title: A dynamic model of nitric oxide inhibition of mitochondrial cytochrome c oxidase.
abstract: Nitric oxide can inhibit mitochondrial cytochrome oxidase in both oxygen competitive and uncompetitive modes. A previous model described these interactions assuming equilibrium binding to the reduced and oxidised enzyme respectively (Mason, et al. Proc. Natl. Acad. Sci. U S A 103 (2006) 708-713). Here we demonstrate that the equilibrium assumption is inappropriate as it requires unfeasibly high association constants for NO to the oxidised enzyme. Instead we develop a model which explicitly includes NO binding and its enzyme-bound conversion to nitrite. Removal of the nitrite complex requires electron transfer to the binuclear centre from haem a. This revised model fits the inhibition constants at any value of substrate concentration (ferrocytochrome c or oxygen). It predicts that the inhibited steady state should be a mixture of the reduced haem nitrosyl complex and the oxidized-nitrite complex. Unlike the previous model, binding to the oxidase is always proportional to the degree of inhibition of oxygen consumption. The model is consistent with data and models from a recent paper suggesting that the primary effect of NO binding to the oxidised enzyme is to convert NO to nitrite, rather than to inhibit enzyme activity (Antunes et al. Antioxid. Redox Signal. 9 (2007) 1569-1579).
authors.affiliation: Department of Biological Sciences, University of Essex, Wivenhoe Park, Colchester, CO4 3SQ, UK. ccooper@essex.ac.uk
authors.forename: Chris E
authors.initials: CE
authors.lastname: Cooper
authors.forename: Maria G
authors.initials: MG
authors.lastname: Mason
authors.forename: Peter
authors.initials: P
authors.lastname: Nicholls
mesh_terms: D004579:Electron Transport; D003576:Electron Transport Complex IV / Q000378:metabolism*; D007700:Kinetics; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology*; D008954:Models, Biological; D009569:Nitric Oxide / Q000494:pharmacology*; D010101:Oxygen Consumption
chemical_list: D009569:Nitric Oxide; D003576:Electron Transport Complex IV