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Molecular Pharmacology

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Research ArticleArticle

Robust Hydrolysis of Prostaglandin Glycerol Esters by Human Monoacylglycerol Lipase (MAGL)

Juha R. Savinainen, Emilia Kansanen, Tatu Pantsar, Dina Navia-Paldanius, Teija Parkkari, Marko Lehtonen, Tuomo Laitinen, Tapio Nevalainen, Antti Poso, Anna-Liisa Levonen and Jarmo T. Laitinen
Molecular Pharmacology November 2014, 86 (5) 522-535; DOI: https://doi.org/10.1124/mol.114.094284
Juha R. Savinainen
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
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Emilia Kansanen
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
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Tatu Pantsar
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
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Dina Navia-Paldanius
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
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Teija Parkkari
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
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Marko Lehtonen
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
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Tuomo Laitinen
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
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Tapio Nevalainen
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
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Antti Poso
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
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Anna-Liisa Levonen
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
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Jarmo T. Laitinen
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
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Abstract

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 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. 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.

Footnotes

    • Received June 25, 2014.
    • Accepted August 19, 2014.
  • J.R.S. and E.K. contributed equally to this work.

  • This research was supported by the Academy of Finland [Grants 139620, 139140, 128056, 133290]; Biocenter Finland/DDCB, the Orion Farmos Foundation, the Emil Aaltonen Foundation, and the Sigrid Juselius Foundation.

  • dx.doi.org/10.1124/mol.114.094284.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 86 (5)
Molecular Pharmacology
Vol. 86, Issue 5
1 Nov 2014
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Research ArticleArticle

Prostaglandin Glycerol Esters as In Vitro Substrates of MAGL

Juha R. Savinainen, Emilia Kansanen, Tatu Pantsar, Dina Navia-Paldanius, Teija Parkkari, Marko Lehtonen, Tuomo Laitinen, Tapio Nevalainen, Antti Poso, Anna-Liisa Levonen and Jarmo T. Laitinen
Molecular Pharmacology November 1, 2014, 86 (5) 522-535; DOI: https://doi.org/10.1124/mol.114.094284

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Research ArticleArticle

Prostaglandin Glycerol Esters as In Vitro Substrates of MAGL

Juha R. Savinainen, Emilia Kansanen, Tatu Pantsar, Dina Navia-Paldanius, Teija Parkkari, Marko Lehtonen, Tuomo Laitinen, Tapio Nevalainen, Antti Poso, Anna-Liisa Levonen and Jarmo T. Laitinen
Molecular Pharmacology November 1, 2014, 86 (5) 522-535; DOI: https://doi.org/10.1124/mol.114.094284
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