Why copper is preferred over iron for oxygen activation and reduction in haem-copper oxidases

Abstract

Heme-copper oxidase (HCO) catalyzes the natural reduction of oxygen to water using a heme-copper center. Despite decades of research on HCO's, the role of nonheme metal and Nature's choice of copper over other metals like iron remains unclear. Here, we use a biosynthetic model of HCO in myoglobin that selectively binds different nonheme metals to demonstrate 30-fold and 11-fold enhancements in oxidase activity of Cu- and Fe-bound HCO mimics respectively, as compared to Zn-bound mimics. Detailed electrochemical, kinetic and vibrational spectroscopic studies, in tandem with theoretical DFT calculations demonstrate that the nonheme metal not only donates electrons to oxygen but also activates it for efficient O-O bond cleavage. Furthermore, the higher redox potential of copper and the enhanced weakening of O-O bond from the higher electron density in the d-orbital of copper are central to its higher oxidase activity over iron. This work resolves a long-standing question in bioenergetics, and renders a chemical-biological basis for designing future oxygen reduction catalysts.