The Biosynthetic Pathways of N‐Acylethanolamines in Mammals


N‐Acylethanolamines (NAEs) constitute a class of endogenous bioactive lipid molecules, including arachidonoylethanolamide (anandamide), palmitoylethanolamide and oleoylethanolamide. Thus, the enzymes responsible for the NAE metabolism in mammalian tissues attract much attention as targets for the development of therapeutic drugs. In the major biosynthetic pathway of NAE, the first reaction is the formation of N‐acyl‐phosphatidylethanolamine (NAPE) from phosphatidylethanolamine by N‐acyltransferase, and the second reaction is the release of NAE from NAPE by NAPE‐hydrolysing phospholipase D (NAPE‐PLD). Recent studies confirmed the presence of multiple N‐acyltransferases distinguished by Ca2+ dependency. While Ca2+‐dependent N‐acyltransferase was identified as the ϵ isoform of cytosolic phospholipase A2, members of the phospholipase A/acyltransferase (PLAAT) family were found to show Ca2+‐independent N‐acyltransferase activity. Furthermore, NAPE‐PLD‐deficient mice produced NAE from NAPE through multistep pathways via lysoNAPE. Here, we outline the recent findings regarding N‐acyltransferases and other enzymes involved in the NAE biosynthesis.

Key Concepts

  • Bioactive N‐acylethanolamines (NAEs) are enzymatically produced from membrane phospholipids via N‐acyl‐phosphatidylethanolamines (NAPEs) in mammals.
  • The enzymes responsible are expected as possible targets for the development of therapeutic drugs.
  • N‐Acyltransferase and NAPE‐hydrolysing phospholipase D (NAPE‐PLD) are two major enzymes involved in the NAE biosynthesis.
  • ϵ isoform of cytosolic phospholipase A2 acts as Ca2+‐dependent N‐acyltransferase.
  • Phospholipase A/acyltransferase (PLAAT) family proteins have Ca2+‐independent N‐acyltransferase activity.
  • The analysis of NAPE‐PLD‐deficient mice exhibited the presence of NAPE‐PLD‐independent pathways for the NAE formation in vivo.
  • N‐Acyl‐plasmenylethanolamine also serves as precursor of NAE.

Keywords: N‐acylethanolamine; N‐acyl‐phosphatidylethanolamine; N‐acyltransferase; anandamide; HRASLS family; NAPE‐PLD; oleoylethanolamide; palmitoylethanolamide; phospholipid; phospholipase A2

Figure 1. Chemical structures and biological activities of representative NAEs.
Figure 2. The major NAE biosynthetic pathway. PA, phosphatidic acid.
Figure 3. Alignment of the amino acid sequences of human, mouse and rat cPLA2ϵs. C2 domain, lipase domain and polybasic domain are shown by single, dashed and double lines, respectively. Asterisks show Ser/Asp catalytic dyad. Closed and shaded boxes indicate identity in all three or any two proteins, respectively.
Figure 4. Alignment of the amino acid sequences of human PLAAT family members. Closed and shaded boxes indicate identity in all five and any three polypeptides, respectively. Proline‐rich domain, H‐box, NC domain and hydrophobic domain are indicated by lines. The asterisks indicate the catalytic His and catalytic nucleophile Cys residues, and the dots indicate Arg residues in the polybasic domain of PLAAT‐1.
Figure 5. NAPE‐PLD‐dependent and ‐independent pathways. DAG, diacylglycerol; PA, phosphatidic acid.


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Binte Mustafiz, Smriti Sultana, Uyama, Toru, Hussain, Zahir, Tsuboi, Kazuhito, and Ueda, Natsuo(Jan 2018) The Biosynthetic Pathways of N‐Acylethanolamines in Mammals. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0027711]