FIGURE 1.

NADPH oxidase isoforms and their assembly. All NOX isoforms have membrane-spanning catalytic subunit that transfers electrons from NADPH through their NADPH and FAD-binding sites and heme groups to reduce O₂ into superoxide anion (A) NOX1, NOX2, and NOX3 are cytosolic activators-dependent with the stabilizing p22^phox membrane subunit. Activation of NOX2 requires assembly with cytosolic p47^phox (equivalent to NoxO1 in NOX1 and NOX3), p67^phox (equivalent to NoxA1 in NOX1 and NOX3), and p40^phox. In resting cells (left panel), NOX2 and p22^phox are associated, co-stabilizing each other. Upon activation (right panel), GDP is exchanged for GTP on Rac. The phosphorylation of p47^phox subunit leads to a conformational change, which brings with p67^phox and p40^phox, to form the active NOX2 enzyme complex (NOX1 and NOX3 are not shown) (B) NOX4 is constitutively active with the stabilizing p22^phox membrane subunit. Its activity can be modulated by Poldip2. Inside the E-loop (3^rd extracellular loop), superoxide is rapidly dismutated into H₂O₂ (C) NOX5, DUOX1, and DUOX2 are Ca²⁺ dependent with EF-hand domains. DUOX1 and DUOX2 (as well as NOX5, not shown) have Ca²⁺ binding domains that undergo conformational change in response to an increase in intracellular Ca²⁺. It is speculated that activation of DUOX1, DUOX2, and NOX5, is through intramolecular protein-protein interaction between the Ca²⁺-binding domain and the C-terminal catalytic domain. GDP, guanosine diphosphate; GTP, guanosine-5′-triphosphate; NADPH, nicotinamide adenine dinucleotide phosphate; NOX, NADPH oxidase.