Superoxide Generation from Nitric Oxide Synthases

Besides nitric oxide (NO), NO synthases (NOS) also produce superoxide (·O2−), a primary reactive oxygen species involved in both cell injury and signaling. Neuronal NOS was first found to produce ·O2− in vitro. Subsequent studies revealed ·O2− generation as a common property of all NOS isoforms. Although NOS was originally shown to produce ·O2− under defined conditions such as substrate or cofactor depletion, recent enzymatic studies found that the reduction of oxygen to ·O2− is an obligatory step in NO synthesis. Tetrahydrobiopterin appears to play a key role in preventing ·O2− release from the NOS oxygenase domain. On the other hand, the NOS reductase domain is also capable of producing significant amounts of ·O2−. Increasing evidence demonstrates that ·O2− generation is involved in both physiological and pathological actions of NOS.