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REDOX-DRIVEN SIGNALING: 2-OXO ACID DEHYDROGENASE COMPLEXES AS SENSORS AND TRANSMITTERS OF METABOLIC IMBALANCE.

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.

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