Itaconyl-CoA forms a stable biradical in methylmalonyl-CoA mutase and derails its activity and repair.

ABSTRACT: Itaconate is an immunometabolite with both anti-inflammatory and bactericidal effects. Its coenzyme A (CoA) derivative, itaconyl-CoA, inhibits B₁₂-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 B₁₂ 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 ~6 angstroms away from the tertiary carbon-centered radical and suggest a means of controlling radical trajectories during MC

SUBMITTER: Ruetz M 

PROVIDER: S-EPMC7070230 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature