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Between 1965 and the mid-1980s, investigators laid a durable foundation for understanding the regulated formation and metabolic disposition of eicosanoids. First, they sought, and found in arachidonic acid, the biosynthetic precursor for the prostaglandins. Second, they identified phospholipids as the cellular compartment that harbored arachidonic acid, and they identified phospholipases as the enzymes essential for its liberation and for the ensuing biosynthesis of prostaglandins (1). Third, they deduced the existence of transient intermediates in the prostanoid biosynthetic pathway, leading to the eventual discovery of the prostaglandin endoperoxides, PGG2 and PGH2 (2, 3). Fourth, they established that the enzyme PGH synthase, or cyclooxygenase (COX), was a molecular target of great medical significance in reproductive, cardiovascular, and inflammatory disorders (4). Fifth, they established that rapid, comprehensive pulmonary metabolism limited the steady-state levels and duration of action of prostanoids, implying that they acted as autocoid lipid mediators, not hormones. Finally, they identified new prostanoids (5, 6) and their biosynthetic enzymes, as well as new lipoxygenase enzymatic pathways and their leukotriene products (7, 8), as medically significant molecules.  Over this period, the most prominent themes in eicosanoid research were the identification of novel eicosanoid mediators, the determination of their molecular structures, and the establishment of their pharmacological activities. In a typical study of the time, investigators exposed tissues or cells to 50–100 μM of exogenous arachidonic acid, a concentration five- to tenfold greater than the Km for COX or lipoxygenases (Km ≈ 10 μM) (see Brash, this Perspective series, ref. 9). The contemporary model for eicosanoid biosynthesis, circa 1985, asserted that liberation of free arachidonic acid by phospholipase was the rate-limiting step in biosynthesis. Accordingly, providing saturating amounts of exogenous arachidonic acid ought to reveal all biosynthetic products and pathways.  By 1985 or thereabouts, the quest for novel eicosanoid mediators of medical significance had reached the point of diminishing returns. Simultaneously, more and more investigators sought to understand the role of eicosanoid biosynthesis in disease processes. Accordingly, investigators shifted from exogenous arachidonic acid and Ca2+ ionophore as preferred tools and embraced natural ligands, relevant to disease, to initiate receptor-coupled activation of eicosanoid formation.  By the late 1980s, two lines of experimental inquiry began to provoke a reconsideration and refinement of the accepted model of eicosanoid biosynthesis. First, kinetic and quantitative aspects of eicosanoid biosynthesis initiated by growth factors or cytokines on mitotically competent cells suggested that it was an oversimplification to regard availability of arachidonic acid as the sole, rate-limiting step in cellular eicosanoid biosynthesis. Second, the discovery of the 5-lipoxygenase activating protein (FLAP) in 1990 proved unambiguously that some eicosanoids (leukotrienes) originated under conditions that were not rate-limited by arachidonic acid availability. The discovery of novel regulatory processes, particularly Ca2++-dependent redistribution of 5-lipoxygenase (5-LO) and the interaction between 5-LO and FLAP (10), offered a new framework on which to reconstruct the earlier model of eicosanoid biosynthesis.  Here, we comment on several mechanisms through which cells attain more subtle control of eicosanoid biosynthesis than would be possible by simply limiting the availability of arachidonic acid. We first discuss the coordinated action of specific phospholipases, the enzymes that generate this substrate, with specific COXs and PGH isomerase enzymes. We then consider the restricted expression of eicosanoid biosynthetic enzymes and, finally, turn to the “suicide” inactivation of these biosynthetic enzymes, a general mechanism that may help terminate their proinflammatory function.

Regulated formation of eicosanoids