NADPH oxidase and molecular genetics of chronic granulomatous disease. Shown is the assembled form of the enzymatically active NADPH oxidase, along with subunits affected in the four different genetic subgroups of CGD, the approximate incidence, and the chromosomal location of the corresponding gene. Flavocytochrome b₅₅₈ is the redox center of the enzyme, and is located in plasma, specific granule, and phagolysosomal membranes. This heterodimer is comprised of the gp91^phox and p22^phox subunits of the NADPH oxidase, which are affected in X-linked and an autosomal recessive form of CGD, respectively. The soluble regulatory proteins p47^phox, p67^phox, and p40^phox are found in the cytosol until phagocyte 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 and p67^phox account for two 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 the oxidase. By a mechanism that is not fully understood, binding of these multiple regulatory subunits activates the flavocytochrome to catalyze the transfer of electrons from cytosolic NADPH across the membrane via the FAD and heme redox centers to molecular oxygen, thereby forming superoxide in the extracellular or intraphagosomal compartment. The Rap1a GTPase co-purifies with flavocytochrome b₅₅₈, but its function in superoxide production is unknown. No cases of CGD have been described due to mutations in p40^phox, Rac, or Rap1a.