Structure and Mechanism of Action of the Alternative Quinol Oxidases

Abstract

In addition to heme-copper oxidases, all higher plants, some algae, yeasts, molds, metazoans, and pathogenic microorganisms such as Trypanosoma brucei contain an additional terminal oxidase, the cyanide- and antimycin-insensitive alternative oxidase (AOX). It is a di-iron carboxylate protein that catalyzes the four-electron reduction of dioxygen to water by ubiquinol, short-circuiting the mitochondrial electron-transport chain prior to proton translocation by complexes III and IV, thereby dramatically reducing ATP formation. In plants, it plays a key role in cellular metabolism, thermogenesis, and energy homeostasis and is generally considered to be a major stress-induced protein. In T. brucei, a parasite that causes human African sleeping sickness, AOX plays a critical role in the survival of the parasite in its bloodstream form. Because AOX is absent from mammals, this protein represents a unique and promising therapeutic target. Despite its bioenergetic and medical importance, however, until recently structural features of any AOX were unknown. In this review we describe recent advances in our understanding of this protein’s structure following the recent successful crystallization of the alternative oxidase from T. brucei. We focus on the nature of the active site and ubiquinol-binding channels and describe a mechanism for the reduction of oxygen to water based on these structural insights.