NADPH oxidase and genetic defects in CGD. The leukocyte NADPH oxidase enzyme complex is composed of membrane and cytosolic subunits that are referred to by their molecular mass (kDa) and the designation “phox,” for phagocyte oxidase. CYBB and CYBA refer to cytochrome b-245 β chain and cytochrome b-245 α chain, respectively, the large and small subunits of flavocytochrome b₅₅₈, whereas NCF refers to neutrophil cytosolic factor, used to designate the cytosolic regulatory subunits of the oxidase. Flavocytochrome b₅₅₈ is the electron transferase and is located in plasma, specific granules (in neutrophils), and phagosome and some endosome membranes. This heterodimer is composed of gp91^phox and p22^phox. The gp91^phox subunit is sometimes referred to as NOX2. CYBC1 (also known as EROS) is an endoplasmic reticulum protein important for expression of the flavocytochrome b₅₅₈ heterodimer. The soluble regulatory proteins p47^phox, p67^phox, and p40^phox form a complex in the cytosol; upon leukocyte activation, phosphorylation-induced conformational changes lead to their binding to flavocytochrome b₅₅₈. The small GTPase Rac is also essential for NADPH oxidase enzymatic activity, which, in its active GTP-bound state, becomes membrane bound and activates p67^phox. Together, these regulatory proteins activate the flavocytochrome b₅₅₈–mediated transfer of electrons from cytosolic NADPH across the membrane via FAD and heme redox centers to molecular oxygen, thereby forming superoxide in the extracellular space or within phagosomes or endosomes. Superoxide is converted into H₂O₂, which can diffuse across membranes, and other ROS. CGD results from inactivating recessive mutations in any 1 of the 5 phox subunits or CYBC1, as indicated with the approximate incidence, gene, and chromosomal location. Professional illustration by Patrick Lane, ScEYEnce Studios.