Journal
SCIENCE
Volume 366, Issue 6465, Pages 589-+Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aay0934
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Funding
- National Institutes of Health [RO1-DK45776, 5 F32 GM113405, K99-GM124296, R35GM122455, R01-DK054514, U19AI107774]
- University of Michigan
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Itaconate is an immunometabolite with both anti-inflammatory and bactericidal effects. Its coenzyme A (CoA) derivative, itaconyl-CoA, inhibits B-12-dependent methylmalonyl-CoA mutase (MCM) by an unknown mechanism. We demonstrate that itaconyl-CoA is a suicide inactivator of human and Mycobacterium tuberculosis MCM, which forms a markedly air-stable biradical adduct with the 5'-deoxyadenosyl moiety of the B-12 coenzyme. Termination of the catalytic cycle in this way impairs communication between MCM and its auxiliary repair proteins. Crystallography and spectroscopy of the inhibited enzyme are consistent with a metal-centered cobalt radical similar to 6 angstroms away from the tertiary carbon-centered radical and suggest a means of controlling radical trajectories during MCM catalysis. Mycobacterial MCM thus joins enzymes in the glyoxylate shunt and the methylcitrate cycle as targets of itaconate in pathogen propionate metabolism.
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