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New Twists in Cyclooxygenase-Initiated Pathways Unorthodox routes to prostanoid formation: new twists in cyclooxygenase-initiated pathways Charles N. Serhan, Ernst Oliw J Clin Invest. 2001;107(12):1481-1489. https://doi.org/10.1172/JCI13375. Perspective 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 […] Find the latest version: https://jci.me/13375/pdf PERSPECTIVE SERIES Prostaglandins and their precursors Garret A. FitzGerald, Series Editor Unorthodox routes to prostanoid formation: new twists in cyclooxygenase-initiated pathways Charles N. Serhan1 and Ernst Oliw2 1Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA 2Division of Biochemical Pharmacology, Department of Pharmaceutical Biosciences, Uppsala Biomedical Center, Uppsala University, Uppsala, Sweden Address correspondence to: Charles N. Serhan, Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA. Phone: (617) 732-8822; Fax: (617) 278-6957; E-mail: [email protected]. Since their discovery in the mid 1930s as potent bioactive dogma of the time that held that fatty acids played only compounds in human semen (1), prostaglandins and structural roles in cells, thus opening the way for discov- their relatives have fascinated several generations of sci- ery of the many other important bioactive fatty entists. Prostanoids, as they are known today, are a spe- acid–derived products. These compounds fall into sever- cific class of bioactive mediators generated via initial al distinct classes and include the leukotrienes (LTs) and actions of cyclooxygenase. They are part of a much larg- the lipoxins (lipoxygenase interaction products or LXs; see er group of compounds, the eicosanoids, which, ref. 9). Eicosanoids play pivotal roles in parturition, although ubiquitous as a group, are produced by a vari- inflammation, hemodynamics, and renal function, and ety of cell type–, tissue-, and species-specific biosynthetic our appreciation of their bioimpact and relevance to pathways. The eicosanoid family encompasses throm- human diseases is still evolving. Here, we focus on newly boxanes, prostacyclins, leukotrienes, hydroxyeicosa- uncovered pathways, involving either the cyclooxygenas- tetraenoic acids (HETEs), epoxyeicosatrienic acids (EETs), es (COXs) or nonenzymatic chemical transformations, lipoxins, and isoprostanes, the last of which can be gen- that lead to the formation of bioactive prostanoids and of erated by nonenzymatic oxidative mechanisms and may previously unknown lipid mediators produced by COX-2. serve as markers of oxidative stress in humans. Each class of enzymatically produced eicosanoids governs a specif- Cyclooxygenase, biosynthesis of prostaglandin H, ic set of functions and is thought to serve as a mediator and the impact of aspirin or autacoid, acting within a local microenvironment to The tissue-specific biosynthetic pathways that generate orchestrate key cellular responses. A goal of this Perspec- specific PGs are well covered in textbooks. In these reac- tive is to provide a succinct view of salient findings and tions, COX carries out a complex free radical reaction historical background in this area necessary for the read- by acting successively as a bis-dioxygenase and a perox- er to evaluate the potential importance of the newly idase (Figure 1, left). This dual role was first postulat- uncovered “unorthodox” routes (2–4) initiated via ed over 35 years ago (6, 8) but can now be rationalized cyclooxygenase (for detailed reviews see refs. 5–7). by models from crystal structures of the enzyme (9, 10). Structures of the first six prostaglandins (PGs) were The orthodox pathway, as it entered the literature in the established by 1962, before their individual biosynthetic 1960s, is as follows (Figure, 1, left): Receptor activation or pathways were studied. These compounds are synthesized cell injury signals for arachidonic acid release from mem- in vivo through what can now be regarded as the “ortho- brane stores. The activity of lipases such as cytosolic dox” cyclooxygenase pathways, which came to light large- phospholipase A2 (reviewed in Fitzpatrick and Soberman, ly through the work of Sune Bergström, who led a team this Perspective series, ref. 11) is typically the limiting fac- then based at the Karolinska Institutet in Stockholm. tor at this step. COX catalyzes the cyclization of arachi- Bergström stated in his 1982 Nobel lecture that, follow- donic acid to PGH2 — hence its other name, ing the structural assignments of the six PGs, “These 20- prostaglandin H synthase or PGHS (5, 6). COX accom- carbon prostaglandins have cis–double bonds located as plishes this by first generating PGG2, after which the per- in certain essential fatty acids, when counting from the oxidase part of the enzyme acts, reducing the carbon 15 carboxyl. This made us suspect that these naturally occur- position hydroperoxide to its corresponding alcohol to ring acids might be precursors” (see ref. 5 and references form PGH2 (Figure 1). These reactions are initiated by within). Indeed, evidence obtained with isotopically stereoselective abstraction of hydrogen at carbon num- labeled 20-carbon fatty acids incubated with sheep vesic- ber 13 (in the S configuration), which guides the mole- ular glands, an abundant source of PGs, confirmed this cule oxygen insertion by COX to form the characteristic assumption. More importantly, this finding shattered a endoperoxide bridge between carbon 9 and 11 and the The Journal of Clinical Investigation | June 2001 | Volume 107 | Number 12 1481 Prostaglandins and their precursors PERSPECTIVE SERIES Garret A. FitzGerald, Series Editor five carbon member ring (see PGG2; Figure 1) that defines hope that new chemical classes of inhibitors display the the PGs. The bis–dioxygenase activity (insertion of a sec- analgesic and anti-inflammatory properties of tradi- ond molecule of O2) involves a radical center formed at tional NSAIDs without their unwanted side effects, most carbon 15 to yield a hydroperoxy group in PGG2, which notably gastrointestinal ulceration and renal toxicity (see is reduced to the alcohol PGH2 (12). The next step, name- Patrono, this Perspective series, ref. 19). The available ly conversion of PGH2 to cell type–specific production of COX-2 inhibitors do not yet fulfill all expectations, as individual prostanoids, is governed by enzymes that are both nephrotoxicity (20) and gastrointestinal side effects expressed in both a tissue- and cell type–selective fashion. still occur, and the latter are common, but the incidence Thus, for example, PGH2 gives rise to prostacyclin in of serious gastrointestinal complications (perforation, endothelial cells and to thromboxane in platelets (6). ulcer, bleeding) appears to be reduced (21). This experi- The preferred substrates of COX contain at least ment is still in progress per se, since many prescriptions three double bonds in well-defined positions. These are have been filled (22) and unexpected effects of these dihomogammalinolenic, arachidonic, and eicosapen- drugs may yet emerge (23). taenoic (EPA) acids, which contain 3, 4, and 5 double bonds, respectively. Other fatty acids lacking the three Unorthodox routes (I): novel routes double bonds in the required positions can be oxy- for prostanoid biogenesis in seminal fluid genated by COX to hydroperoxy fatty acids, but not to PGs were initially discovered in human seminal fluid and PGs. Thus, Mead acid (C20:3n-9) is transformed to 13- originate from the seminal vesicles. Semen contains PGs hydroxy-5,8,11-eicosatrienoic acid by COX-1 (13), and derived from the three fatty acids, dihomogammalinole- there are many exciting new transformations of differ- ic, arachidonic, and eicosapentaenoic acids. The two most ent new substrates of COX enzymes, and particularly abundant PGs are 19R-hydroxy-PGE1 and 19R-hydroxy-
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