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

Natalia Battista,Monica Bari,Tiziana Bisogno

doi:10.3390/biom9120822

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.

Highlights

N-acyl amino acids (NAAAs) are an important family of endogenous signaling molecules in which an amide bond covalently links an amino acid to the acyl moiety of a long-chain fatty acid. lipid containing amino acids, some of them produced in response to certain stress conditions, were identified in different bacterial membranes, little is known about their specific molecular functions [1,2]
Both NAraAla and NAraGABA were slightly oxidized by COX-2 and, unlike N-arachidonoyl glycine (NAraGly), they α-amidating monooxygenase (PAM), an enzyme in thewas production of peptide were metabolized by COX-1 though the rate involved of conversion even lower than foramides, COX-2 catalyzed the oxidative cleavageα-amidating of N-oleoyl glycine (NOleGly) to the primary fatty acid an amide, oleamide
Reduced NOleSer levels were detected in mice KO for the maternally imprinted gene in the Prader Willi syndrome (PWS) critical region, Magel2, causing osteoblast dysfunction, increased osteoclastogenesis and osteoclast activity [66]. Different technologies, such as proteomics, lipidomics, bioinformatics as well as systems biology approaches let to the identification of many NAAAs in the mammalian body

Summary

Introduction

N-acyl amino acids (NAAAs) are an important family of endogenous signaling molecules in which an amide bond covalently links an amino acid to the acyl moiety of a long-chain fatty acid. The development of functional proteomic technology for enzymes allowed the identification of a new class of metabolites significantly elevated in mice in which the gene encoding for AEA-hydrolyzing enzyme fatty acid amide hydrolase (FAAH) has been ablated [8]. These compounds were identified as amides between very long-chain fatty acids and sulfur-containing amino acid, taurine, (N-acyl taurines, NATs) [8]. Biomolecules 2019, 9, 822 rapidly growing in recent years and they have been emerging as important family of endogenous signaling molecules, only a limited amount of research has been reported on some of these compounds and their physiological role(s) is not known. In this review we summarize literature data on the most widely studied member of NAAA family, i.e., N-acyl glycines (NAGlys) and NASers, to underscore that the understanding of biochemical and molecular mechanisms, underlying their pharmacological actions, may serve to find way to properly exploit their therapeutic potential

Metabolic Pathways for NAAAs

N-Acyl Glycines

N-Acyl-Serines

Conclusions