Carbon metabolism of intracellular bacteria

Muñoz‐Elías, Ernesto J.; McKinney, John D.

doi:10.1111/j.1462-5822.2005.00648.x

Cited by 230 publications

(206 citation statements)

References 132 publications

(162 reference statements)

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“…Mtb is an obligate human pathogen predominantly growing intracellularly within phagosomes of host phagocytes, although other cell types and niches might also be occupied during different phases of infection. Notwithstanding, there is strong evidence that host lipids provide the main carbon and energy sources for Mtb during infection, with carbohydrates being largely inaccessible for the bacilli (2)(3)(4)(5). Support for this, among further findings, comes from the observed up-regulation of lipid catabolism genes of Mtb during intracellular replication in macrophages (4) and from the joint essentiality of the two isocitrate lyase isoforms, icl1 and icl2, for growth of Mtb in mice (6).…”

mentioning

confidence: 52%

Trehalose-recycling ABC transporter LpqY-SugA-SugB-SugC is essential for virulence of Mycobacterium tuberculosis

Kalscheuer

Weinrick

Usha

et al. 2010

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

172

245

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Mycobacterium tuberculosis (Mtb) is an exclusively human pathogen that proliferates within phagosomes of host phagocytes. Host lipids are believed to provide the major carbon and energy sources for Mtb, with only limited availability of carbohydrates. There is an apparent paradox because five putative carbohydrate uptake permeases are present in Mtb, but there are essentially no host carbohydrates inside phagosomes. Nevertheless, carbohydrate transporters have been implicated in Mtb pathogenesis, suggesting that acquisition of host sugars is important during some stages of infection. Here we show, however, that the LpqY-SugA-SugB-SugC ATP-binding cassette transporter is highly specific for uptake of the disaccharide trehalose, a sugar not present in mammals, thus refuting a role in nutrient acquisition from the host. Trehalose release is known to occur as a byproduct of the biosynthesis of the mycolic acid cell envelope by Mtb's antigen 85 complex. The antigen 85 complex constitutes a group of extracellular mycolyl transferases, which transfer the lipid moiety of the glycolipid trehalose monomycolate (TMM) to arabinogalactan or another molecule of TMM, yielding trehalose dimycolate. These reactions also lead to the concomitant extracellular release of the trehalose moiety of TMM. We found that the LpqY-SugA-SugB-SugC ATP-binding cassette transporter is a recycling system mediating the retrograde transport of released trehalose. Perturbations in trehalose recycling strongly impaired virulence of Mtb. This study reveals an unexpected accessory component involved in the formation of the mycolic acid cell envelope in mycobacteria and provides a previously unknown role for sugar transporters in bacterial pathogenesis. microbial pathogenesis | mycolic acid biosynthesis | cell wall formation | carbon metabolism T uberculosis, caused by the bacterium Mycobacterium tuberculosis (Mtb), remains a major threat to global health, claiming the life of two million individuals each year (1). Mtb is an obligate human pathogen predominantly growing intracellularly within phagosomes of host phagocytes, although other cell types and niches might also be occupied during different phases of infection. Notwithstanding, there is strong evidence that host lipids provide the main carbon and energy sources for Mtb during infection, with carbohydrates being largely inaccessible for the bacilli (2-5). Support for this, among further findings, comes from the observed up-regulation of lipid catabolism genes of Mtb during intracellular replication in macrophages (4) and from the joint essentiality of the two isocitrate lyase isoforms, icl1 and icl2, for growth of Mtb in mice (6). It has to be mentioned that the importance of some lipid catabolic pathways for in vivo carbon metabolism of Mtb may be somewhat overestimated, as attenuation of mutants might be caused by accumulation of toxic intermediates of incomplete metabolism rather than by blocked utilization of a substrate (7). Nevertheless, the published literature strongly suggests that Mtb ...

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mentioning

confidence: 52%

Trehalose-recycling ABC transporter LpqY-SugA-SugB-SugC is essential for virulence of Mycobacterium tuberculosis

Kalscheuer

Weinrick

Usha

et al. 2010

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

172

245

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“…It is now widely accepted that metabolic adaptation to the host environment is a defining feature of the pathogenicity of Mtb (38,78). However, we lack biochemical knowledge of its metabolic networks and how they are regulated.…”

Section: Discussionmentioning

confidence: 99%

Succinylome Analysis Reveals the Involvement of Lysine Succinylation in Metabolism in Pathogenic Mycobacterium tuberculosis*

