Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109, USA.
Department of Chemistry, University of Michigan, Ann Arbor, MI 48109, USA.
Science. 2019 Nov 1;366(6465):589-593. doi: 10.1126/science.aay0934.
Itaconate is an immunometabolite with both anti-inflammatory and bactericidal effects. Its coenzyme A (CoA) derivative, itaconyl-CoA, inhibits B-dependent methylmalonyl-CoA mutase (MCM) by an unknown mechanism. We demonstrate that itaconyl-CoA is a suicide inactivator of human and MCM, which forms a markedly air-stable biradical adduct with the 5'-deoxyadenosyl moiety of the B 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 MCM catalysis. Mycobacterial MCM thus joins enzymes in the glyoxylate shunt and the methylcitrate cycle as targets of itaconate in pathogen propionate metabolism.
衣康酸是一种具有抗炎和杀菌作用的免疫代谢物。它的辅酶 A（CoA）衍生物衣康酰-CoA 通过未知机制抑制 B 依赖性甲基丙二酰辅酶 A 变位酶（MCM）。我们证明衣康酰-CoA 是人和 MCM 的自杀失活剂，它与 B 辅酶的 5'-脱氧腺苷部分形成明显稳定的双自由基加合物。以这种方式终止催化循环会损害 MCM 与其辅助修复蛋白之间的通讯。抑制酶的晶体学和光谱学与位于三级碳中心自由基~6 埃的金属中心钴自由基一致，并为控制 MCM 催化过程中自由基轨迹提供了一种方法。分枝杆菌 MCM 因此与乙醛酸支路和甲基柠檬酸循环中的酶一起成为病原体丙酸代谢中衣康酸的靶标。
