N-Acyl Amino Acids: Metabolism, Molecular Targets, and Role in Biological Processes

Abstract

The lipid signal is becoming increasingly crowded as increasingly fatty acid amide derivatives are being identified and considered relevant therapeutic targets. The identification of N-arachidonoyl-ethanolamine as endogenous ligand of cannabinoid type-1 and type-2 receptors as well as the development of different–omics technologies have the merit to have led to the discovery of a huge number of naturally occurring N-acyl-amines. Among those mediators, N-acyl amino acids, chemically related to the endocannabinoids and belonging to the complex lipid signaling system now known as endocannabinoidome, have been rapidly growing for their therapeutic potential. Here, we review the current knowledge of the mechanisms for the biosynthesis and inactivation of the N-acyl amino acids, as well as the various molecular targets for some of the N-acyl amino acids described so far.

Endocannabinoid-Like Lipid Neuromodulators in the Regulation of Dopamine Signaling: Relevance for Drug Addiction

“…Very little is known about the biosynthesis of N- acyl amino acids, except for N-acyl glycines, where it is hypothesized that glycine is directly condensed with the free fatty acid or CoenzymeA derivative acyl moiety by cytochrome C or glycine NAT -like 2 and 3 enzymes (Huang et al, 2001 ; McCue et al, 2008 ; Waluk et al, 2010 ; see Burstein, 2018 ; Battista et al, 2019 ; for comprehensive reviews of N-acyl amino acids).…”

“…When catabolized, NAEs and N- acyl amino acids are hydrolyzed to free fatty acids and ethanolamine or amino acids (Cravatt et al, 1996 ; Deutsch et al, 2002 ; Battista et al, 2019 ), respectively ( Figure 1 ). This hydrolysis is catalyzed mainly by two major intracellular enzymes, although alternative pathways have been described (Bornheim et al, 1993 ; Hampson et al, 1995 ; Ueda et al, 1995 ; Yu et al, 1997 ; Kozak et al, 2002 ).…”

“…PEA, OEA, and N- oleoylglycine targets have been identified as the PPAR, and specifically the α-isoform (PPARα). Very little is known about the functional relevance of N- acyl amino acids and their receptors such as GPR18, GPR55, or GPR92; this topic is discussed in Burstein ( 2018 ) and Battista et al ( 2019 ).…”

“…N -acyl amino acids are another related family of lipid signaling molecules in which an amino acid is covalently linked by an amide bond to the acyl moiety of a long-chain fatty acid. Among N-acyl amino acids, N-acyl glycines (particularly N- arachidonylglycine and N- oleoylglycine) are emerging as an intriguing class of neuromodulators, although largely uncharacterized so far (Bradshaw et al, 2009 ; Burstein, 2018 ; Battista et al, 2019 ; Table 1 ).…”

Bioactive Lipids in Health and Disease

“…Battista et al [ 9 ] conduct a very interesting and comprehensive review of the mechanisms for the biosynthesis and inactivation of the N -acyl amino acids, as well as of their molecular targets, with a particular focus on the role played by N -acyl-Glyines and N -Acyl-Serines in biological processes. These mediators, belonging to the complex lipid signaling system now known as endocannabinoidome, could have a crucial effect in terms of their therapeutic potential.…”