NADPHOxidase

NADPH oxidase is a family of enzyme complexes that catalyze the production of reactive oxygen species by transferring electrons from NADPH to molecular oxygen. The best known member, NOX2, functions in phagocytes to generate a respiratory burst that helps kill engulfed microbes; other NADPH oxidases are expressed in various tissues where ROS participate in signaling and homeostasis.

The canonical NOX2 complex consists of a membrane-bound flavocytochrome b558 formed by gp91phox (NOX2) and p22phox, together with cytosolic subunits p47phox, p67phox, p40phox, and the small GTPase Rac. Activation triggers assembly of these components at the membrane, enabling electron transfer from NADPH through FAD and heme centers to oxygen, producing superoxide. The NOX family includes additional members (NOX1–5 and DUOX1–2) with differing regulatory mechanisms, tissue distributions, and cofactors; some are calcium-dependent or contain peroxidase-like domains.

The primary ROS generated are superoxide and its dismutation product hydrogen peroxide; in phagocytes, myeloperoxidase uses H2O2 to form hypochlorous acid, contributing to microbial killing. In nonphagocytic cells, ROS act as signaling molecules that influence processes such as cell proliferation, differentiation, and responses to stress.

Clinical relevance includes chronic granulomatous disease (CGD), caused by mutations in NOX components leading to recurrent bacterial and fungal infections. CGD can be X-linked (gp91phox) or autosomal recessive (p47phox, p67phox, p22phox). Diagnosis uses the nitroblue tetrazolium test or dihydrorhodamine flow cytometry. Dysregulated NOX activity is also associated with inflammatory, cardiovascular, and neurodegenerative diseases and with cancer. Regulation involves phosphorylation of cytosolic subunits, translocation to the membrane, and Rac activation; inhibitors such as diphenyleneiodonium and more selective compounds are used in research.