title: Monoglyceride lipase: Structure and inhibitors.
abstract: Monoglyceride lipase (MGL), the main enzyme responsible for the hydrolytic deactivation of the endocannabinoid 2-arachidonoyl-sn-glycerol (2-AG), is an intracellular serine hydrolase that plays critical roles in many physiological and pathological processes, such as pain, inflammation, neuroprotection and cancer. The crystal structures of MGL that are currently available provide valuable information about how this enzyme might function and interact with site-directed small-molecule inhibitors. On the other hand, its conformational equilibria and the contribution of regulatory cysteine residues present within the substrate-binding pocket or on protein surface remain open issues. Several classes of MGL inhibitors have been developed, from early reversible ones, such as URB602 and pristimerin, to carbamoylating agents that react with the catalytic serine, such as JZL184 and more recent O-hexafluoroisopropyl carbamates. Other inhibitors that modulate MGL activity by interacting with conserved regulatory cysteines act through mechanisms that deserve to be more thoroughly investigated.
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, I-43124 Parma, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Scalvini
authors.affiliation: Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, CA 92697, United States; Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, United States; Unit of Drug Discovery and Development, Istituto Italiano di Tecnologia, Genova, Italy. Electronic address: piomelli@uci.edu.
authors.forename: Daniele
authors.initials: D
authors.lastname: Piomelli
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, I-43124 Parma, Italy. Electronic address: marco.mor@unipr.it.
authors.forename: Marco
authors.initials: M
authors.lastname: Mor
mesh_terms: D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D011487:Protein Conformation
chemical_list: D004791:Enzyme Inhibitors; D008994:Monoacylglycerol Lipases
keywords: 2-Arachidonoyl-sn-glycerol (2-AG); Cysteines; Endocannabinoids; Inhibitors; Lid domain; Monoglyceride lipase (MGL)