ubiquinol and 3-methoxy-2-(2-styrylphenyl)propenic-acid-methyl-ester

The unique bifurcated oxidation of ubiquinol at center P (Qo) of the cytochrome bc1 complex is the reaction within the Q-cycle reaction scheme that is most critical for the link between electron transfer and vectorial proton translocation. While there is a general consensus about the overall reaction at center P, the nature of the intermediates and the way the reaction is controlled to ensure obligatory bifurcation is still controversial. By reducing the reaction to its essential steps, a kinetic net rate model is developed in which the activation barrier is associated with the deprotonation of ubiquinol, but the steady state rate is kinetically controlled by the occupancy of the ubiquinol anion and the semiquinone state. This concept is used to interpret experimental data and is discussed in terms of various mechanistic models that are under discussion. It is outlined how other aspects of the center P mechanism like the proposed "prosthetic" ubiquinone and the moving domain of the "Rieske" protein could be incorporated in the kinetic framework.

Topics: Animals; Electron Transport; Electron Transport Complex III; Enzyme Inhibitors; Heme; Iron-Sulfur Proteins; Mitochondria; Models, Chemical; Models, Molecular; Motion; Protein Conformation; Protein Structure, Tertiary; Protons; Stilbenes; Structure-Activity Relationship; Thermodynamics; Ubiquinone

Native structures of ubihydroquinone:cytochrome c oxidoreductase (bc(1) complex) from different sources, and structures with inhibitors in place, show a 16-22 A displacement of the [2Fe-2S] cluster and the position of the C-terminal extrinsic domain of the iron sulfur protein. None of the structures shows a static configuration that would allow catalysis of all partial reactions of quinol oxidation. We have suggested that the different conformations reflect a movement of the subunit necessary for catalysis. The displacement from an interface with cytochrome c(1) in native crystals to an interface with cytochrome b is induced by stigmatellin or 5-n-undecyl-6-hydroxy-4,7-dioxobenzothiazole (UHDBT) and involves ligand formation between His-161 of the [2Fe-2S] binding cluster and the inhibitor. The movement is a rotational displacement, so that the same conserved docking surface on the iron sulfur protein interacts with cytochrome c(1) and with cytochrome b. The mobile extrinsic domain retains essentially the same tertiary structure, and the anchoring N-terminal tail remains in the same position. The movement occurs through an extension of a helical segment in the short linking span. We report details of the protein structure for the two main configurations in the chicken heart mitochondrial complex and discuss insights into mechanism provided by the structures and by mutant strains in which the docking at the cytochrome b interface is impaired. The movement of the iron sulfur protein represents a novel mechanism of electron transfer, in which a tethered mobile head allows electron transfer through a distance without the entropic loss from free diffusion.

Topics: Amino Acid Sequence; Animals; Anti-Bacterial Agents; Binding Sites; Chickens; Computer Simulation; Crystallography; Cytochrome b Group; Electron Transport Complex III; Enzyme Inhibitors; Iron-Sulfur Proteins; Ligands; Mitochondria, Heart; Molecular Sequence Data; Mutation; Oxidation-Reduction; Polyenes; Protein Engineering; Protein Structure, Secondary; Sequence Alignment; Stilbenes; Thiazoles; Ubiquinone