An essential bifunctional enzyme in Mycobacterium tuberculosis for itaconate dissimilation and leucine catabolism

Hua Wang, Alexander A. Fedorov, Elena V. Fedorov, Debbie M. Hunt, Angela Rodgers, Holly L. Douglas, Acely Garza-Garcia, Jeffrey B. Bonanno, Steven C. Almo, Luiz Pedro Sório de Carvalho

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Mycobacterium tuberculosis (Mtb) is the etiological agent of tuberculosis. One-fourth of the global population is estimated to be infected with Mtb, accounting for ∼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 β-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.

Original languageEnglish (US)
Pages (from-to)15907-15913
Number of pages7
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number32
DOIs
StatePublished - Aug 6 2019

Fingerprint

Mycobacterium tuberculosis
Leucine
Enzymes
Mycobacterium Infections
Lyases
itaconic acid
X Ray Crystallography
Gene Deletion
Enzyme Assays
Coenzyme A
Anti-Infective Agents
Tuberculosis
Macrophages
Genome
Infection
Population

Keywords

  • Carbon–carbon bond lyase
  • Enzyme function
  • Itaconate catabolism
  • Leucine catabolism
  • Mycobacterium
  • Tuberculosis

ASJC Scopus subject areas

  • General

Cite this

An essential bifunctional enzyme in Mycobacterium tuberculosis for itaconate dissimilation and leucine catabolism. / Wang, Hua; Fedorov, Alexander A.; Fedorov, Elena V.; Hunt, Debbie M.; Rodgers, Angela; Douglas, Holly L.; Garza-Garcia, Acely; Bonanno, Jeffrey B.; Almo, Steven C.; de Carvalho, Luiz Pedro Sório.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 116, No. 32, 06.08.2019, p. 15907-15913.

Research output: Contribution to journalArticle

Wang, Hua ; Fedorov, Alexander A. ; Fedorov, Elena V. ; Hunt, Debbie M. ; Rodgers, Angela ; Douglas, Holly L. ; Garza-Garcia, Acely ; Bonanno, Jeffrey B. ; Almo, Steven C. ; de Carvalho, Luiz Pedro Sório. / An essential bifunctional enzyme in Mycobacterium tuberculosis for itaconate dissimilation and leucine catabolism. In: Proceedings of the National Academy of Sciences of the United States of America. 2019 ; Vol. 116, No. 32. pp. 15907-15913.
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