近日，美国密歇根大学Ruma Banerjee研究组最新研究，揭示了衣康酰-CoA在甲基丙二酰-CoA变位酶中形成稳定的双自由基，破坏其活性和修复作用。 该研究发表在11月1日出版的国际学术期刊《科学》上。
研究人员证实衣康酰-CoA是人类和结核分枝杆菌甲基丙二酰CoA变位酶（MCM）的自灭活剂，它与B12辅酶的5'-脱氧腺苷基团形成空气条件下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及其辅助修复蛋白之间的连接。
抑制酶的晶体学和光谱学显示其与距叔碳中心自由基约6埃的钴自由基金属中心一致，并提出了在MCM催化过程中控制自由基轨迹的方法。 因此，分枝杆菌MCM将乙醛酸循环和柠檬酸甲酯循环中的酶作为衣康酸酯在病原体丙酸酯代谢中的靶标。
据悉，衣康酸酯是具有抗炎和杀菌作用的免疫代谢产物。 它的辅酶A（CoA）衍生物衣康酰-CoA通过未知机制抑制B12依赖性甲基丙二酰CoA变位酶。
附：英文原文
Title: Itaconyl-CoA forms a stable biradical in methylmalonyl-CoA mutase and derails its activity and repair
Author: Markus Ruetz, Gregory C. Campanello, Meredith Purchal, Hongying Shen, Liam McDevitt, Harsha Gouda, Shoko Wakabayashi, Junhao Zhu, Eric J. Rubin, Kurt Warncke, Vamsi K. Mootha, Markos Koutmos, Ruma Banerjee
Issue&Volume: 2019/11/01
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 MCM catalysis. Mycobacterial MCM thus joins enzymes in the glyoxylate shunt and the methylcitrate cycle as targets of itaconate in pathogen propionate metabolism.
DOI: 10.1126/science.aay0934
Source: https://science.sciencemag.org/content/366/6465/589