Effect of synthetic and natural phospholipids on N-acylphosphatidylethanolamine-hydrolyzing phospholipase D activity

• Published in: Chemistry and physics of lipids Vol. 162; no. 1; pp. 53 - 61
• Main Authors: Petersen, Gitte, Pedersen, Anders H., Pickering, Darryl S., Begtrup, Mikael, Hansen, Harald S.
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 01.11.2009
• Subjects: Anandamide; Cannabinoid; Cell Line; Cephalosporins - pharmacology; Diether phospholipid substrate; Dose-Response Relationship, Drug; Humans; Molecular Structure; NAPE-PLD; Oleoylethanolamide; Palmitoylethanolamide; Phospholipase D - antagonists & inhibitors; Phospholipase D - chemistry; Phospholipase D - metabolism; Phospholipids - chemical synthesis; Phospholipids - chemistry; Phospholipids - pharmacology; Stereoisomerism; Structure-Activity Relationship; FAAH; Palmitoylethanolamide; OEA; GP-NAE; Oleoylethanolamide; NAPE; Cannabinoid; PEA; Diether phospholipid substrate; CB 1; Anandamide; NAE; NAPE-PLD; AEA
• ISSN: 0009-3084; 1873-2941
• DOI: 10.1016/j.chemphyslip.2009.08.005

N-Acylethanolamines (NAEs) constitute a family of endogenous bioactive lipids that includes arachidonoylethanolamide (anandamide), palmitoylethanolamide (PEA) and oleoylethanolamide (OEA). These lipids are formed from their respective N-acylated ethanolamine phospholipid (NAPE) precursor by the action of a phospholipase D enzyme (NAPE-PLD). Anandamide, OEA, and PEA are all bioactive lipids that may influence, amongst others: neuroinflammation, food intake, and oocyte implantation. Here we have synthesized a number of NAPE analogues with variation in the phosphoester structure. The NAPE analogues as well as selected phospholipids and beta-lactamase substrates were tested as potential modifiers of cloned human NAPE-PLD in an enzyme assay involving a 14C-labeled diether-NAPE substrate. One hit was identified, namely 1,2-dihexanoyl-glycero- N-(3-(tetradecanoylamino)propyl)phosphoramidate (AHP-71B) which showed inhibitory activity and may serve as template for further structure–activity developments. Furthermore, it was found that NAPE-PLD was activated by phosphatidylethanolamine and inhibited by the beta-lactamase substrate nitrocefin.