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PMID: 18096503 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol.

Chemistry & biology ·Vol. 14 ·No. 12 ·2007-12-00 ·Pages 1347-56

Blankman JL, Simon GM, Cravatt BF

Abstract

Endogenous ligands for cannabinoid receptors ("endocannabinoids") include the lipid transmitters anandamide and 2-arachidonoylglycerol (2-AG). Endocannabinoids modulate a diverse set of physiological processes and are tightly regulated by enzymatic biosynthesis and degradation. Termination of anandamide signaling by fatty acid amide hydrolase (FAAH) is well characterized, but less is known about the inactivation of 2-AG, which can be hydrolyzed by multiple enzymes in vitro, including FAAH and monoacylglycerol lipase (MAGL). Here, we have taken a functional proteomic approach to comprehensively map 2-AG hydrolases in the mouse brain. Our data reveal that approximately 85% of brain 2-AG hydrolase activity can be ascribed to MAGL, and that the remaining 15% is mostly catalyzed by two uncharacterized enzymes, ABHD6 and ABHD12. Interestingly, MAGL, ABHD6, and ABHD12 display distinct subcellular distributions, suggesting that they may control different pools of 2-AG in the nervous system.

MeSH Terms
Animals Arachidonic Acids/metabolism Benzamides/pharmacology Biotin/analogs & derivatives,pharmacology Brain/drug effects,enzymology,metabolism COS Cells Carbamates/pharmacology Catalysis/drug effects Chlorocebus aethiops Endocannabinoids Enzyme Inhibitors/pharmacology Glycerides/metabolism Hydrolases/genetics,metabolism Lactones/pharmacology Membrane Proteins/metabolism Mice Mice, Inbred C57BL Monoacylglycerol Lipases/genetics,metabolism Organophosphorus Compounds/pharmacology Orlistat Proteomics/methods Subcellular Fractions/metabolism Transfection
Chemicals
10-(fluoroethoxyphosphinyl)-N-(biotinamidopentyl)decanamide Arachidonic Acids Benzamides Carbamates Endocannabinoids Enzyme Inhibitors Glycerides Lactones Membrane Proteins Organophosphorus Compounds cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester Biotin glyceryl 2-arachidonate Orlistat Hydrolases ABHD6 protein, mouse Abhd12 protein, mouse Monoacylglycerol Lipases
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Blankman Jacqueline L
The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA.
Simon Gabriel M
Cravatt Benjamin F
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Article Info
Journal
Chemistry & biology
Abbr.
Chem Biol
ISSN
1074-5521
DOI
10.1016/j.chembiol.2007.11.006
Published
2007-12-00
Pages
1347-56
Language
English
Region
United States
NLM ID
9500160
PMCID
PMC2692834
Subset
IM
Grants
NIDA NIH HHS · DA015197 · United States
NIDA NIH HHS · R01 DA015197 · United States
NIDA NIH HHS · P01 DA017259-04 · United States
NIDA NIH HHS · P01 DA017259-020001 · United States
NIDA NIH HHS · R01 DA015197-05 · United States
NIDA NIH HHS · DA017259 · United States
NIDA NIH HHS · P01 DA017259 · United States
NIDA NIH HHS · P01 DA017259-030001 · United States
Corrections
CommentIn
PMID: 18096497
External Links
PubMed source DOI: 10.1016/j.chembiol.2007.11.006 PMC Full Text View journal details
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