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Endocannabinoid metabolism in the absence of fatty acid amide hydrolase (FAAH): Discovery of phosphorylcholine derivatives of N-acyl ethanolamines

Academic Article
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Overview

related to degree

  • Mulder, Anke M, Ph.D. in Biology, Scripps Research 2004 - 2010

authors

  • Mulder, Anke M
  • Cravatt, Benjamin

publication date

  • 2006

journal

  • Biochemistry  Journal

abstract

  • Lipid transmitters are tightly regulated by a balance of biosynthetic and degradative enzymes. Termination of the activity of the N-acyl ethanolamine (NAE) class of lipid-signaling molecules, including the endocannabinoid anandamide (AEA), is principally mediated by the integral membrane enzyme fatty acid amide hydrolase (FAAH) in vivo. FAAH(-/-) mice are highly sensitized to the pharmacological effects of AEA; however, these animals eventually recover from AEA treatment, implying the existence of alternative routes for NAE metabolism. Here, we have pursued the characterization of these pathways by profiling the metabolome of FAAH(-/-) mice treated with AEA. Multiple AEA-induced metabolites were observed in brains from FAAH(-/-) mice, including a major product with a mass shift of +165 Da (m/z 513). The structure of this product was determined to be O-phosphorylcholine (PC)-AEA. Analysis of untreated mice identified PC-NAEs as endogenous constituents of the central nervous system (CNS) that were highly elevated in FAAH(-/-) animals. PC-NAEs were very poor substrates for FAAH; however, a vanadate-sensitive enzymatic activity was detected in brain membranes that converted PC-NAEs back to their parent NAEs. The choline-specific phosphodiesterase NPP6 was identified as a candidate enzyme responsible for this activity. These data indicate the presence of a complete metabolic pathway for the production and degradation of PC-NAEs in the CNS that constitutes an alternative route for endocannabinoid metabolism.

subject areas

  • Amidohydrolases
  • Animals
  • Arachidonic Acids
  • Brain Chemistry
  • Cannabinoid Receptor Modulators
  • Endocannabinoids
  • Ethanolamines
  • Mice
  • Models, Biological
  • Phosphoric Diester Hydrolases
  • Phosphorylcholine
  • Polyunsaturated Alkamides
  • Spinal Cord
  • Substrate Specificity
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Identity

International Standard Serial Number (ISSN)

  • 0006-2960

Digital Object Identifier (DOI)

  • 10.1021/bi061122s

PubMed ID

  • 16981687
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Additional Document Info

start page

  • 11267

end page

  • 11277

volume

  • 45

issue

  • 38

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