Heme-copper oxidases: could they be stochastic machines?

Heme-copper oxidases (HCOs) are the terminal enzymes of many aerobic respiratory chains, including the mitochondrial one. HCOs reduce molecular oxygen in a process coupled with proton pumping [1,2]. Despite decades of intense work, some features of this proton pump mechanism still remain controversial [1-3]. Currently accepted models require, more or less explicitly, an ordered sequence of events, and can be considered deterministic. Taking into account the cytochrome c oxidase clusters of structures and experimental data on which there is a general consensus, we suggested a stochastic pump mechanism for this enzyme class [4]. From a biochemical point of view, the model is essentially based on the decoupling of the redox linked events at the proton loading site from the fluctuations of the access barriers to the intramolecular proton conduction pathways. This model predicts some pump features that can be hardly explained by deterministic models, such as the convex dependence of the stoichiometry of the pump on the electron transfer rate [1,3,5]. Furthermore, this stochastic model provides a rational explanation for contrasting evidences from single-molecule experiments performed on HCOs incorporated in proteoliposomes and predicts when it is more likely to observe leak states during HCO turnover [6,7]. [1] M. Wikström, K. Krab, V. Sharma, Chem. Rev. 118 (2018) 2469-2490. [2] S. Yoshikawa, A. Shimada, Chem. Rev. 115 (2015) 1936-1989. [3] N. Capitanio, L.L. Palese, G. Capitanio, et al., Biochim. Biophys. Acta 1817 (2012) 558-566. [4] L.L. Palese, Phys. Chem. Chem. Phys. 21 (2019) 4822-4830. [5] N. Capitanio, G. Capitanio, D.A. Demarinis, et al., Biochemistry 35 (1996) 10800-10806. [6] Li M, Jørgensen SK, McMillan DG, et al., J. Am. Chem. Soc. 137 (2015) 16055-16063. [7] Berg J, Block S, Höök F, et al., Isr. J. Chem. 57 (2017) 437 – 445.