The mechanism of monoacylglycerol lipase (MGL) inactivation

Abstract

The endocannabionoid signaling system is composed of two main cannabinoid receptors (CB1 and CB2 ), their principal endogenous ligands (anandamide (AEA) and 2-arachidonoylglycerol (2-AG)) and enzymes primarily responsible for degrading endocanabinoids such as fatty acid amide hydrolase (FAAH), monoacylglycerol lipase (MGL), abhydrolase domain-containing protein-6 and N-acylethanolamine-hydrolyzing acid amidase (NAAA) that are responsible for reduction of endocanabinoid system activity and its consequent (patho) physiological effects. Although FAAH may inactivate 2-AG in vitro, its main in vivo biological substrate is anandamide, whereas MGL exclusively hydrolyzes 2-AG to stoichiometric amounts of arachidonic acid (AA) and glycerol in vivo. Unlike anandamide, that is a partial agonist for CB1 receptor and full agonist for CB2 receptor, 2-AG acts as a full agonist at both receptors. The amount of brain 2-AG is much higher than that of anandamide, making MGL a particularly critical modulator of endocannabinoid transmission in the central nervosu system (CNS). Several pharmacological considerations mandate increased knowledge of MGL's structure and function. Endocannabinoid-system hypoactivity has been implicated in pain, anxiety, and stress-related responses. In human cancer cells, MGL hydrolysis of cellular lipid stores controls the production of fatty acid-derived oncogenic lipid messengers that promote cancer cell migration and invasiveness. The key roles that MGL plays in tuning homeostatic endocannabinoid signaling and supporting aggressive tumorigenesis make MGL inhibition a promising therapeutic modality for managing pain and treating inflammatory, neurodegenerative, and immunological disorders as well as cancer. Thorough understanding of MGL's (patho) physiological relevance and its optimal exploitation as a pharmacotherapeutic target have been hampered by at least two factors: (1) the limited availability of MGL inhibitors that are both potent and selective; (2) gaps in our understanding of the details associated with MGL's catalytic mechanism and the enzyme's interaction with known inactivators so as to inform the design of improved small-molecule MGL inhibitors as potential drugs.