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.

Keywords: 2-Arachidonoyl-sn-glycerol (2-AG); Cysteines; Endocannabinoids; Inhibitors; Lid domain; Monoglyceride lipase (MGL).

Figure 1

Schematic overview of 2-AG metabolism.

Figure 2

Superposition of MGL-crystallized structures with regulatory cysteines (Cys201, Cys208 and Cys242) shown as bold sticks. The catalytic triad residues are shown as sticks. The crystal structures present different conformations of the lid domain. The lid domain in its open conformation (PDB: 3HJU) is colored in light blue; the lid domain in closed conformation (PDB: 3PE6) is colored in green.

Figure 3

Crystallized MGL-inhibitor complexes. Panel A: superposition of MGL crystal structures (represented with grey cartoon; the lid domain is blue-colored; side chains of the catalytic triad and of Cys242 are represented in sticks with grey carbons) covalently bound to the irreversible inhibitors SAR629 (PDB: 3JWE, orange carbons) and SAR127303 (PDB: 4UUQ, cyan carbons). Panel B: crystal structure of MGL (PDB: 3PE6) in complex with the inhibitor ZYH (green carbons).

Figure 4

Structures of MGL inhibitors targeting the catalytic pocket.

Figure 5

Structures of MGL inhibitors that interact with regulatory cysteines.