Recent insights into the molecular mechanism of ubiquinol oxidation by cytochrome bc1.

This review summarizes the long-standing effort to understand the mechanism of quinol oxidation catalyzed by cytochrome bc1. Cytochrome bc1 is an enzyme involved in both the respiratory and photosynthetic electron transport chains. It couples quinol oxidation with quinone reduction at two separate active sites (Qo and Qi, respectively) catalyzing proton and electron transfer with high efficiency. At the Qo site, the reaction involves the separation of two electrons derived from the quinol oxidation, which are transferred to opposite sides of the enzyme across the membrane, the so-called electron bifurcation (EB). Despite many years of studies, the molecular mechanism of EB and the molecular basis of its efficiency remain a matter of debate. Here, we reflect on major issues that remain unsolved and thus hamper understanding of EB. We then discuss new perspectives afforded by recent experimental and computational studies that lead to consideration of a new mechanism of EB. This mechanism, named EMergent Electron Transfer (EMET), proposes a departure from a canonical reaction scheme to explain the high fidelity of EB. Ultimately, the theory of EMET provides a constructive conceptual framework for further experimental explorations.