Abstract
The function of monoacylglycerol lipase (MGL), a key actor in the hydrolytic deactivation of the endocannabinoid 2-arachidonoyl-sn-glycerol (2AG), is tightly controlled by the cell’s redox state: oxidative signals such as hydrogen peroxide suppress MGL activity in a reversible manner through sulfenylation of the peroxidatic cysteines, C201 and C208. Here, using as a starting point the crystal structures of human MGL (hMGL), we present evidence from molecular dynamics and metadynamics simulations along with high-resolution mass spectrometry studies indicating that sulfenylation of C201 and C208 alters the conformational equilibrium of the membrane-associated lid domain of MGL to favour closed conformations of the enzyme that do not permit the entry of substrate into the active site.
Highlights
Monoacylglycerol lipase (MGL), a presynaptic serine-hydrolase of the α/βhydrolases superfamily, terminates the biological actions of the major lipid neurotransmitter found in the CNS, the endocannabinoid 2-arachidonoyl-sn-glycerol (2-AG)[1,2]
The results of our study show that, to what has been observed for the rat form of MGL14, activity of the human enzyme is higher under reductive conditions, and that its cysteine residue C201 can be reversibly oxidized to sulfenic acid
Our molecular simulations offer a plausible explanation for monoacylglycerol lipase (MGL) inhibition by oxidative stimuli mediated by the regulatory cysteines, C201 and C208, located within the enzyme lid domain
Summary
Monoacylglycerol lipase (MGL), a presynaptic serine-hydrolase of the α/βhydrolases superfamily, terminates the biological actions of the major lipid neurotransmitter found in the CNS, the endocannabinoid 2-arachidonoyl-sn-glycerol (2-AG)[1,2]. Recent work has provided evidence that the interaction between hMGL and models of biological membranes, mimicking the transition from a cytosolic form of the enzyme to a membrane-bound one, cause major rearrangements of the lid-domain conformation[16]. Such rearrangements are associated with an improvement of the enzyme kinetics parameters, suggesting that MGL, to other lipases, is subject to interfacial activation[17,18,19]. The available three-dimensional structures of the enzyme present the lid domain in two different conformations, characterized by a closed gate over the catalytic triad (3PE6) or, by an open active site-access channel (3HJU). The lid-domain conformational space has been widely investigated in the last decade, and the results of different molecular modelling studies of the human[21] and of the bacterial form of the enzyme[22] consistently reveal that the lid domain of MGL spontaneously undergoes wide conformational modifications
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