Cell biology of the 5-lipoxygenase pathway.

Abstract

The initial enzymatic steps in leukotriene synthesis occur at the nuclear envelope. Cytosolic phospholipase A2 translocates from the cytoplasm to selectively hydrolyze nuclear envelope phospholipids, releasing free arachidonate. 5-Lipoxygenase-activating protein, an arachidonate transfer protein, then binds arachidonate and presents it to 5-lipoxygenase (5-LO), which catalyzes a two-step reaction to produce leukotriene A4. In resting human and rat peripheral blood neutrophils, 5-LO is localized to the cytoplasm; in rat basophilic leukemia cells and human alveolar macrophages, however, it is found predominantly in the nucleus. Immunofluorescence microscopy studies demonstrate that both cytoplasmic and nuclear 5-LO move to the nuclear envelope following cell activation. Many questions remain unanswered regarding the significance of nuclear 5-LO, potential autocrine actions of leukotrienes, and intracellular trafficking of these enzymes and their products.