US scientists have demonstrated the existence of undiscovered chemical pathways to an important class of bioactive lipids in the nervous system. 

Endocannabinoids are lipid messengers that play a key role in both central and peripheral tissues, where they participate in diverse physiological processes including appetite, pain-sensation, mood, and memory. Unlike other neurotransmitters such as amino acids and neuropeptides, they are not water soluble so cannot be stored in the body and are made on-demand from phospholipid precursors involving complex multiple pathways. A complete understanding of these mechanisms is crucial to understanding their effects in mammalian physiology, explains Benjamin Cravatt and Gabriel Simon at the Scripps Research Institute in La Jolla. 

In vitro studies have suggested a number of pathways to make N-acyl-ethanolamines (NAEs), a key endocannabionid lipid as alternatives to the well known conversion of N-acyl phosphatidyl entanolamine (NAPE) by reaction with phosphodiesterase enzymes known as NAPE-PLD and GDE-1. Now, Cravatt and Simon have demonstrated the existence of other pathways using additional enzymes in an in vivo study. 

By studying mice deficient in the enzymes GDE1 and NAPE-PLD, the pair discovered that although there were significant reductions in NAPE to NAE conversion by the known pathways, there was no overall change in NAE levels in the mice brain tissue. 'This result supports the existence of additional NAPE-catabolising enzymes that are operant in situ, and likely in vivo,' explains Cravatt.

Edward Tate, an expert in enzymology and chemical genetics at Imperial College London, UK comments that the move from in vitro to in vivo models is an interesting step to take. 'This work provides another piece in the puzzle of in vivo NAPE/NAE biochemistry and has given a strong indication of where to start looking for the next one,' he adds. 

The researchers say that their next step will be to investigate whether alternative pathways for NAE that do not involve NAPE as the required precursor exist. 

Philippa Ross 

Enjoy this story? Spread the word using the 'tools' menu on the left or add a comment to the Chemistry World blog.