Prostaglandin Terminal Synthases as Novel Drug Targets

Abstract

Prostanoids are lipid metabolites of ω3 and ω6 20-carbon essential fatty acids such as arachidonic acid and have a broad range of biological activities. Three kinds of enzymes—phospholipase A2 (PLA2), cyclooxygenase (COX), and prostaglandin (PG) terminal synthase—are involved in the biosynthesis of prostanoids. Arachidonic acid released from membrane glycerophospholipids by PLA2 enzymes is then supplied to either of the two COX isozymes, COX-1 and COX-2. The COX metabolite PGH2 is then converted to each prostanoid by specific PG terminal synthases. Nonsteroidal antiinflammatory drugs (NSAIDs) exert their antiinflammatory and antitumor effects by inhibiting COX and thereby reducing prostanoid production. However, gastrointestinal, renal, and the recently reported cardiovascular side effects associated with the pharmacological inhibition of the COX enzymes have led to renewed attention to other potential targets for NSAIDs. As new methods appear for the selective modulation of prostanoid production, PG terminal synthases have gained attention as a novel target for NSAIDs. To date, multiple PG terminal synthases have been identified, and mice with specific deletions in each of these PG terminal synthases have been engineered. In this review, we summarize the current understanding of the in vivo roles of PG terminal synthases by knockout mouse studies.