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Modeling the detailed kinetics of mitochondrial cytochrome c oxidase: Catalytic mechanism and nitric oxide inhibition. J Appl Physiol (1985) 2016 Nov 01;121(5):1196-1207

Date

09/17/2016

Pubmed ID

27633738

Pubmed Central ID

PMC5142251

DOI

10.1152/japplphysiol.00524.2016

Scopus ID

2-s2.0-85021095865 (requires institutional sign-in at Scopus site)   25 Citations

Abstract

Cytochrome c oxidase (CcO) catalyzes the exothermic reduction of O2 to H2O by using electrons from cytochrome c, and hence plays a crucial role in ATP production. Although details on the enzyme structure and redox centers involved in O2 reduction have been known, there still remains a considerable ambiguity on its mechanism of action, e.g., the number of sequential electrons donated to O2 in each catalytic step, the sites of protonation and proton pumping, and nitric oxide (NO) inhibition mechanism. In this work, we developed a thermodynamically constrained mechanistic mathematical model for the catalytic action of CcO based on available kinetic data. The model considers a minimal number of redox centers on CcO and couples electron transfer and proton pumping driven by proton motive force (PMF), and accounts for the inhibitory effects of NO on the reaction kinetics. The model is able to fit well all the available kinetic data under diverse experimental conditions with a physiologically realistic unique parameter set. The model predictions show that: 1) the apparent Km of O2 varies considerably and increases from fully reduced to fully oxidized cytochrome c depending on pH and the energy state of mitochondria, and 2) the intermediate enzyme states depend on pH and cytochrome c redox fraction and play a central role in coupling mitochondrial respiration to PMF. The developed CcO model can easily be integrated into existing mitochondrial bioenergetics models to understand the role of the enzyme in controlling oxidative phosphorylation in normal and disease conditions.

Author List

Pannala VR, Camara AK, Dash RK

Authors

Amadou K. Camara PhD Professor in the Anesthesiology department at Medical College of Wisconsin
Ranjan K. Dash PhD Professor in the Biomedical Engineering department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Catalysis
Cell Respiration
Electron Transport
Electron Transport Complex IV
Hydrogen-Ion Concentration
Kinetics
Mitochondria
Models, Biological
Nitric Oxide
Oxidation-Reduction
Oxidative Phosphorylation
Oxygen
Protons
Thermodynamics