1 Belozersky Institute of Physicochemical Biology, Lomonosov Moscow State University, Moscow, Russian Federation.
2 Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, Russian Federation.
Antioxid Redox Signal. 2019 Jun 1;30(16):1911-1947. doi: 10.1089/ars.2017.7311. Epub 2018 Oct 18.
This article develops a holistic view on production of reactive oxygen species (ROS) by 2-oxo acid dehydrogenase complexes. Recent Advances: Catalytic and structural properties of the complexes and their components evolved to minimize damaging effects of side reactions, including ROS generation, simultaneously exploiting the reactions for homeostatic signaling.
Side reactions of the complexes, characterized in vitro, are analyzed in view of protein interactions and conditions in vivo. Quantitative data support prevalence of the forward 2-oxo acid oxidation over the backward NADH oxidation in feeding physiologically significant ROS production by the complexes. Special focus on interactions between the active sites within 2-oxo acid dehydrogenase complexes highlights the central relevance of the complex-bound thiyl radicals in regulation of and signaling by complex-generated ROS. The thiyl radicals arise when dihydrolipoyl residues of the complexes regenerate FADH from the flavin semiquinone coproduced with superoxide anion radical in 1e oxidation of FADH by molecular oxygen.
Interaction of 2-oxo acid dehydrogenase complexes with thioredoxins (TRXs), peroxiredoxins, and glutaredoxins mediates scavenging of the thiyl radicals and ROS generated by the complexes, underlying signaling of disproportional availability of 2-oxo acids, CoA, and NAD in key metabolic branch points through thiol/disulfide exchange and medically important hypoxia-inducible factor, mammalian target of rapamycin (mTOR), poly (ADP-ribose) polymerase, and sirtuins. High reactivity of the coproduced ROS and thiyl radicals to iron/sulfur clusters and nitric oxide, peroxynitrite reductase activity of peroxiredoxins and transnitrosylating function of thioredoxin, implicate the side reactions of 2-oxo acid dehydrogenase complexes in nitric oxide-dependent signaling and damage.
本文从整体上研究了 2-氧代酸脱氢酶复合物产生活性氧（ROS）的机制。
该复合物及其组成部分的催化和结构特性经过演化，可以最小化副反应（包括 ROS 生成）的破坏性影响，同时利用这些反应进行体内平衡信号传递。
复合物的副反应在体内的蛋白相互作用和条件下进行了分析。定量数据支持正向 2-氧代酸氧化比反向 NADH 氧化更有利于复合物产生生理上有意义的 ROS。特别关注 2-氧代酸脱氢酶复合物内活性部位之间的相互作用，突出了复合物结合的硫基自由基在调节和信号传递中对复合物生成的 ROS 的核心重要性。当复合物的二氢乳酰残基从黄素半醌中再生 FADH 时，复合物结合的硫基自由基就会产生，黄素半醌是在分子氧 1e 氧化 FADH 时与超氧阴离子自由基共同产生的。
2-氧代酸脱氢酶复合物与硫氧还蛋白（TRX）、过氧化物酶和谷氧还蛋白的相互作用介导了复合物生成的硫基自由基和 ROS 的清除，这为关键代谢分支点上 2-氧代酸、CoA 和 NAD 的不成比例可用性的信号传递提供了基础，通过硫醇/二硫键交换和医学上重要的缺氧诱导因子、哺乳动物雷帕霉素靶蛋白（mTOR）、多聚（ADP-核糖）聚合酶和 sirtuins。共同产生的 ROS 和硫基自由基与铁/硫簇和一氧化氮的高反应性、过氧化物酶的过氧亚硝酸盐还原酶活性和硫氧还蛋白的转亚硝酰基功能，暗示了 2-氧代酸脱氢酶复合物的副反应在一氧化氮依赖的信号传递和损伤中起作用。
