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J. Biol. Chem., Vol. 281, Issue 50, 38459-38465, December 15, 2006

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Similar Transition States Mediate the Q-cycle and Superoxide Production by the Cytochrome bc₁ Complex^*

Isaac Forquer, Raul Covian, Michael K. Bowman^¶, Bernard L. Trumpower, and David M. Kramer¹

From the Institute of Biological Chemistry, Washington State University, Pullman, Washington 99164-6340, the Department of Biochemistry, Dartmouth Medical School, Hanover, New Hampshire 03755, and ^¶Structural Biology and Microimaging, Battelle Northwest Laboratory, Richland, Washington 99352-0999

The cytochrome bc complexes found in mitochondria, chloroplasts and many bacteria play critical roles in their respective electron transport chains. The quinol oxidase (Q_o) site in this complex oxidizes a hydroquinone (quinol), reducing two one-electron carriers, a low potential cytochrome b heme and the "Rieske" iron-sulfur cluster. The overall electron transfer reactions are coupled to transmembrane translocation of protons via a "Q-cycle" mechanism, which generates proton motive force for ATP synthesis. Since semiquinone intermediates of quinol oxidation are generally highly reactive, one of the key questions in this field is: how does the Q_o site oxidize quinol without the production of deleterious side reactions including superoxide production? We attempt to test three possible general models to account for this behavior: 1) The Q_o site semiquinone (or quinol-imidazolate complex) is unstable and thus occurs at a very low steady-state concentration, limiting O₂ reduction; 2) the Q_o site semiquinone is highly stabilized making it unreactive toward oxygen; and 3) the Q_o site catalyzes a quantum mechanically coupled two-electron/two-proton transfer without a semiquinone intermediate. Enthalpies of activation were found to be almost identical between the uninhibited Q-cycle and superoxide production in the presence of antimycin A in wild type. This behavior was also preserved in a series of mutants with altered driving forces for quinol oxidation. Overall, the data support models where the rate-limiting step for both Q-cycle and superoxide production is essentially identical, consistent with model 1 but requiring modifications to models 2 and 3.

Received for publication, May 30, 2006 , and in revised form, September 14, 2006.

^* This work was supported by NIGMS/National Institutes of Health (NIH) Grant GM61904 (to M. K. B.), NIGMS/NIH Grant GM 20379 (to B. L. T.), and United States Department of Energy Grant DE-FG02-04ER1559 (to D. M. K.). Part of this work was performed at the WR Wiley Environmental Molecular Sciences Laboratory, a national scientific user facility sponsored by the United States Department of Energy's Office of Biological and Environmental Research and located at Pacific Northwest National Laboratory, operated by Battelle for the United States Department of Energy. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Institute of Biological Chemistry, Washington State University, 299 Clark Hall, Pullman, WA 99164-6340. Tel.: 509-335-4964; Fax: 509-335-7643; E-mail: dkramer{at}wsu.edu.

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