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Glyoxylate detoxification is an essential function of malate synthase required for carbon assimilation in Mycobacterium tuberculosis.

TitleGlyoxylate detoxification is an essential function of malate synthase required for carbon assimilation in Mycobacterium tuberculosis.
Publication TypeJournal Article
Year of Publication2017
AuthorsPuckett S, Trujillo C, Wang Z, Eoh H, Ioerger TR, Krieger I, Sacchettini J, Schnappinger D, Rhee KY, Ehrt S
JournalProc Natl Acad Sci U S A
Volume114
Issue11
PaginationE2225-E2232
Date Published2017 03 14
ISSN1091-6490
KeywordsAnimals, Carbon, Disease Models, Animal, Fatty Acids, Female, Gene Knockout Techniques, Glyoxylates, Inactivation, Metabolic, Macrophages, Malate Synthase, Metabolic Networks and Pathways, Mice, Mutation, Mycobacterium tuberculosis, Tuberculosis, Virulence
Abstract

The glyoxylate shunt is a metabolic pathway of bacteria, fungi, and plants used to assimilate even-chain fatty acids (FAs) and has been implicated in persistence of Mycobacterium tuberculosis (Mtb). Recent work, however, showed that the first enzyme of the glyoxylate shunt, isocitrate lyase (ICL), may mediate survival of Mtb during the acute and chronic phases of infection in mice through physiologic functions apart from fatty acid metabolism. Here, we report that malate synthase (MS), the second enzyme of the glyoxylate shunt, is essential for in vitro growth and survival of Mtb on even-chain fatty acids, in part, for a previously unrecognized activity: mitigating the toxicity of glyoxylate excess arising from metabolism of even-chain fatty acids. Metabolomic profiling revealed that MS-deficient Mtb cultured on fatty acids accumulated high levels of the ICL aldehyde endproduct, glyoxylate, and increased levels of acetyl phosphate, acetoacetyl coenzyme A (acetoacetyl-CoA), butyryl CoA, acetoacetate, and β-hydroxybutyrate. These changes were indicative of a glyoxylate-induced state of oxaloacetate deficiency, acetate overload, and ketoacidosis. Reduction of intrabacterial glyoxylate levels using a chemical inhibitor of ICL restored growth of MS-deficient Mtb, despite inhibiting entry of carbon into the glyoxylate shunt. In vivo depletion of MS resulted in sterilization of Mtb in both the acute and chronic phases of mouse infection. This work thus identifies glyoxylate detoxification as an essential physiologic function of Mtb malate synthase and advances its validation as a target for drug development.

DOI10.1073/pnas.1617655114
Alternate JournalProc Natl Acad Sci U S A
PubMed ID28265055
PubMed Central IDPMC5358392
Grant ListR01 AI092573 / AI / NIAID NIH HHS / United States
T32 AI007621 / AI / NIAID NIH HHS / United States
U19 AI111143 / AI / NIAID NIH HHS / United States

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