A calcium-dependent acyltransferase that produces N-acyl phosphatidylethanolamines

An activity-based proteomic strategy identifies PLA2G4E as the calcium-dependent N-acyltransferase that generates an unusual triacylated class of lipids, the NAPEs, which are precursors to bioactive lipids including the endogenous cannabinoid anandamide. More than 30 years ago, a calcium-dependent enzyme activity was described that generates N -acyl phosphatidylethanolamines (NAPEs), which are precursors for N -acyl ethanolamine (NAE) lipid transmitters, including the endocannabinoid anandamide. The identity of this calcium-dependent N-acyltransferase (Ca-NAT) has remained mysterious. Here, we use activity-based protein profiling to identify the poorly characterized serine hydrolase PLA2G4E as a mouse brain Ca-NAT and show that this enzyme generates NAPEs and NAEs in mammalian cells.