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1 Department of Biological Sciences, University of Essex, Colchester, Essex, United Kingdom
2 Molecular Biosciences, University of California, Davis, California, United States
* To whom correspondence should be addressed. E-mail: ccooper{at}essex.ac.uk.
Nitric oxide (NO) is an intercellular signaling molecule; amongst its many and varied roles are the control of blood flow and blood pressure via activation of the heme enzyme, soluble guanylate cyclase. A growing body of evidence suggests that an additional target for NO is the mitochondrial oxygen consuming heme/copper enzyme, cytochrome c oxidase. This review describes the molecular mechanism of this interaction and its consequence for its likely physiological role. The oxygen reactive site in cytochrome oxidase contains both heme iron (a3) and copper (CuB) centers. NO inhibits cytochrome oxidase in both an oxygen competitive (at heme a3) and oxygen independent (at CuB) manner. Prior to inhibition of oxygen consumption changes can be observed in enzyme and substrate (cytochrome c) redox state changes. Physiological consequences can be mediated either by direct "metabolic" effects on oxygen consumption or via indirect "signaling" effects via mitochondrial redox state changes and free radical production. The detailed kinetics suggest, but do not prove, that cytochrome oxidase can be a target for NO even under circumstances when guanylate cyclase, its primary high affinity target, is not fully activated. In vivo organ and whole body measures of nitric oxide synthase inhibition suggest a possible role for NO inhibition of cytochrome oxidase. However, a detailed mapping of NO and oxygen levels, combined with direct measures of cytochrome oxidase/NO binding in physiology is still awaited.
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