Virulence of Mycobacterium tuberculosis depends on lipoamide dehydrogenase, a member of three multienzyme complexes.
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.
Department of Microbiology and Immunology, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA.
Aditya
A
Venugopal
Ruslana
R
Bryk
Shuangping
S
Shi
Kyu
K
Rhee
Poonam
P
Rath
Dirk
D
Schnappinger
Sabine
S
Ehrt
Carl
C
Nathan
D000597:Amino Acids, Branched-Chain / Q000378:metabolism; D000818:Animals; D058491:Bacterial Load; D008058:Dihydrolipoamide Dehydrogenase / Q000172:deficiency / Q000378:metabolism*; D004195:Disease Models, Animal; D008168:Lung / Q000382:microbiology; D008264:Macrophages / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009097:Multienzyme Complexes / Q000172:deficiency / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000472:pathogenicity*; D013154:Spleen / Q000382:microbiology; D014376:Tuberculosis / Q000382:microbiology / Q000473:pathology; D014774:Virulence; D037521:Virulence Factors / Q000172:deficiency / Q000378:metabolism*
D000597:Amino Acids, Branched-Chain; D009097:Multienzyme Complexes; D037521:Virulence Factors; D008058:Dihydrolipoamide Dehydrogenase
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