The O2 J generated by this enzyme serves as the starting material for the production of a vast assortment of reactive oxidants, including oxidized halogens, free radicals, and singlet oxygen. These oxidants are used by phagocytes to kill invading microorganisms, but they also cause a lot of what the military would call ‘‘collateral damage’’to nearby tissues, so their production has to be tightly regulated to make sure they are only generated when and where required. In the 40 years since Sbarra and Karnovsky first reported findings suggesting the existence of such an enzyme in neutrophils, a great deal has been learned about the leukocyte oxidase. Research over this period of time has shown that the core enzyme comprises five components: p40PHOX (PHOX for PHagocyte OXidase), p47PHOX, p67PHOX, p22PHOX and gp91PHOX. In the resting cell, three of these five components—p40PHOX, p47PHOX and p67PHOX—exist in the cytosol as a complex. The other two components—p22PHOX and gp91PHOX—are located in the membranes of secretory vesicles* and specific granules, where they occur as a heterodimeric flavohemoprotein known as cytochrome b558. Separating these two groups of components by distributing them between distinct subcellular compartments guarantees that the oxidase is inactive in the resting cell. When the resting cell is exposed to any of a very wide variety of stimuli, the cytosolic component p47PHOX becomes heavily phosphorylated and the entire cytosolic complex migrates to the membrane, where it associates with cytochrome b558 to assemble the active oxidase (Fig 1). The assembled oxidase is now able to transfer electrons from the substrate to oxygen by means of its electron-carrying prosthetic groups—its flavin and then (according to most investigators, but not me) its heme group (s). Activation requires the participation, not only of the core subunits, but of two low-molecular-weight guanine nucleotide-binding proteins: Rac2, which in the resting cell is located in the cytoplasm in a dimeric complex with Rho-GDI (Guanine nucleotide Dissociation Inhibitor), and Rap1A, which is located in membranes from which it can be copurified with the cytochrome. During activation, Rac2 binds guanosine triphosphate (GTP) and migrates to the membrane along with the core cytosolic complex. At the same time, cytochrome b558 and Rap1A are delivered to the cell surface by fusion of the secretory vesicle membranes and later the specific granule membranes with the plasma membrane of the cell. This fusion event also releases the contents of the organelles to the exterior. When phagocytosis takes place, the plasma membrane is internalized as the wall of the phagocytic vesicle, with what was once the outer membrane surface now facing the interior of the vesicle. From this location, the enzyme pours O2 J into the vesicle, and the rapid conversion of this O2 J into its successor products bathes the internalized target in a lethal mixture of corrosive oxidants.

The leukocyte NADPH oxidase continues to be the object of a considerable amount of investigation by scientists who are curious as to how it works. Interest in the leukocyte oxidase has increased with the growing recognition that oxidases closely related to the leukocyte oxidase can be found in a variety of cells in which the enzymes serve a variety of purposes. The following is a review of some of the new information obtained through these recent studies.