Respiration and Oxidative Phosphorylation in Mycobacteria

Abstract

The genus Mycobacterium comprises a group of obligately aerobic bacteria that have adapted to inhabit a wide range of intracellular and extracellular environments. A fundamental feature in this adaptation is the ability of mycobacteria to respire and generate energy for growth or to sustain latency. Mycobacteria harbor multiple primary dehydrogenases to fuel the electron transport chain and two terminal respiratory oxidases, an aa 3 -type cytochrome c oxidase and cytochrome bd-type menaquinol oxidase, are present for dioxygen reduction coupled to the generation of a protonmotive force. In mycobacteria, Type II NADH dehydrogenases are favoured over complex I for NADH oxidation and menaquinone acts as the primary conduit between electron-donating and electron-accepting reactions. The molecular mechanisms regulating the expression of the electron transport chain components in mycobacteria remains unknown. Despite being obligate aerobes, mycobacteria have the ability to metabolize in the absence of oxygen and a number of reductases are present to facilitate the turnover of reducing equivalents under these conditions (e.g., nitrate reductase, fumarate reductase). Hydrogenases and ferredoxins are also present in the genomes of mycobacteria suggesting the ability of these bacteria to adapt to an anaerobic-type of metabolism in the absence of oxygen. The exact roles of reductases and hydrogenases is poorly understood. ATP synthesis by the membrane-bound F1FO-ATP synthase (see Chap. 6) is essential for growing and non-growing mycobacteria and the enzyme is able to function over a wide range of proton-motive force values (aerobic to hypoxic). Research into mycobacterial respiration and oxidative phosphorylation have been energized by the discovery of a new drug (TMC207) that targets the ATP synthase of mycobacteria, suggesting that inhibitors of respiration and ATP synthesis will provide the next generation of front line drugs to combat tuberculosis and nontuberculous mycobacterial disease.