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Endocannabinoid biosynthesis proceeding through glycerophospho-N-acyl ethanolamine and a role for alpha/beta-hydrolase 4 in this pathway.

Abstract
N-Acyl ethanolamines (NAEs) are a large class of signaling lipids implicated in diverse physiological processes, including nociception, cognition, anxiety, appetite, and inflammation. It has been proposed that NAEs are biosynthesized from their corresponding N-acyl phosphatidylethanolamines (NAPEs) in a single enzymatic step catalyzed by a phospholipase D (NAPE-PLD). The recent generation of NAPE-PLD(-/-) mice has revealed that these animals possess lower brain levels of saturated NAEs but essentially unchanged concentrations of polyunsaturated NAEs, including the endogenous cannabinoid anandamide. These findings suggest the existence of additional enzymatic routes for the production of NAEs in vivo. Here, we report evidence for an alternative pathway for NAE biosynthesis that proceeds through the serine hydrolase-catalyzed double-deacylation of NAPE to generate glycerophospho-NAE, followed by the phosphodiesterase-mediated cleavage of this intermediate to liberate NAE. Furthermore, we describe the functional proteomic isolation and identification of a heretofore uncharacterized enzyme alpha/beta-hydrolase 4 (Abh4) as a lysophospholipase/phospholipase B that selectively hydrolyzes NAPEs and lysoNAPEs. Abh4 accepts lysoNAPEs bearing both saturated and polyunsaturated N-acyl chains as substrates and displays a distribution that closely mirrors lysoNAPE-lipase activity in mouse tissues. These results support the existence of an NAPE-PLD-independent route for NAE biosynthesis and suggest that Abh4 plays a role in this metabolic pathway by acting as a (lyso)NAPE-selective lipase.
AuthorsGabriel M Simon, Benjamin F Cravatt
JournalThe Journal of biological chemistry (J Biol Chem) Vol. 281 Issue 36 Pg. 26465-72 (Sep 08 2006) ISSN: 0021-9258 [Print] United States
PMID16818490 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Cannabinoid Receptor Modulators
  • Endocannabinoids
  • Ethanolamines
  • Glycerophosphates
  • N-acylethanolamines
  • Recombinant Proteins
  • Dioxygenases
  • ALKBH4 protein, mouse
  • AlkB Homolog 4, Lysine Demethylase
  • Hydrolases
  • Phospholipases
  • Lipase
  • N-acylphosphatidylethanolamine phospholipase D, mouse
  • Phospholipase D
Topics
  • AlkB Homolog 4, Lysine Demethylase
  • Amino Acid Sequence
  • Animals
  • Cannabinoid Receptor Modulators (biosynthesis)
  • Dioxygenases
  • Endocannabinoids
  • Ethanolamines (chemistry, metabolism)
  • Glycerophosphates (metabolism)
  • Humans
  • Hydrolases (classification, genetics, metabolism)
  • Lipase (metabolism)
  • Mice
  • Mice, Knockout
  • Molecular Sequence Data
  • Phospholipase D (genetics, metabolism)
  • Phospholipases (classification, genetics, metabolism)
  • Phylogeny
  • Recombinant Proteins (genetics, metabolism)
  • Sequence Alignment
  • Substrate Specificity
  • Tissue Distribution

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