Proton-pumping mechanism of cytochrome C oxidase.

Cytochrome c oxidase (CcO), as the terminal oxidase of cellular respiration, coupled with a proton-pumping process, reduces molecular oxygen (O(2)) to water. This intriguing and highly organized chemical process represents one of the most critical aspects of cellular respiration. It employs transition metals (Fe and Cu) at the O(2) reduction site and has been considered one of the most challenging research subjects in life science. Extensive X-ray structural and mutational analyses have provided two different proposals with regard to the mechanism of proton pumping. One mechanism is based on bovine CcO and includes an independent pathway for the pumped protons. The second mechanistic proposal includes a common pathway for the pumped and chemical protons and is based upon bacterial CcO. Here, recent progress in experimental evaluations of these proposals is reviewed and strategies for improving our understanding of the mechanism of this physiologically important process are discussed.