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E1 of α-ketoglutarate dehydrogenase defends Mycobacterium tuberculosis against glutamate anaplerosis and nitroxidative stress.

TitleE1 of α-ketoglutarate dehydrogenase defends Mycobacterium tuberculosis against glutamate anaplerosis and nitroxidative stress.
Publication TypeJournal Article
Year of Publication2015
AuthorsMaksymiuk C, Balakrishnan A, Bryk R, Rhee KY, Nathan C
JournalProc Natl Acad Sci U S A
Volume112
Issue43
PaginationE5834-43
Date Published2015 Oct 27
ISSN1091-6490
KeywordsAnimals, Glutamic Acid, Ketoglutarate Dehydrogenase Complex, Mice, Mice, Inbred C57BL, Mycobacterium tuberculosis, Nitrosation, Oxidative Stress
Abstract

Enzymes of central carbon metabolism (CCM) in Mycobacterium tuberculosis (Mtb) make an important contribution to the pathogen's virulence. Evidence is emerging that some of these enzymes are not simply playing the metabolic roles for which they are annotated, but can protect the pathogen via additional functions. Here, we found that deficiency of 2-hydroxy-3-oxoadipate synthase (HOAS), the E1 component of the α-ketoglutarate (α-KG) dehydrogenase complex (KDHC), did not lead to general metabolic perturbation or growth impairment of Mtb, but only to the specific inability to cope with glutamate anaplerosis and nitroxidative stress. In the former role, HOAS acts to prevent accumulation of aldehydes, including growth-inhibitory succinate semialdehyde (SSA). In the latter role, HOAS can participate in an alternative four-component peroxidase system, HOAS/dihydrolipoyl acetyl transferase (DlaT)/alkylhydroperoxide reductase colorless subunit gene (ahpC)-neighboring subunit (AhpD)/AhpC, using α-KG as a previously undescribed source of electrons for reductase action. Thus, instead of a canonical role in CCM, the E1 component of Mtb's KDHC serves key roles in situational defense that contribute to its requirement for virulence in the host. We also show that pyruvate decarboxylase (AceE), the E1 component of pyruvate dehydrogenase (PDHC), can participate in AceE/DlaT/AhpD/AhpC, using pyruvate as a source of electrons for reductase action. Identification of these systems leads us to suggest that Mtb can recruit components of its CCM for reactive nitrogen defense using central carbon metabolites.

DOI10.1073/pnas.1510932112
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID26430237
PubMed Central IDPMC4629369
Grant ListR01 AI064768 / AI / NIAID NIH HHS / United States
R01AI64768 / AI / NIAID NIH HHS / United States