Cannabinoids

The Biosynthesis, Fate and Pharmacological Properties of Endocannabinoids 151

Fig. 2. Major biosynthetic pathways and enzymes for the endocannabinoid anandamide (AEA)
and otherN-acylethanolamines. Thecircled Pindicates a phosphate group.N-ArPE,N-arachidonoyl-
phosphatidylethanolamine;PE, phosphatidylethanolamine;PLD, phospholipase D;sPLA 2 , secretory phos-
pholipase A 2 of group IB

metalloproteinase family of hydrolases of theβ-lactamase fold (Okamoto et al.

2004). Several independent lines of evidence strongly suggest that this pathway is
the one mostly responsible for AEA biosynthesis in intact cells, and in particular:

• The finding of a similar distribution of NArPE and AEA in nine different brain
  areas (Bisogno et al. 1999a), and of increasing levels of both NArPE and AEA in
  rat brain at different stages of development (Berrendero et al. 1999), confirms a
  precursor/product relationship for the two compounds.


• The Ca2+sensitivity of both thetrans-acylase and NAPE-PLD is in agreement
  with the fact that AEA biosynthesis is triggered by neuronal depolarization and
  other Ca2+mobilizing stimuli.


• The fact that this biosynthetic pathway is common to other NAEs, and that
  the percentage fatty acyl chain composition of these compounds in tissues is
  ultimately dependent on that of thesn-1 position of phospholipids (Fig. 2),
  explains why AEA is the minor of its congeners.