The organization and consequences of eicosanoid signaling.

Abstract

Organization of leukotriene and prostaglandin synthesis As described in the introduction to this Perspective series (1), signaling by arachidonic acid represents a paradigm for the use of oxygen in the transmission of information. At the same time, arachidonic acid signaling can also contribute to the propagation of cellular damage. This duality is typified by a signaling cascade that (a) prevents the activation of 5-lipoxygenase (5-LO) in resting cells and (b) results in the formation and release of leukotrienes (LTs), which requires the sequential activation and interaction of at least eight different proteins. In fact, all lipoxygenases require membrane translocation to exert activity. In the case of the formation of COX products, particularly prostaglandin E2 (PGE2) and PGD2, humans have evolved two sets of biosynthetic enzymes that differ not only in their cell- and tissue-specific localization, but also in their subcellular localization and requirement for reduced glutathione, a cellular defense against oxidative damage. This review will focus on three aspects of arachidonic acid biology. First, the compartmentalization and organization of eicosanoid synthesis, specifically LTs and PGs, will be discussed. This will illustrate the elaborate mechanisms that keep unwanted lipoxygenation at arm’s length and also show that the enzymes such as glutathione-Stransferases, epoxide hydrolases, and carrier proteins that are commonly thought of as biosynthetic also belong to families that are generally considered to play a role in detoxification. Second, the potential cellular oxidative damage that is produced as a by-product of the use of oxygen and lipid substrates is examined. Finally, mechanisms that are used to amplify signaling diversity from a core of LTs and PGs are discussed. The role of leukotrienes C4 and D4 in disease