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Proc Natl Acad Sci U S A. 2017 Mar 14;114(11):E2225-E2232. doi: 10.1073/pnas.1617655114. Epub 2017 Mar 6.

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

Author information

1
Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY 10021.
2
Department of Medicine, Weill Cornell Medical College, New York, NY 10021.
3
Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843.
4
Department of Medicine, Weill Cornell Medical College, New York, NY 10021; sae2004@med.cornell.edu kyr9001@med.cornell.edu.
5
Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY 10021; sae2004@med.cornell.edu kyr9001@med.cornell.edu.

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.

KEYWORDS:

glyoxylate detoxification; malate synthase; metabolism; tuberculosis

PMID:
28265055
PMCID:
PMC5358392
DOI:
10.1073/pnas.1617655114
[Indexed for MEDLINE]
Free PMC Article

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