Title | Glyoxylate detoxification is an essential function of malate synthase required for carbon assimilation in Mycobacterium tuberculosis. |
Publication Type | Journal Article |
Year of Publication | 2017 |
Authors | Puckett S, Trujillo C, Wang Z, Eoh H, Ioerger TR, Krieger I, Sacchettini J, Schnappinger D, Rhee KY, Ehrt S |
Journal | Proc Natl Acad Sci U S A |
Volume | 114 |
Issue | 11 |
Pagination | E2225-E2232 |
Date Published | 2017 03 14 |
ISSN | 1091-6490 |
Keywords | Animals, 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. |
DOI | 10.1073/pnas.1617655114 |
Alternate Journal | Proc Natl Acad Sci U S A |
PubMed ID | 28265055 |
PubMed Central ID | PMC5358392 |
Grant List | R01 AI092573 / AI / NIAID NIH HHS / United States T32 AI007621 / AI / NIAID NIH HHS / United States U19 AI111143 / AI / NIAID NIH HHS / United States |
Submitted by wcm_microbiolog... on October 15, 2020 - 2:10pm