NADPH oxidase and molecular genetics of CGD. Shown are the membrane and cytosolic subunits of the leukocyte NADPH oxidase, indicating those involved in the 5 different genetic subgroups of CGD, the approximate incidence, and the gene and chromosomal location. CYBB and CYBA refer to the large and small subunits of flavocytochrome b₅₅₈, whereas the NCF refers to neutrophil cytosolic factor, used to designate the cytosolic regulatory subunits of the oxidase. Flavocytochrome b₅₅₈ is the redox center of the enzyme, and is located in plasma, specific granule (in neutrophils), and phagolysosomal membranes. This heterodimer is composed of the gp91^phox (phox stands for phagocyte oxidase) and p22^phox subunits of the NADPH oxidase, which are affected in X-linked and an autosomal recessive form of CGD, respectively. The gp91^phox subunit is sometimes referred to as NOX2. The soluble regulatory proteins p47^phox, p67^phox, and p40^phox are found in the cytosol until leukocyte activation by soluble or particulate inflammatory stimuli, upon which they move to the membrane, where p47^phox and p67^phox bind flavocytochrome b₅₅₈. Mutations in the genes encoding p47^phox, p67^phox, and p40^phox account for 3 other autosomal recessive forms of CGD. Another essential regulatory component of the NADPH oxidase is the small GTPase, Rac, which in its active GTP-bound state becomes membrane-bound and associates with p67^phox. By a mechanism that is not fully understood, these multiple regulatory subunits activate the flavocytochrome to catalyze the 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.