Cytochrome C Oxidase - Structure

Structure

The complex is a large integral membrane protein composed of several metal prosthetic sites and 13 protein subunits in mammals. In mammals, ten subunits are nuclear in origin, and three are synthesized in the mitochondria. The complex contains two hemes, a cytochrome a and cytochrome a₃, and two copper centers, the Cu_A and Cu_B centers. In fact, the cytochrome a₃ and Cu_B form a binuclear center that is the site of oxygen reduction. Cytochrome c which is reduced by the preceding component of the respiratory chain, (cytochrome bc1 complex, complex III) and docks near the Cu_A binuclear center, passing an electron to it and being oxidized back to cytochrome c containing Fe3+. The reduced Cu_A binuclear center now passes an electron on to cytochrome a, which in turn passes an electron on to the cytochrome a₃- Cu_B binuclear center. The two metal ions in this binuclear center are 4.5 Å apart and coordinate a hydroxide ion in the fully oxidized state.

Crystallographic studies of cytochrome c oxidase show an unusual post-translational modification, linking C6 of Tyr(244) and the ε-N of His(240) (bovine enzyme numbering). It plays a vital role in enabling the cytochrome a₃- Cu_B binuclear center to accept four electrons in reducing molecular oxygen to water. The mechanism of reduction was formerly thought to involve a peroxide intermediate, which was believed to lead to superoxide production. However, the currently accepted mechanism involves a rapid four-electron reduction involving immediate oxygen-oxygen bond cleavage, avoiding any intermediate likely to form superoxide.