Superoxide Generation from Nitric Oxide Synthases

Abstract

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.