Anandamide biosynthesis catalyzed by the sequential actions of a phospholipase (ABH4) and phosphodiesterase (GDE1) on the precursor N‐acyl phosphatidylethanolamines

Abstract

Anandamide is a member of the N‐acyl ethanolamine (NAE) family of signaling lipids and an endogenous ligand of cannabinoid receptors that is implicated in many physiological processes including pain, inflammation, appetite, and cognition. The biosynthetic precursor for NAEs are N‐acyl phosphatidyl ethanolamines (NAPEs) but the precise enzymatic steps leading to release of NAEs from NAPEs are unclear. Three pathways have been proposed: (1) direct release of NAE from NAPE by a D‐type phospholipase (NAPE‐PLD), (2) phospholipase C‐mediated cleavage of NAPE generating phospho‐NAE followed by action of a phosphatase and (3) double O‐deacylation of NAPE followed by cleavage of the phosphodiester bond of the resulting GP‐NAE. Evidence is presented in support of the third pathway: In mice containing a targeted deletion of the NAPE‐PLD gene, AEA levels were unchanged in brain and enzymatic conversion of NAPE to NAE absolutely required cleavage of the O‐acyl chains. Here we present evidence that a B‐type phospholipase (ABH4) and a metal‐dependent phosphodiesterase (GDE1) act on NAPEs and GP‐NAEs, respectively, to generate anandamide via the deacylation pathway.