Location, location, location: Compartmentalization of early events in leukotriene biosynthesis

Leukotrienes (LTs), derived from arachidonic acid (AA) released from the membrane by the action of phospholipase A2, are potent lipid mediators of the inflammatory response. In 1983, Dahlén et al. demonstrated that LTC4, LTD4, and LTE4 mediate antigen-induced constriction of bronchi in tissue obtained from subjects with asthma (Dahlén, S. E., Hansson, G., Hedqvist, P., Björck, T., Granström, E., and Dahlén, B. (1983) Proc. Natl. Acad. Sci. U.S.A. 80, 1712-1716). Over the last 25+ years, substantial progress has been made in understanding how LTs exert their effects, and a broader appreciation for the numerous biological processes they mediate has emerged. LT biosynthesis is initiated by the action of 5-lipoxygenase (5-LOX), which catalyzes the transformation of AA to LTA4 in a two-step reaction. Ca2+ targets 5-LOX to the nuclear membrane, where it co-localizes with the 5-LOX-activating protein FLAP and, when present, the downstream enzyme LTC4 synthase, both transmembrane proteins. Crystal structures of the AA-metabolizing LOXs, LTC 4 synthase, and FLAP combined with biochemical data provide a framework for understanding how subcellular organizations optimize the biosynthesis of these labile hydrophobic signaling compounds, which must navigate pathways that include both membrane and soluble enzymes. The insights these structures afford and the questions they engender are discussed in this minireview. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc