Location, Location, Location: Compartmentalization of Early Events in Leukotriene Biosynthesis

摘要: Leukotrienes (LTs), derived from arachidonic acid (AA) released the membrane by action of phospholipase A2, are potent lipid mediators inflammatory response. In 1983, Dahlen et al. demonstrated that LTC4, LTD4, and LTE4 mediate antigen-induced constriction bronchi in tissue obtained subjects with asthma (Dahlen, S. E., Hansson, G., Hedqvist, P., Bjorck, T., Granstrom, Dahlen, B. (1983) Proc. Natl. Acad. Sci. U.S.A. 80, 1712–1716). Over last 25+ years, substantial progress has been made understanding how LTs exert their effects, a broader appreciation for numerous biological processes they emerged. LT biosynthesis is initiated 5-lipoxygenase (5-LOX), which catalyzes transformation AA to LTA4 two-step reaction. Ca2+ targets 5-LOX nuclear membrane, where it co-localizes 5-LOX-activating protein FLAP and, when present, downstream enzyme LTC4 synthase, both transmembrane proteins. Crystal structures AA-metabolizing LOXs, combined biochemical data provide framework subcellular organizations optimize these labile hydrophobic signaling compounds, must navigate pathways include soluble enzymes. The insights afford questions engender discussed this minireview.