Redox-Driven Signaling: 2-Oxo Acid Dehydrogenase Complexes as Sensors and Transmitters of Metabolic Imbalanceстатья
Статья опубликована в высокорейтинговом журнале
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Статья опубликована в журнале из списка Web of Science и/или Scopus
Дата последнего поиска статьи во внешних источниках: 4 сентября 2019 г.
Аннотация:SIGNIFICANCE:The paper 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.
CRITICAL ISSUES:
Side reactions of the complexes, characterized in vitro, are analysed 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 FADH2 from the flavin semiquinone co-produced with superoxide anion radical in 1e- oxidation of FADH2 by molecular oxygen.
FUTURE DIRECTIONS:
Interaction of 2-oxo acid dehydrogenase complexes with thioredoxins, 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 HIF, mTOR, PARP and sirtuins. High reactivity of the co-produced ROS and thiyl radicals to iron-sulfur clusters and nitric oxide, peroxynitrite reductase activity of peroxyredoxins and transnitrosylating function of thioredoxin, implicate the side reactions of 2-oxo acid dehydrogenase complexes in nitric-oxide-dependent signaling and damage.