Cytochrome bd and Gaseous Ligands in Bacterial Physiology

Cytochrome bd is a unique prokaryotic respiratory terminal oxidase that does not belong to the extensively investigated family of haem-copper oxidases (HCOs). The enzyme catalyses the four-electron reduction of O₂ to 2H₂O, using quinols as physiological reducing substrates. The reaction is electrogenic and cytochrome bd therefore sustains bacterial energy metabolism by contributing to maintain the transmembrane proton motive force required for ATP synthesis. As compared to HCOs, cytochrome bd displays several distinctive features in terms of (i) metal composition (it lacks Cu and harbours a d-type haem in addition to two haems b), (ii) overall three-dimensional structure, that only recently has been solved, and arrangement of the redox cofactors, (iii) lesser energetic efficiency (it is not a proton pump), (iv) higher O₂ affinity, (v) higher resistance to inhibitors such as cyanide, nitric oxide (NO) and hydrogen sulphide (H₂S) and (vi) ability to efficiently metabolize potentially toxic reactive oxygen and nitrogen species like hydrogen peroxide (H₂O₂) and peroxynitrite (ONOO^-). Compelling evidence suggests that, beyond its bioenergetic role, cytochrome bd plays multiple functions in bacterial physiology and affords protection against oxidative and nitrosative stress. Relevant to human pathophysiology, thanks to its peculiar properties, the enzyme has been shown to promote virulence in several bacterial pathogens, being currently recognized as a target for the development of new antibiotics. This review aims to give an update on our current understanding of bd-type oxidases with a focus on their reactivity with gaseous ligands and its potential impact on bacterial physiology and human pathophysiology.