TY - JOUR T1 - Robust Hydrolysis of Prostaglandin Glycerol Esters by Human Monoacylglycerol Lipase (MAGL) JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.114.094284 SP - mol.114.094284 AU - Juha R Savinainen AU - Emilia Kansanen AU - Tatu Pantsar AU - Dina Navia-Paldanius AU - Teija Parkkari AU - Marko Lehtonen AU - Tuomo Laitinen AU - Tapio Nevalainen AU - Antti Poso AU - Anna-Liisa Levonen AU - Jarmo T. Laitinen Y1 - 2014/01/01 UR - http://molpharm.aspetjournals.org/content/early/2014/08/19/mol.114.094284.abstract N2 - The primary route of inactivation of the endocannabinoid 2-arachidonoylglycerol (2-AG) in the CNS is through enzymatic hydrolysis, mainly carried out by monoacylglycerol lipase (MAGL), along with small contribution by the α/β-hydrolase domain (ABHD) proteins ABHD6 and ABHD12. Recent methodological progress allowing kinetic monitoring of glycerol liberation has facilitated substrate profiling of the human endocannabinoid hydrolases and these studies have revealed that the three enzymes have distinct monoacylglycerol substrate and isomer preferences. Here we have extended this substrate profiling to cover four prostaglandin glycerol esters, namely 15-deoxy-Δ12,14-prostaglandin J2-2-glycerol (15d-PGJ2-G), PGD2-G, PGE2-G, and PGF2α-G. We found that the three enzymes hydrolyzed the tested substrates, albeit with distinct rates and preferences. While hABHD12 showed only marginal activity towards PGE2-G, hABHD6 preferentially hydrolyzed PGD2-G and hMAGL robustly hydrolyzed all four. This was particularly intriguing for MAGL activity towards 15d-PGJ2-G whose hydrolysis rate rivaled that of the best monoacylglycerol substrates. Molecular modeling studies combined with kinetic analysis supported favorable interaction with the hMAGL active site. Long and short MAGL isoforms shared similar substrate profile and hMAGL hydrolyzed 15d-PGJ2-G also in living cells. The ability of 15d-PGJ2-G to activate the canonical nuclear factor erythroid 2-related factor (Nrf2) signaling pathway utilized by 15d-PGJ2 was assessed and these studies revealed for the first time that 15d-PGJ2 and 15d-PGJ2-G similarly activated Nrf2 signaling as well as transcription of target genes of this pathway. Our study challenges previous claims regarding the ability of MAGL to catalyze PG-G hydrolysis and extend the MAGL substrate profile beyond the classical monoacylglycerols. ER -