title: Methylcitrate cycle defines the bactericidal essentiality of isocitrate lyase for survival of Mycobacterium tuberculosis on fatty acids.
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.
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Weill Cornell Medical College, New York, NY 10065.
authors.forename: Hyungjin
authors.initials: H
authors.lastname: Eoh
authors.forename: Kyu Y
authors.initials: KY
authors.lastname: Rhee
mesh_terms: D000085:Acetates / Q000494:pharmacology; D002244:Carbon / Q000494:pharmacology; D002247:Carbon Isotopes; D002951:Citrates / Q000378:metabolism*; D005227:Fatty Acids / Q000633:toxicity*; D007522:Isocitrate Lyase / Q000172:deficiency / Q000378:metabolism*; D055432:Metabolomics; D050296:Microbial Viability / Q000187:drug effects; D008954:Models, Biological; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology*; D010641:Phenotype; D011422:Propionates / Q000494:pharmacology
chemical_list: D000085:Acetates; D002247:Carbon Isotopes; D002951:Citrates; D005227:Fatty Acids; D011422:Propionates; C031605:2-methylcitric acid; D002244:Carbon; D007522:Isocitrate Lyase
keywords: membrane bioenergetics; metabolic essentiality; metabolic homeostasis