Since their discovery in the mid 1930s as potent bioactive compounds in human semen (1), prostaglandins and their relatives have fascinated several generations of scientists. Prostanoids, as they are known today, are a specific class of bioactive mediators generated via initial actions of cyclooxygenase. They are part of a much larger group of compounds, the eicosanoids, which, although ubiquitous as a group, are produced by a variety of cell type–, tissue-, and species-specific biosynthetic pathways. The eicosanoid family encompasses thromboxanes, prostacyclins, leukotrienes, hydroxyeicosatetraenoic acids (HETEs), epoxyeicosatrienic acids (EETs), lipoxins, and isoprostanes, the last of which can be generated by nonenzymatic oxidative mechanisms and may serve as markers of oxidative stress in humans. Each class of enzymatically produced eicosanoids governs a specific set of functions and is thought to serve as a mediator or autacoid, acting within a local microenvironment to orchestrate key cellular responses. A goal of this Perspective is to provide a succinct view of salient findings and historical background in this area necessary for the reader to evaluate the potential importance of the newly uncovered “unorthodox” routes (2–4) initiated via cyclooxygenase (for detailed reviews see refs. 5–7).

Structures of the first six prostaglandins (PGs) were established by 1962, before their individual biosynthetic pathways were studied. These compounds are synthesized in vivo through what can now be regarded as the “orthodox” cyclooxygenase pathways, which came to light largely through the work of Sune Bergström, who led a team then based at the Karolinska Institutet in Stockholm. Bergström stated in his 1982 Nobel lecture that, following the structural assignments of the six PGs,“These 20-carbon prostaglandins have cis–double bonds located as in certain essential fatty acids, when counting from the carboxyl. This made us suspect that these naturally occurring acids might be precursors”(see ref. 5 and references within). Indeed, evidence obtained with isotopically labeled 20-carbon fatty acids incubated with sheep vesicular glands, an abundant source of PGs, confirmed this assumption. More importantly, this finding shattered a dogma of the time that held that fatty acids played only structural roles in cells, thus opening the way for discovery of the many other important bioactive fatty acid–derived products. These compounds fall into several distinct classes and include the leukotrienes (LTs) and the lipoxins (lipoxygenase interaction products or LXs; see ref. 9). Eicosanoids play pivotal roles in parturition, inflammation, hemodynamics, and renal function, and our appreciation of their bioimpact and relevance to human diseases is still evolving. Here, we focus on newly uncovered pathways, involving either the cyclooxygenases (COXs) or nonenzymatic chemical transformations, that lead to the formation of bioactive prostanoids and of previously unknown lipid mediators produced by COX-2.