Functional Active-Site Models of Cytochrome c Oxidase

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DESCRIPTION (provided by applicant): Most of the energy in our bodies is generated within the mitochondria by a respiratory process called oxidative phosphorylation. This energy derives from the activation and reduction of dioxygen. This four-electron reduction process is catalyzed by the terminal respiratory enzyme, cytochrome c oxidase (CcO). Important medical disorders are related to oxygen/energy metabolism. Oxidative stress is important in the pathology of many diseases, such as those of the nervous system, Alzheimer's disease, stroke, cardiovascular disorders, and cell death. The reactive oxygen species, which cause inflammation and cell damage, are primarily formed during mitochondria! metabolism. Over 95 percent of the oxygen consumed by humans is used in respiration. In the mitochondria, reducing equivalents (electrons) derived enzymatically from food, react with dioxygen in a series of electron-transfer reactions to develop a proton gradient that ultimately produces ATP, the biological energy currency. Energy releasing electron/proton transfers to molecular oxygen are coupled to the transfer of other protons across the mitochondrial membrane. Subsequent relaxation of this proton gradient through ATPase provides energy storage in ATP. This 4-electron reduction of dioxygen occurs at remarkably fast rates; up to 250 dioxygen molecules (1000 electrons) can be transformed per second. This project is directed towards the invention and synthesis of compounds that imitate the active site in CcO. These compounds, which have a heme and a copper in close proximity, are intended to function like the enzyme by catalyzing the electrochemical reduction of molecular oxygen under physiological conditions without releasing reactive oxygen species such as superoxide and hydrogen peroxide. Through careful study of the mechanisms by which these synthetic, functional enzyme-mimics, reduce dioxygen, we intend to gain an understanding of the mechanisms that describe the function of the enzyme itself. The role that the copper ion (CuB) and a phenolic group, in the amino acid tyrosine (Tyr244) play in the catalytic function of CcO are of particular interest.