Flavo-diiron enzymes: nitric oxide or dioxygen reductases?

Flavo-diiron enzymes are among the most recently recognized sub-class of non-heme diiron proteins. The active sites of flavo-diiron enzymes consist of a unique juxtaposition of a flavin cofactor and a histidine, glutamate, aspartate-ligated, solvent-bridged diiron site. Flavo-diiron enzymes were initially thought to function as scavenging dioxygen reductases (s-O₂Rs), based on their ability to catalyze the reduction of dioxygen to water, thus protecting air-sensitive bacteria and archaea against “oxidative stress”. However, genetic and biochemical evidence strongly suggests that, at least in some bacteria, flavo-diiron enzymes function as scavenging nitric oxide reductases (s-NORs), catalyzing the reduction of nitric oxide to nitrous oxide, thus, protecting against “nitrosative stress” under anaerobic growth conditions. Key unsettled questions include: should flavo-diiron enzymes be divided into s-NOR and s-O₂R categories, and, if so, what features of the active sites distinguish the two activities? If not, how does the active site accommodate and optimize the relative levels of these activities? Systematic investigations of the structures and catalytic mechanisms of several flavo-diiron enzymes constitute an approach to answer these questions. The current state of knowledge and progress toward this end is reviewed here.