Endocannabinoid-metabolizing enzyme (ECME)

Endocannabinoid-metabolizing enzymes are a functional class of proteins responsible for the degradation and inactivation of endogenous cannabinoid ligands, primarily anandamide (AEA) and 2-arachidonoylglycerol (2-AG). The most significant members of this group include fatty acid amide hydrolase (FAAH), which is the principal enzyme for AEA hydrolysis, and monoacylglycerol lipase (MAGL), which accounts for the majority of 2-AG breakdown in the brain [UniProt: O00519, Q99685]. Other enzymes such as N-acylethanolamine-hydrolyzing acid amidase (NAAA) and alpha/beta-hydrolase domain-containing proteins (ABHD6 and ABHD12) also contribute to the metabolism of these signaling lipids [PubMed: 21233327]. By controlling the spatial and temporal availability of endocannabinoids, these enzymes serve as key regulators of the endocannabinoid system, which modulates pain, mood, appetite, and inflammation [PubMed: 23544157]. Pharmacological inhibition of these enzymes is a major therapeutic strategy aimed at enhancing endocannabinoid tone to treat conditions like chronic pain and anxiety without the adverse effects associated with direct cannabinoid receptor agonists [PubMed: 21828244]. However, the development of such inhibitors requires high selectivity to avoid off-target effects, as highlighted by the clinical failure and toxicity of certain non-selective compounds [PubMed: 27806211].

Other names

Endocannabinoid hydrolaseEndocannabinoid degradation enzymeFatty acid amide hydrolase (FAAH)Monoacylglycerol lipase (MAGL)N-acylethanolamine-hydrolyzing acid amidase (NAAA)

Inhibition of these enzymes prevents the hydrolysis of endocannabinoids such as anandamide and 2-arachidonoylglycerol, thereby increasing their local concentrations and prolonging their activation of cannabinoid receptors (CB1 and CB2) [PubMed: 23544157].