NADPHOxidaseSystem

NADPH oxidase system refers to a multicomponent enzyme complex that generates reactive oxygen species by transferring electrons from NADPH to molecular oxygen, forming superoxide. In phagocytes, this process is known as the respiratory burst and is a key mechanism of innate immunity against invading microbes.

The core components include a membrane-bound cytochrome b558 complex composed of gp91phox (NOX2) and p22phox (CYBA), which hosts the catalytic site and electron transport chain. The cytosolic subunits p47phox (NCF1), p67phox (NCF2), and p40phox (NCF4) accompany Rac1 or Rac2 small GTPases. Upon activation, these cytosolic subunits translocate to the membrane to assemble with cytochrome b558, forming an active NADPH oxidase. Other NOX family members (NOX1-5, DUOX1-2) are expressed in various tissues and have distinct regulatory subunits and tissue distribution.

Mechanistically, electrons move from NADPH to FAD and then through heme groups in gp91phox, reducing oxygen to superoxide (O2−). Superoxide can dismutate to hydrogen peroxide (H2O2); in the presence of myeloperoxidase, H2O2 contributes to the production of antimicrobial hypochlorous acid. ROS produced by NADPH oxidase participate in microbial killing and also in redox signaling pathways.

Clinical relevance includes chronic granulomatous disease (CGD), caused by mutations in components of the NOX2 complex (for example CYBB, CYBA, NCF1, NCF2, NCF4), leading to diminished respiratory burst and increased susceptibility to catalase-positive bacteria and fungi. Regulation involves phosphorylation of cytosolic subunits, PKC, Rac activation, and calcium signaling. Beyond immunity, NOX enzymes function in nonphagocytic cells to modulate signaling, angiogenesis, and tissue remodeling, with dysregulation linked to inflammatory and fibrotic diseases.