Itaconate brings metalloenzyme to a halt

Abstract

Radical Enzymes 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 B12. 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 B12 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][1]; see also p. [574][2] [1]: /lookup/doi/10.1126/science.aay0934 [2]: /lookup/doi/10.1126/science.aaz4540