PMID- 25140003
OWN - NLM
STAT- MEDLINE
DCOM- 20150107
LR  - 20140926
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  - United States
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 - mol.114.094284 [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.