Anandamide biosynthesis catalyzed by the phosphodiesterase GDE1 and detection of glycerophospho-N-acyl ethanolamine precursors in mouse brain

J Biol Chem. 2008 Apr 4;283(14):9341-9. doi: 10.1074/jbc.M707807200. Epub 2008 Jan 27.


Anandamide (AEA) is an endogenous ligand of cannabinoid receptors and a well characterized mediator of many physiological processes including inflammation, pain, and appetite. The biosynthetic pathway(s) for anandamide and its N-acyl ethanolamine (NAE) congeners remain enigmatic. Previously, we proposed an enzymatic route for producing NAEs that involves the double-O-deacylation of N-acyl phosphatidylethanolamines (NAPEs) by alpha/beta-hydrolase 4 (ABDH4 or Abh4) to form glycerophospho (GP)-NAEs, followed by conversion of these intermediates to NAEs by an unidentified phosphodiesterase. Here, we report the detection and measurement of GP-NAEs, including the anandamide precursor glycerophospho-N-arachidonoylethanolamine (GP-NArE), as endogenous constituents of mouse brain tissue. Inhibition of the phosphodiesterase-mediated degradation of GP-NAEs ex vivo resulted in a striking accumulation of these lipids in brain extracts, suggesting a rapid endogenous flux through this pathway. Furthermore, we identify the glycerophosphodiesterase GDE1, also known as MIR16, as a broadly expressed membrane enzyme with robust GP-NAE phosphodiesterase activity. Together, these data provide evidence for a multistep pathway for the production of anandamide in the nervous system by the sequential actions of Abh4 and GDE1.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AlkB Homolog 4, Lysine Demethylase
  • Animals
  • Arachidonic Acids / biosynthesis*
  • Brain / enzymology*
  • Brain Chemistry / physiology*
  • Dioxygenases
  • Endocannabinoids
  • Male
  • Mice
  • Phosphatidylethanolamines / metabolism*
  • Phospholipases / metabolism*
  • Phosphoric Diester Hydrolases / metabolism*
  • Polyunsaturated Alkamides


  • Arachidonic Acids
  • Endocannabinoids
  • Phosphatidylethanolamines
  • Polyunsaturated Alkamides
  • glycerophosphoethanolamine
  • Dioxygenases
  • ALKBH4 protein, mouse
  • AlkB Homolog 4, Lysine Demethylase
  • Phospholipases
  • Phosphoric Diester Hydrolases
  • glycerophosphodiester phosphodiesterase
  • anandamide