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Prostaglandin (PG) E2 is almost ubiquitous in humans and evokes potent diverse actions. Utility is the price of its perfection. PGE2 is a founding member of the PGs, a class of mediators that belongs to the still growing family of bioactive autacoids known as the eicosanoids (1–3). The main classes include enzymatically generated products such as thromboxanes, leukotrienes, lipoxins, and EETs, as well as others that are produced via nonenzymatic mechanisms, e.g., isoprostanes and cyclopentaeone PGs that are increasing in number and appreciation (4, 5). PGE2 regulates key responses in the major human systems including reproductive, gastrointestinal, neuroendocrine, and immune (Fig. 1). Formed by conversion of arachidonic acid via cyclooxygenase (COX) and specific synthases, PGE2 stereospecifically exerts potent (nano- to micromolar range) tissue- and cell type-selective actions (1–6). The importance of PGs in inflammation was brought into view by the discovery of J. Vane and colleagues (7) that nonsteroidal antiinflammatory drugs (NSAIDs) like aspirin, that at the time were used clinically without a known mechanism, act by inhibiting COX production of PGs and thromboxanes. Although highly effective, the COX inhibitors (both COX-1 and COX-2) of today's clinics are still rather blunt therapies at the molecular level, because they not only block the formation of individual PGs but also knock out other “bystander” eicosanoids that may be needed to maintain homeostasis. This can lead to unwanted side effects in multiple systems, i.e., ulcers and constipation. Hence there remains considerable room for improvement in this clinical area. In this issue of PNAS, Trebino et al. (8) studied the pathogenesis of collagen-induced arthritis by using microsomal PGE synthase-1 (mPGES1) deficient mice and demonstrate the contributions of this enzyme and PGE2 in chronic inflammation and pain. Their results provide in vivo validation of this …

Success of prostaglandin E 2 in structure–function is a challenge for structure-based therapeutics

Success of prostaglandin E ₂ in structure–function is a challenge for structure-based therapeutics