Fumarase Deficiency Causes Protein and Metabolite Succination and Intoxicates Mycobacterium tuberculosis.

TitleFumarase Deficiency Causes Protein and Metabolite Succination and Intoxicates Mycobacterium tuberculosis.
Publication TypeJournal Article
Year of Publication2017
AuthorsRuecker N, Jansen R, Trujillo C, Puckett S, Jayachandran P, Piroli GG, Frizzell N, Molina H, Rhee KY, Ehrt S
JournalCell Chem Biol
Date Published2017 Mar 16
KeywordsAnimals, Bacterial Proteins, Chromatography, High Pressure Liquid, Citric Acid Cycle, Cysteine, Female, Fumarate Hydratase, Fumarates, Mice, Mice, Inbred C57BL, Mycobacterium tuberculosis, Oxidative Stress, Peptides, Protein Processing, Post-Translational, Tandem Mass Spectrometry

Enzymes of central carbon metabolism are essential mediators of Mycobacterium tuberculosis (Mtb) physiology and pathogenicity, but are often perceived to lack sufficient species selectivity to be pursued as potential drug targets. Fumarase (Fum) is an enzyme of the canonical tricarboxylic acid cycle and is dispensable in many organisms. Transposon mutagenesis studies in Mtb, however, indicate that Fum is required for optimal growth. Here, we report the generation and characterization of a genetically engineered Mtb strain in which Fum expression is conditionally regulated. This revealed that Fum deficiency is bactericidal in vitro and during both the acute and chronic phases of mouse infection. This essentiality is linked to marked accumulations of fumarate resulting in protein and metabolite succination, a covalent modification of cysteine thiol residues. These results identify Mtb Fum as a potentially species-specific drug target whose inactivation may kill Mtb through a covalently irreversible form of metabolic toxicity.

Alternate JournalCell Chem Biol
PubMed ID28219662
PubMed Central IDPMC5357164
Grant ListR01 AI063446 / AI / NIAID NIH HHS / United States
R01 NS092938 / NS / NINDS NIH HHS / United States

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