Involvement of the γ Isoform of cPLA2 in the Biosynthesis of Bioactive N-Acylethanolamines

• Published in: Molecules (Basel, Switzerland) Vol. 26; no. 17; p. 5213
• Main Authors: Guo, Yiman, Uyama, Toru, Rahman, S. M. Khaledur, Sikder, Mohammad Mamun, Hussain, Zahir, Tsuboi, Kazuhito, Miyake, Minoru, Ueda, Natsuo
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 27.08.2021; MDPI
• Subjects: Acyltransferase; Analgesics; Anandamide; Biosynthesis; Cannabinoid receptors; Cannabinoids; Chromatography; endocannabinoid; Enzymes; Ethanolamine; Fatty acids; Glycerol; Inflammation; Isoforms; Lysophospholipase; Metabolism; N-Acylethanolamine; N-acyltransferase; Palmitylethanolamide; Phosphatidylethanolamine; Phospholipase; Phospholipase A1; Phospholipase A2; Proteins
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules26175213

Arachidonylethanolamide (anandamide) acts as an endogenous ligand of cannabinoid receptors, while other N-acylethanolamines (NAEs), such as palmitylethanolamide and oleylethanolamide, show analgesic, anti-inflammatory, and appetite-suppressing effects through other receptors. In mammalian tissues, NAEs, including anandamide, are produced from glycerophospholipid via N-acyl-phosphatidylethanolamine (NAPE). The ɛ isoform of cytosolic phospholipase A2 (cPLA2) functions as an N-acyltransferase to form NAPE. Since the cPLA2 family consists of six isoforms (α, β, γ, δ, ɛ, and ζ), the present study investigated a possible involvement of isoforms other than ɛ in the NAE biosynthesis. Firstly, when the cells overexpressing one of the cPLA2 isoforms were labeled with [14C]ethanolamine, the increase in the production of [14C]NAPE was observed only with the ɛ-expressing cells. Secondly, when the cells co-expressing ɛ and one of the other isoforms were analyzed, the increase in [14C]N-acyl-lysophosphatidylethanolamine (lysoNAPE) and [14C]NAE was seen with the combination of ɛ and γ isoforms. Furthermore, the purified cPLA2γ hydrolyzed not only NAPE to lysoNAPE, but also lysoNAPE to glycerophospho-N-acylethanolamine (GP-NAE). Thus, the produced GP-NAE was further hydrolyzed to NAE by glycerophosphodiesterase 1. These results suggested that cPLA2γ is involved in the biosynthesis of NAE by its phospholipase A1/A2 and lysophospholipase activities.