Abstract
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.
Highlights
We recently reported that cytosolic phospholipase A2 (cPLA2) -expressing cells pretreated with [14 C]ethanolamine produce a large amount of [14 C]NAPE in response to the Ca2+ ionophore ionomycin [18]
Considering the wide distribution of cPLA2 γ in mouse tissues, cPLA2 γ may function as an alternative of ABHD4 in the NAE biosynthesis
We first suggested that in living cells, the γ isoform of cPLA2 has PLA1 /A2 activity to generate lysoNAPE from NAPE, which was produced by the isoform of cPLA2
Summary
N-Acylethanolamines (NAEs) are a class of bioactive lipids consisting of long-chain fatty acids and ethanolamine, and are widely present in animal and plant tissues [1]. (PE), resulting in the formation of N-acyl-phosphatidylethanolamine (NAPE), a unique phospholipid molecule with three fatty acyl chains The enzymes catalyzing this reaction are collectively called N-acyltransferases, which are classified into two groups by. The phospholipase D (PLD)-type enzyme NAPE-PLD directly produces NAE [9], while the alternative pathway does not involve NAPE-PLD, but consists of consecutive hydrolytic reactions via N-acyl-lysophosphatidylethanolamine (lysoNAPE) and glycerophospho-Nacylethanolamine (GP-NAE) (Figure 1) [10,11]. This pathway involves several hydrolases such as group IB, IIA, and V of secretory phospholipase A2 s (sPLA2 s) [12], α/β-hydrolase domain containing 4 (ABHD4) [13], and glycerophosphodiesterase (GDE) 1 [14].
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