Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 116, Issue 32, Pages 15907-15913Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1906606116
Keywords
enzyme function; carbon-carbon bond lyase; Mycobacterium tuberculosis; itaconate catabolism; leucine catabolism
Categories
Funding
- Cancer Research UK [FC001029]
- Medical Research Council [FC001029]
- Wellcome Trust [FC001029, FC001060]
- Francis Crick Institute - Cancer Research UK [FC001060]
- UK MRC Grant [FC001060]
- Wellcome Trust New Investigator Award [104785/B/14/Z]
- DOE Office of Science [DE-AC02-06CH11357]
- NIH Shared Instrumentation Grant [S10 OD020068]
- US NIH [P01 GM118303]
- MRC [MC_U117533887] Funding Source: UKRI
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Mycobacterium tuberculosis (Mtb) is the etiological agent of tuberculosis. One-fourth of the global population is estimated to be infected with Mtb, accounting for similar to 1.3 million deaths in 2017. As part of the immune response to Mtb infection, macrophages produce metabolites with the purpose of inhibiting or killing the bacterial cell. Itaconate is an abundant host metabolite thought to be both an antimicrobial agent and a modulator of the host inflammatory response. However, the exact mode of action of itaconate remains unclear. Here, we show that Mtb has an itaconate dissimilation pathway and that the last enzyme in this pathway, Rv2498c, also participates in L-leucine catabolism. Our results from phylogenetic analysis, in vitro enzymatic assays, X-ray crystallography, and in vivo Mtb experiments, identified Mtb Rv2498c as a bifunctional beta-hydroxyacyl-CoA lyase and that deletion of the rv2498c gene from the Mtb genome resulted in attenuation in a mouse infection model. Altogether, this report describes an itaconate resistance mechanism in Mtb and an L-leucine catabolic pathway that proceeds via an unprecedented (R)-3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) stereospecific route in nature.
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