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

Itaconate brings metalloenzyme to a halt Controlled radicals enable unusual enzymatic transformations, but radical generation and management require dedicated systems. Ruetz et al. investigated how the immunometabolite itaconate might undermine these intricate systems to inhibit propionate metabolism, a crucial metabolic pathway in pathogenic Mycobacterium tuberculosis (Mtb) (see the Perspective by Boal). They found that the coenzyme A (CoA) derivative of itaconate can irreversibly inhibit the enzyme methylmalonyl-CoA mutase (MCM), which uses the radical-generating cofactor adenosylcobalamin, or coenzyme B 12 . Itaconyl-CoA derails the normal radical reaction catalyzed by MCM, forming a long-lived, biradical species, which is incapable of completing the catalytic cycle and cannot be recycled by the endogenous coenzyme B 12 regeneration machinery. Itaconate blocks Mtb growth on propionate, and this inhibition mechanism may be relevant to how macrophages resist Mtb infection. Science , this issue p. 589 ; see also p. 574