Lipid-metabolizing serine hydrolases in the mammalian central nervous system: endocannabinoids and beyond

The metabolic serine hydrolases hydrolyze ester, amide, or thioester bonds found in broad small molecule substrates using a conserved activated serine nucleophile. The mammalian central nervous system (CNS) express a diverse repertoire of serine hydrolases that act as (phospho)lipases or lipid amidases to regulate lipid metabolism and signaling vital for normal neurocognitive function and CNS integrity. Advances in genomic DNA sequencing have provided evidence for the role of these lipid-metabolizing serine hydrolases in neurologic, psychiatric, and neurodegenerative disorders. This review briefly summarizes recent progress in understanding the biochemical and (patho)physiological roles of these lipid-metabolizing serine hydrolases in the mammalian CNS with a focus on serine hydrolases involved in the endocannabinoid system. The development and application of specific inhibitors for an individual serine hydrolase, if available, are also described. This article is part of a Special Issue entitled Novel functions of phospholipase A2 Guest Editors: Makoto Murakami and Gerard Lambeau.