The overall aim of this proposal is to understand catalysis in the cytochrome (cyt) bc1 membrane protein complexes. This is a part of our larger goal of understanding the multiple biological roles of these membrane proteins in humans, pathogens and pathological processes. The main biological role of cyt bc1 is in energy transduction in the mitochondrion. It couples electron transport to the transduction of protons across a membrane in a reaction scheme known as the Q-cycle, thereby helping establish a proton gradient or proton motive force (pmf) to drive ATP synthesis. There are also controversial claims that cyt bc1 is a culprit in aging and a number of diseases and pathophysiological processes by directly generating superoxide (SO) and driving production of peroxide, hydroxyl radicals and peroxynitrite. Several conflicting models of how these complexes function have been proposed, differing in the details of the electron transfers, chemical reactions, intermediates, and even the structure of the active enzyme substrate complex. Resolution of these conflicts is crucial for understanding the basis of normal function and SO production by the complex. Although a number of crystal structures of the cyt bc1 complex of mitochondria and the related cyt b6f from chloroplasts have been published, none show the substrate quinol in the oxidative active site, leaving open the specific reactions that occur at this site. Under certain conditions, cyt bc1 can divert up to half the electrons that flow through it into SO. The mechanism of SO production is very closely related to its normal physiological reactions. This proposal puts forth a set of Specific Aims that, taken together, will advance our understanding of: a) the role of semiquinone as an intermediate in the catalytic oxidation of quinol by cyt bc1; b) the overall reaction mechanism in cyt bc1; and c) whether cyt bc1 can play a role in human diseases through production of SO. ? ? ?
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