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A Quinol Anion as Catalytic Intermediate Coupling Proton Translocation With Electron Transfer in E. coli Respiratory Complex I.

ABSTRACT: Energy-converting NADH:ubiquinone oxidoreductase, respiratory complex I, plays a major role in cellular energy metabolism. It couples NADH oxidation and quinone reduction with the translocation of protons across the membrane, thus contributing to the protonmotive force. Complex I has an overall L-shaped structure with a peripheral arm catalyzing electron transfer and a membrane arm engaged in proton translocation. Although both reactions are arranged spatially separated, they are tightly coupled by a mechanism that is not fully understood. Using redox-difference UV-vis spectroscopy, an unknown redox component was identified in Escherichia coli complex I as reported earlier. A comparison of its spectrum with those obtained for different quinone species indicates features of a quinol anion. The re-oxidation kinetics of the quinol anion intermediate is significantly slower in the D213G^H variant that was previously shown to operate with disturbed quinone chemistry. Addition of the quinone-site inhibitor piericidin A led to strongly decreased absorption peaks in the difference spectrum. A hypothesis for a mechanism of proton-coupled electron transfer with the quinol anion as catalytically important intermediate in complex I is discussed.

SUBMITTER: Nuber F

PROVIDER: S-EPMC8138167 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Despite advances in hydrogen atom transfer (HAT) catalysis, there are currently no molecular HAT catalysts that are capable of homolysing the strong nitrogen-hydrogen (N-H) bonds of N-alkyl amides. The motivation to develop amide homolysis protocols stems from the utility of the resultant amidyl radicals, which are involved in various synthetically useful transformations, including olefin amination and directed carbon-hydrogen (C-H) bond functionalization. In the latter process-a subset of the classical Hofmann-Löffler-Freytag reaction-amidyl radicals remove hydrogen atoms from unactivated aliphatic C-H bonds. Although powerful, these transformations typically require oxidative N-prefunctionalization of the amide starting materials to achieve efficient amidyl generation. Moreover, because these N-activating groups are often incorporated into the final products, these methods are generally not amenable to the direct construction of carbon-carbon (C-C) bonds. Here we report an approach that overcomes these limitations by homolysing the N-H bonds of N-alkyl amides via proton-coupled electron transfer. In this protocol, an excited-state iridium photocatalyst and a weak phosphate base cooperatively serve to remove both a proton and an electron from an amide substrate in a concerted elementary step. The resultant amidyl radical intermediates are shown to promote subsequent C-H abstraction and radical alkylation steps. This C-H alkylation represents a catalytic variant of the Hofmann-Löffler-Freytag reaction, using simple, unfunctionalized amides to direct the formation of new C-C bonds. Given the prevalence of amides in pharmaceuticals and natural products, we anticipate that this method will simplify the synthesis and structural elaboration of amine-containing targets. Moreover, this study demonstrates that concerted proton-coupled electron transfer can enable homolytic activation of common organic functional groups that are energetically inaccessible using traditional HAT-based approaches.

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A Quinol Anion as Catalytic Intermediate Coupling Proton Translocation With Electron Transfer in E. coli Respiratory Complex I.

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