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Metabolism of endocannabinoids and related N‐acylethanolamines: Canonical and alternative pathways

Endocannabinoids are endogenous ligands of the cannabinoid receptors CB1 and CB2. Two arachidonic acid derivatives, arachidonoylethanolamide (anandamide) and 2‐arachidonoylglycerol, are considered to be physiologically important endocannabinoids. In the known metabolic pathway in mammals, anandamide and other bioactive N‐acylethanolamines, such as palmitoylethanolamide and oleoylethanolamide, are biosynthesized from glycerophospholipids by a combination of Ca2+‐dependent N‐acyltransferase and N‐acyl‐phosphatidylethanolamine‐hydrolyzing phospholipase D, and are degraded by fatty acid amide hydrolase. However, recent studies have shown the involvement of other enzymes and pathways, which include the members of the tumor suppressor HRASLS family (the phospholipase A/acyltransferase family) functioning as Ca2+‐independent N‐acyltransferases, N‐acyl‐phosphatidylethanolamine‐hydrolyzing phospholipaseD‐independent multistep pathways via N‐acylated lysophospholipid, and N‐acylethanolamine‐hydrolyzing acid amidase, a lysosomal enzyme that preferentially hydrolyzes palmitoylethanolamide. Although their physiological significance is poorly understood, these new enzymes/pathways may serve as novel targets for the development of therapeutic drugs. For example, selective N‐acylethanolamine‐hydrolyzing acid amidase inhibitors are expected to be new anti‐inflammatory and analgesic drugs. In this minireview, we focus on advances in the understanding of these enzymes/pathways. In addition, recent findings on 2‐arachidonoylglycerol metabolism are described.