Challenges in elucidating structure and mechanism

Authors: Volker Zickermann Stefan Dröse Maja A Tocilescu Klaus Zwicker Stefan Kerscher Ulrich Brandt

Publish Date: 2008/11/04

Volume: 40, Issue: 5, Pages: 475-

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Abstract

Proton pumping NADHubiquinone oxidoreductase complex I is the most complicated and least understood enzyme of the respiratory chain All redox prosthetic groups reside in the peripheral arm of the Lshaped structure The NADH oxidation domain harbouring the FMN cofactor is connected via a chain of iron–sulfur clusters to the ubiquinone reduction site that is located in a large pocket formed by the PSST and 49kDa subunits of complex I An access path for ubiquinone and different partially overlapping inhibitor binding regions were defined within this pocket by site directed mutagenesis A combination of biochemical and single particle analysis studies suggests that the ubiquinone reduction site is located well above the membrane domain Therefore direct coupling mechanisms seem unlikely and the redox energy must be converted into a conformational change that drives proton pumping across the membrane arm It is not known which of the subunits and how many are involved in proton translocation Complex I is a major source of reactive oxygen species ROS that are predominantly formed by electron transfer from FMNH2 Mitochondrial complex I can cycle between active and deactive forms that can be distinguished by the reactivity towards divalent cations and thiolreactive agents The physiological role of this phenomenon is yet unclear but it could contribute to the regulation of complex I activity invivo

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