virulence in many pathogenic bacteria, including Mycobacterium tuberculosis. In addition, microbial sulfur metabolic pathways are largely absent in humans and therefore, represent unique targets for therapeutic intervention. In this review, we summarize our current understanding of the enzymes associated with the production of sulfated and reduced sulfur-containing metabolites in Mycobacteria. Small molecule inhibitors of these catalysts represent valuable chemical tools that can be used to investigate the role of sulfur metabolism throughout the Mycobacterial lifecycle and may also represent new leads for drug development. In this light, we also summarize recent progress made in the development of inhibitors of sulfur metabolism enzymes.

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“…1B) (9). Both gene clusters contain polyketide synthase (pks), acyltransferase (pap), and lipid transport (mmpL) genes in a similar genomic arrangement (Fig.…”

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confidence: 99%

PapA3 Is an Acyltransferase Required for Polyacyltrehalose Biosynthesis in Mycobacterium tuberculosis

Hatzios

Schelle

Holsclaw

et al. 2009

Journal of Biological Chemistry

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Mycobacterium tuberculosis possesses an unusual cell wall that is replete with virulence-enhancing lipids. One cell wall molecule unique to pathogenic M. tuberculosis is polyacyltrehalose (PAT), a pentaacylated, trehalose-based glycolipid. Little is known about the biosynthesis of PAT, although its biosynthetic gene cluster has been identified and found to resemble that of the better studied M. tuberculosis cell wall component sulfolipid-1. In this study, we sought to elucidate the function of papA3, a gene from the PAT locus encoding a putative acyltransferase. To determine whether PapA3 participates in PAT assembly, we expressed the protein heterologously and evaluated its acyltransferase activity in vitro. The purified enzyme catalyzed the sequential esterification of trehalose with two palmitoyl groups, generating a diacylated product similar to the 2,3-diacyltrehalose glycolipids of M. tuberculosis. Notably, PapA3 was selective for trehalose; no activity was observed with other structurally related disaccharides. Disruption of the papA3 gene from M. tuberculosis resulted in the loss of PAT from bacterial lipid extracts. Complementation of the mutant strain restored PAT production, demonstrating that PapA3 is essential for the biosynthesis of this glycolipid in vivo. Furthermore, we determined that the PAT biosynthetic machinery has no cross-talk with that for sulfolipid-1 despite their related structures.Mycobacterium tuberculosis, the bacterium that causes tuberculosis in humans, has a complex cell wall that contains a number of unique glycolipids intimately linked to mycobacterial pathogenesis (1, 2). The biosynthesis of many of these virulence factors, including the trehalose mycolates, phenolic glycolipids, and sulfolipid-1 (SL-1), 3 is largely understood (3-5). In contrast, relatively little is known about the biosynthesis of other prominent M. tuberculosis glycolipids, such as di-, tri-, and polyacyltrehaloses. These acyltrehaloses are located in the outer surface of the cell wall and contain di-and tri-methyl branched fatty acids that are only found in pathogenic species of mycobacteria (6, 7). Previous studies suggest a role for these glycolipids in anchoring the bacterial capsule, which impedes phagocytosis by host cells (6). The major polyacyltrehalose (PAT) of M. tuberculosis, also referred to as pentaacyl or polyphthienoyl trehalose, consists of five acyl chains, four mycolipenic (phthienoic) acids and one fully saturated fatty acid, linked to trehalose (Fig. 1A) (8). The mycolipenic acid side chains of PAT are products of the polyketide synthase gene pks3/4 (7). Disruption of pks3/4 (also referred to as msl3 (7)) abolishes PAT biosynthesis and causes cell aggregation. At present, the remaining proteins required for PAT assembly have not been characterized.Interestingly, the PAT biosynthetic gene cluster strongly resembles that of SL-1, which is a structurally similar trehalosebased glycolipid unique to pathogenic mycobacteria (Fig. 1B) (9). Both gene clusters contain polyketide synthase (pks), ...

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Sulfate Metabolism in Mycobacteria

Cited by 82 publications

References 77 publications

Identification of gene targets against dormant phase Mycobacterium tuberculosis infections

Identification of gene targets against dormant phase Mycobacterium tuberculosis infections

New Targets and Inhibitors of Mycobacterial Sulfur Metabolism

PapA3 Is an Acyltransferase Required for Polyacyltrehalose Biosynthesis in Mycobacterium tuberculosis

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