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.