Heme-copper and Heme O2-derived synthetic (bioinorganic) chemistry toward an understanding of cytochrome c oxidase dioxygen chemistry

Abstract

Cytochrome c oxidase (CcO), also widely known as mitochondrial electron-transport-chain complex IV, is a multi-subunit transmembrane protein responsible for catalyzing the last step of the electron transport chain, dioxygen reduction to water, which is essential to the establishment and maintenance of the membrane proton gradient that drives ATP synthesis. Although many intermediates in the CcO catalytic cycle have been spectroscopically and/or computationally authenticated, the specifics regarding the IP intermediate, hypothesized to be a heme-Cu (hydro)peroxo species whose O−O bond homolysis is supported by a hydrogen-bonding network of water molecules, are largely obscured by the fast kinetics of the A (FeIII–O2•–/CuI/Tyr) → PM (FeIV=O/CuII–OH/Tyr•) step. In this review, we have focused on the recent advancements in the design, development, and characterization of synthetic heme-peroxo‑copper model complexes, which can circumvent the abovementioned limitation, for the investigation of the formation of IP and its O−O cleavage chemistry. Novel findings regarding (a) proton and electron transfer (PT/ET) processes, together with their contributions to exogenous phenol induced O−O cleavage, (b) the stereo-electronic tunability of the secondary coordination sphere (especially hydrogen-bonding) on the geometric and spin state alteration of the heme-peroxo‑copper unit, and (c) a plausible mechanism for the Tyr-His cofactor biogenesis, are discussed in great detail. Additionally, since the ferric-superoxide and the ferryl-oxo (Compound II) species are critically involved in the CcO catalytic cycle, this review also highlights a few fundamental aspects of these heme-only (i.e., without copper) species, including the structural and reactivity influences of electron-donating trans-axial ligands and Lewis acid-promoted H-bonding.