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Free-energy studies reveal a possible mechanism for oxidation-dependent inhibition of MGL.

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.

SUBMITTER: Scalvini L

PROVIDER: S-EPMC4976315 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Free-energy studies reveal a possible mechanism for oxidation-dependent inhibition of MGL.

Scalvini Laura L Vacondio Federica F Bassi Michele M Pala Daniele D Lodola Alessio A Rivara Silvia S Jung Kwang-Mook KM Piomelli Daniele D Mor Marco M

Scientific reports 20160808

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 ...[more]

PMID: 27499063

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