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Virulence of Mycobacterium tuberculosis depends on lipoamide dehydrogenase, a member of three multienzyme complexes.

TitleVirulence of Mycobacterium tuberculosis depends on lipoamide dehydrogenase, a member of three multienzyme complexes.
Publication TypeJournal Article
Year of Publication2011
AuthorsVenugopal A, Bryk R, Shi S, Rhee K, Rath P, Schnappinger D, Ehrt S, Nathan C
JournalCell Host Microbe
Volume9
Issue1
Pagination21-31
Date Published2011 Jan 20
ISSN1934-6069
KeywordsAmino Acids, Branched-Chain, Animals, Bacterial Load, Dihydrolipoamide Dehydrogenase, Disease Models, Animal, Lung, Macrophages, Mice, Mice, Inbred C57BL, Multienzyme Complexes, Mycobacterium tuberculosis, Spleen, Tuberculosis, Virulence, Virulence Factors
Abstract

Mycobacterium tuberculosis (Mtb) adapts to persist in a nutritionally limited macrophage compartment. Lipoamide dehydrogenase (Lpd), the third enzyme (E3) in Mtb's pyruvate dehydrogenase complex (PDH), also serves as E1 of peroxynitrite reductase/peroxidase (PNR/P), which helps Mtb resist host-reactive nitrogen intermediates. In contrast to Mtb lacking dihydrolipoamide acyltransferase (DlaT), the E2 of PDH and PNR/P, Lpd-deficient Mtb is severely attenuated in wild-type and immunodeficient mice. This suggests that Lpd has a function that DlaT does not share. When DlaT is absent, Mtb upregulates an Lpd-dependent branched-chain keto acid dehydrogenase (BCKADH) encoded by pdhA, pdhB, pdhC, and lpdC. Without Lpd, Mtb cannot metabolize branched-chain amino acids and potentially toxic branched-chain intermediates accumulate. Mtb deficient in both DlaT and PdhC phenocopies Lpd-deficient Mtb. Thus, Mtb critically requires BCKADH along with PDH and PNR/P for pathogenesis. These findings position Lpd as a potential target for anti-infectives against Mtb.

DOI10.1016/j.chom.2010.12.004
Alternate JournalCell Host Microbe
PubMed ID21238944
PubMed Central IDPMC3040420
Grant ListR21 AI081094 / AI / NIAID NIH HHS / United States
R01 AI064768-04 / AI / NIAID NIH HHS / United States
R01 AI064768-05 / AI / NIAID NIH HHS / United States
R01 AI064768-01 / AI / NIAID NIH HHS / United States
R01 AI064768-03 / AI / NIAID NIH HHS / United States
R01 AI064768 / AI / NIAID NIH HHS / United States
R01 AI064768-02 / AI / NIAID NIH HHS / United States

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