Methylcitrate cycle defines the bactericidal essentiality of isocitrate lyase for survival of mycobacterium tuberculosis on fatty acids Academic Article uri icon

Overview

MeSH Major

  • Citrates
  • Fatty Acids
  • Isocitrate Lyase
  • Microbial Viability
  • Mycobacterium tuberculosis

abstract

  • Few mutations attenuate Mycobacterium tuberculosis (Mtb) more profoundly than deletion of its isocitrate lyases (ICLs). However, the basis for this attenuation remains incompletely defined. Mtb's ICLs are catalytically bifunctional isocitrate and methylisocitrate lyases required for growth on even and odd chain fatty acids. Here, we report that Mtb's ICLs are essential for survival on both acetate and propionate because of its methylisocitrate lyase (MCL) activity. Lack of MCL activity converts Mtb's methylcitrate cycle into a "dead end" pathway that sequesters tricarboxylic acid (TCA) cycle intermediates into methylcitrate cycle intermediates, depletes gluconeogenic precursors, and results in defects of membrane potential and intrabacterial pH. Activation of an alternative vitamin B12-dependent pathway of propionate metabolism led to selective corrections of TCA cycle activity, membrane potential, and intrabacterial pH that specifically restored survival, but not growth, of ICL-deficient Mtb metabolizing acetate or propionate. These results thus resolve the biochemical basis of essentiality for Mtb's ICLs and survival on fatty acids.

publication date

  • April 2014

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3977286

Digital Object Identifier (DOI)

  • 10.1073/pnas.1400390111

PubMed ID

  • 24639517

Additional Document Info

start page

  • 4976

end page

  • 81

volume

  • 111

number

  • 13