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 mitochondrial 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 (Tyr-244) play in the catalytic function of CcO are of particular interest.
| Collman, James P; Ghosh, Somdatta (2010) Recent applications of a synthetic model of cytochrome c oxidase: beyond functional modeling. Inorg Chem 49:5798-810 |
| Collman, James P; Ghosh, Somdatta; Dey, Abhishek et al. (2009) Using a functional enzyme model to understand the chemistry behind hydrogen sulfide induced hibernation. Proc Natl Acad Sci U S A 106:22090-5 |
| Collman, James P; Ghosh, Somdatta; Dey, Abhishek et al. (2009) Catalytic reduction of O2 by cytochrome C using a synthetic model of cytochrome C oxidase. J Am Chem Soc 131:5034-5 |
| Collman, James P; Dey, Abhishek; Yang, Ying et al. (2009) O2 reduction by a functional heme/nonheme bis-iron NOR model complex. Proc Natl Acad Sci U S A 106:10528-33 |
| Collman, James P; Decréau, Richard A; Lin, Hengwei et al. (2009) Role of a distal pocket in the catalytic O2 reduction by cytochrome c oxidase models immobilized on interdigitated array electrodes. Proc Natl Acad Sci U S A 106:7320-3 |
| Collman, James P; Dey, Abhishek; Barile, Christopher J et al. (2009) Inhibition of electrocatalytic O(2) reduction of functional CcO models by competitive, non-competitive, and mixed inhibitors. Inorg Chem 48:10528-34 |
| Collman, James P; Decreau, Richard A; Dey, Abhishek et al. (2009) Water may inhibit oxygen binding in hemoprotein models. Proc Natl Acad Sci U S A 106:4101-5 |
| Collman, James P; Dey, Abhishek; Decreau, Richard A et al. (2008) Model studies of azide binding to functional analogues of CcO. Inorg Chem 47:2916-8 |
| Collman, James P; Decreau, Richard A (2008) Functional biomimetic models for the active site in the respiratory enzyme cytochrome c oxidase. Chem Commun (Camb) :5065-76 |
| Collman, James P; Dey, Abhishek; Decreau, Richard A et al. (2008) Interaction of nitric oxide with a functional model of cytochrome c oxidase. Proc Natl Acad Sci U S A 105:9892-6 |
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