Yang

Wang

Chen

et al. 2015

Molecular & Cellular Proteomics

122

139

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Mycobacterium tuberculosis (Mtb), the causative agent of human tuberculosis, remains one of the most prevalent human pathogens and a major cause of mortality worldwide. Metabolic network is a central mediator and defining feature of the pathogenicity of Mtb. Increasing evidence suggests that lysine succinylation dynamically regulates enzymes in carbon metabolism in both bacteria and human cells; however, its extent and function in Mtb remain unexplored. Here, we performed a global succinylome analysis of the virulent Mtb strain H37Rv by using high accuracy nano-LC-MS/MS in combination with the enrichment of succinylated peptides from digested cell lysates and subsequent peptide identification. In total, 1545 lysine succinylation sites on 626 proteins were identified in this pathogen. The identified succinylated proteins are involved in various biological processes and a large proportion of the succinylation sites are present on proteins in the central metabolism pathway. Site-specific mutations showed that succinylation is a negative regulatory modification on the enzymatic activity of acetylCoA synthetase. Molecular dynamics simulations demonstrated that succinylation affects the conformational stability of acetyl-CoA synthetase, which is critical for its enzymatic activity. Further functional studies showed that CobB, a sirtuin-like deacetylase in Mtb, functions as a desuccinylase of acetyl-CoA synthetase in in vitro assays. Together, our findings reveal widespread roles for lysine succinylation in regulating metabolism and diverse processes in Mtb. Our data provide a rich resource for functional analyses of lysine succinylation and facilitate the dissection of metabolic networks in this life-threatening pathogen.

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“…Analyses of the Mtb icl mutants suggested that fatty acids are an important carbon and energy source for Mtb during infection (3,4). However, fatty acids are toxic to MtbΔicl1/2 even in the presence of carbohydrates, complicating the mechanistic interpretation of the attenuation of this mutant in mice.…”

Section: Discussionmentioning

confidence: 99%

“…New drugs are urgently needed to control infections with Mtb, which kills ≈2 million people annually (1,2). Mounting evidence suggests that Mtb preferentially uses fatty acids during in vivo growth (3,4). The enzymes required for fatty acid metabolism in Mtb, however, remain incompletely defined.…”

mentioning

confidence: 99%

Gluconeogenic carbon flow of tricarboxylic acid cycle intermediates is critical for Mycobacterium tuberculosis to establish and maintain infection

Marrero¹,

Rhee

Schnappinger³

et al. 2010

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

313

315

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Metabolic adaptation to the host niche is a defining feature of the pathogenicity of Mycobacterium tuberculosis (Mtb). In vitro, Mtb is able to grow on a variety of carbon sources, but mounting evidence has implicated fatty acids as the major source of carbon and energy for Mtb during infection. When bacterial metabolism is primarily fueled by fatty acids, biosynthesis of sugars from intermediates of the tricarboxylic acid cycle is essential for growth. The role of gluconeogenesis in the pathogenesis of Mtb however remains unaddressed. Phosphoenolpyruvate carboxykinase (PEPCK) catalyzes the first committed step of gluconeogenesis. We applied genetic analyses and 13 C carbon tracing to confirm that PEPCK is essential for growth of Mtb on fatty acids and catalyzes carbon flow from tricarboxylic acid cycle-derived metabolites to gluconeogenic intermediates. We further show that PEPCK is required for growth of Mtb in isolated bone marrow-derived murine macrophages and in mice. Importantly, Mtb lacking PEPCK not only failed to replicate in mouse lungs but also failed to survive, and PEPCK depletion during the chronic phase of infection resulted in mycobacterial clearance. Mtb thus relies on gluconeogenesis throughout the infection. PEPCK depletion also attenuated Mtb in IFNγ-deficient mice, suggesting that this enzyme represents an attractive target for chemotherapy.carbon metabolism | gluconeogenesis | metabolomics | microbial pathogenesis | phosphoenolpyruvate carboxykinase

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Carbon metabolism of intracellular bacteria

Cited by 230 publications

References 132 publications

Trehalose-recycling ABC transporter LpqY-SugA-SugB-SugC is essential for virulence of Mycobacterium tuberculosis

Trehalose-recycling ABC transporter LpqY-SugA-SugB-SugC is essential for virulence of Mycobacterium tuberculosis

Succinylome Analysis Reveals the Involvement of Lysine Succinylation in Metabolism in Pathogenic Mycobacterium tuberculosis*

Gluconeogenic carbon flow of tricarboxylic acid cycle intermediates is critical for Mycobacterium tuberculosis to establish and maintain infection

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