PMID- 25140003 OWN - NLM STAT- MEDLINE DCOM- 20150107 LR - 20250213 IS - 1521-0111 (Electronic) IS - 0026-895X (Linking) VI - 86 IP - 5 DP - 2014 Nov TI - Robust hydrolysis of prostaglandin glycerol esters by human monoacylglycerol lipase (MAGL). PG - 522-35 LID - 10.1124/mol.114.094284 [doi] AB - The primary route of inactivation of the endocannabinoid 2-arachidonoylglycerol in the central nervous system is through enzymatic hydrolysis, mainly carried out by monoacylglycerol lipase (MAGL), along with a small contribution by the alpha/beta-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-Delta(12,14)-prostaglandin J2-2-glycerol (15d-PGJ2-G), PGD2-G, PGE2-G, and PGF2 alpha-G. We found that the three enzymes hydrolyzed the tested substrates, albeit with distinct rates and preferences. Although human ABHD12 (hABHD12) showed only marginal activity toward PGE2-G, hABHD6 preferentially hydrolyzed PGD2-G, and human MAGL (hMAGL) robustly hydrolyzed all four. This was particularly intriguing for MAGL activity toward 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 a 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 used 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 classic monoacylglycerols. CI - Copyright (c) 2014 by The American Society for Pharmacology and Experimental Therapeutics. FAU - Savinainen, Juha R AU - Savinainen JR AD - School of Medicine, Institute of Biomedicine (J.R.S., D.N-P., Te.P., J.T.L.), A.I. Virtanen Institute for Molecular Sciences (E.K., A-L.L.), School of Pharmacy (Ta.P., Te.P., M.L., T.L., T.N., A.P.), Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland. FAU - Kansanen, Emilia AU - Kansanen E AD - School of Medicine, Institute of Biomedicine (J.R.S., D.N-P., Te.P., J.T.L.), A.I. Virtanen Institute for Molecular Sciences (E.K., A-L.L.), School of Pharmacy (Ta.P., Te.P., M.L., T.L., T.N., A.P.), Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland. FAU - Pantsar, Tatu AU - Pantsar T AD - School of Medicine, Institute of Biomedicine (J.R.S., D.N-P., Te.P., J.T.L.), A.I. Virtanen Institute for Molecular Sciences (E.K., A-L.L.), School of Pharmacy (Ta.P., Te.P., M.L., T.L., T.N., A.P.), Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland. FAU - Navia-Paldanius, Dina AU - Navia-Paldanius D AD - School of Medicine, Institute of Biomedicine (J.R.S., D.N-P., Te.P., J.T.L.), A.I. Virtanen Institute for Molecular Sciences (E.K., A-L.L.), School of Pharmacy (Ta.P., Te.P., M.L., T.L., T.N., A.P.), Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland. FAU - Parkkari, Teija AU - Parkkari T AD - School of Medicine, Institute of Biomedicine (J.R.S., D.N-P., Te.P., J.T.L.), A.I. Virtanen Institute for Molecular Sciences (E.K., A-L.L.), School of Pharmacy (Ta.P., Te.P., M.L., T.L., T.N., A.P.), Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland. FAU - Lehtonen, Marko AU - Lehtonen M AD - School of Medicine, Institute of Biomedicine (J.R.S., D.N-P., Te.P., J.T.L.), A.I. Virtanen Institute for Molecular Sciences (E.K., A-L.L.), School of Pharmacy (Ta.P., Te.P., M.L., T.L., T.N., A.P.), Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland. FAU - Laitinen, Tuomo AU - Laitinen T AD - School of Medicine, Institute of Biomedicine (J.R.S., D.N-P., Te.P., J.T.L.), A.I. Virtanen Institute for Molecular Sciences (E.K., A-L.L.), School of Pharmacy (Ta.P., Te.P., M.L., T.L., T.N., A.P.), Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland. FAU - Nevalainen, Tapio AU - Nevalainen T AD - School of Medicine, Institute of Biomedicine (J.R.S., D.N-P., Te.P., J.T.L.), A.I. Virtanen Institute for Molecular Sciences (E.K., A-L.L.), School of Pharmacy (Ta.P., Te.P., M.L., T.L., T.N., A.P.), Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland. FAU - Poso, Antti AU - Poso A AD - School of Medicine, Institute of Biomedicine (J.R.S., D.N-P., Te.P., J.T.L.), A.I. Virtanen Institute for Molecular Sciences (E.K., A-L.L.), School of Pharmacy (Ta.P., Te.P., M.L., T.L., T.N., A.P.), Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland. FAU - Levonen, Anna-Liisa AU - Levonen AL AD - School of Medicine, Institute of Biomedicine (J.R.S., D.N-P., Te.P., J.T.L.), A.I. Virtanen Institute for Molecular Sciences (E.K., A-L.L.), School of Pharmacy (Ta.P., Te.P., M.L., T.L., T.N., A.P.), Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland. FAU - Laitinen, Jarmo T AU - Laitinen JT AD - School of Medicine, Institute of Biomedicine (J.R.S., D.N-P., Te.P., J.T.L.), A.I. Virtanen Institute for Molecular Sciences (E.K., A-L.L.), School of Pharmacy (Ta.P., Te.P., M.L., T.L., T.N., A.P.), Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland jarmo.laitinen@uef.fi. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20140819 PL - Netherlands TA - Mol Pharmacol JT - Molecular pharmacology JID - 0035623 RN - 0 (15-deoxyprostaglandin J2) RN - 0 (Endocannabinoids) RN - 0 (Esters) RN - 0 (Monoglycerides) RN - 0 (NF-E2-Related Factor 2) RN - 0 (NFE2L2 protein, human) RN - 0 (Prostaglandins) RN - 0 (Protein Isoforms) RN - EC 3.- (Hydrolases) RN - EC 3.1.1.23 (Monoacylglycerol Lipases) RN - PDC6A3C0OX (Glycerol) RN - RXY07S6CZ2 (Prostaglandin D2) SB - IM MH - Catalytic Domain/physiology MH - Cells, Cultured MH - Endocannabinoids/metabolism MH - Esters/*metabolism MH - Glycerol/*metabolism MH - HEK293 Cells MH - Human Umbilical Vein Endothelial Cells MH - Humans MH - Hydrolases/metabolism MH - Hydrolysis MH - Kinetics MH - Monoacylglycerol Lipases/*metabolism MH - Monoglycerides/metabolism MH - NF-E2-Related Factor 2/metabolism MH - Prostaglandin D2/analogs & derivatives/metabolism MH - Prostaglandins/*metabolism MH - Protein Isoforms/metabolism MH - Signal Transduction/physiology EDAT- 2014/08/21 06:00 MHDA- 2015/01/08 06:00 CRDT- 2014/08/21 06:00 PHST- 2014/08/21 06:00 [entrez] PHST- 2014/08/21 06:00 [pubmed] PHST- 2015/01/08 06:00 [medline] AID - S0026-895X(24)03998-1 [pii] AID - 10.1124/mol.114.094284 [doi] PST - ppublish SO - Mol Pharmacol. 2014 Nov;86(5):522-35. doi: 10.1124/mol.114.094284. Epub 2014 Aug 19.