Abstract
Significance: Cytochrome bd is a ubiquinol:oxygen oxidoreductase of many prokaryotic respiratory chains with a unique structure and functional characteristics. Its primary role is to couple the reduction of molecular oxygen, even at submicromolar concentrations, to water with the generation of a proton motive force used for adenosine triphosphate production. Cytochrome bd is found in many bacterial pathogens and, surprisingly, in bacteria formally denoted as anaerobes. It endows bacteria with resistance to various stressors and is a potential drug target. Recent Advances: We summarize recent advances in the biochemistry, structure, and physiological functions of cytochrome bd in the light of exciting new three-dimensional structures of the oxidase. The newly discovered roles of cytochrome bd in contributing to bacterial protection against hydrogen peroxide, nitric oxide, peroxynitrite, and hydrogen sulfide are assessed. Critical Issues: Fundamental questions remain regarding the precise delineation of electron flow within this multihaem oxidase and how the extraordinarily high affinity for oxygen is accomplished, while endowing bacteria with resistance to other small ligands. Future Directions: It is clear that cytochrome bd is unique in its ability to confer resistance to toxic small molecules, a property that is significant for understanding the propensity of pathogens to possess this oxidase. Since cytochrome bd is a uniquely bacterial enzyme, future research should focus on harnessing fundamental knowledge of its structure and function to the development of novel and effective antibacterial agents.
Highlights
Cytochrome bd, first described in 1928 [(345), see Cook and Poole [75] and references therein], is a respiratory terminal oxidase far uniquely identified in the electron transport chain of prokaryotic organisms [36, 48, 151, 163, 252]
The three-dimensional structure of cytochrome bd has remained a mystery for a long time, but it was recently solved for two members of this protein family, the enzymes from Geobacillus thermodenitrificans [281] and, more recently, from Escherichia coli [280, 317], revealing unexpected structural differences between the two proteins, most likely of evolutionary significance
The CydDC system transports to the periplasm reducing molecules, notably GSH and cysteine, which stimulate the ATPase activity of the isolated CydDC complex
Summary
Cytochrome bd is found only in bacteria but is widely distributed among taxa and physiological types. Its current importance and high profile were slow to be recognized: since its discovery by Keilin, Warburg and pioneers in respiratory metabolism in the 1930s (when it was named cytochrome a2), publications on this oxidase accrued very slowly. The explosion of interest is a result of the recognition that cytochrome bd represents a novel class of oxidase and that its unique structure, catalytic capabilities, tolerance of stress, and importance to pathogens are worthy of detailed study. The novel features of cytochrome bd pose additional challenges, its ability to confer upon bacterial resistance to oxidative stress, NO and a number of important antimicrobial compounds. Its unique structure and function make it a profitable area of study for developing novel therapeutics, thereby contributing to overcoming the global scourge of resistance to established, and overused, antibiotics
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