Identification of glycineN‐acyltransferase‐like 2 (GLYATL2) as a transferase that producesN‐acyl glycines in humans

Abstract

The discovery of glycine conjugates of long-chain fatty acids (N-acyl glycines) in the brain and other non-neuronal tissues has led to the identification of an emerging class of bioactive lipids. The biological activities of N-acyl glycines include antinociceptive, anti-inflammatory and antiproliferative effects, and activation of G-protein-coupled receptors. However, despite the fact that N-acyl glycines are emerging as a distinct lipid signaling family, pathways for their production are not fully elucidated. Here we report on the characterization of human glycine N-acyltransferase-like 2 (hGLYATL2), a member of a gene family of 4 putative glycine conjugating enzymes, and show that it synthesizes various N-acyl glycines. Recombinantly expressed hGLYATL2 efficiently conjugated oleoyl-CoA, arachidonoyl-CoA, and other medium- and long-chain acyl-CoAs to glycine. The enzyme was specific for glycine as an acceptor molecule, and preferentially produced N-oleoyl glycine. The hGLYATL2 enzyme is localized to the endoplasmic reticulum, and the mRNA shows highest expression in salivary gland and trachea, but is also detected in spinal cord and skin fibroblasts. The expression pattern and the identification of high levels of N-acyl glycines in skin and lung may indicate a role for N-acyl glycines in barrier function/immune response and the potential role of hGLYATL2 in this regard is discussed.

Primary fatty acid amide metabolism: conversion of fatty acids and an ethanolamine in N18TG2 and SCP cells

“…A number of N -fatty acylglycines have been identifi ed from mammalian sources ( 37,39 ), and there is evidence that these members of the fatty acid amide family are also cell signaling lipids (40)(41)(42). The biosynthesis of these lipids is also unclear; suggested pathways include glycine conjugation of the fatty acyl-CoA thioesters ( 34,43 ) and sequential oxidation of the N -acylethanolamines ( 44,45 ) ( Fig. 1 ).…”

Reversible Lysine Acetylation Regulates Activity of Human Glycine N-Acyltransferase-like 2 (hGLYATL2)

“…Proteins-The hGLYATL2 open reading frame was previously cloned into the pMal-c2x vector (New England Biolabs, Beverly, MA) (14). Two mutations were introduced into the hGLYATL2 protein; K19R, which is a conserved substitution in the sense that the Arg has the same charge and is about the same size as Lys but cannot be acetylated.…”

“…Two of these enzymes identified in mouse mitochondria were members of the gene family of glycine N-acyltransferases (GLYATs). 2 GLYATs are a family of enzymes that conjugate various xenobiotics and acyl-CoA esters to glycine (12)(13)(14). Lysine 19 of the murine GLYAT was shown to be acetylated (11), and this lysine is conserved in GLYAT enzymes in several different species (including human GLYATL2).…”

“…Lysine 19 of the murine GLYAT was shown to be acetylated (11), and this lysine is conserved in GLYAT enzymes in several different species (including human GLYATL2). We have recently characterized the hGLYATL2 enzyme and showed that it conjugates medium-and long-chain saturated and unsaturated acyl-CoA esters to glycine, resulting in the production of mainly N-oleoyl glycine but also other N-acyl glycines including N-arachidonoyl glycine (14). N-Arachidonoyl glycine and N-oleoyl glycine are structurally and functionally related to endocannabinoids and have been identified as signaling molecules that regulate functions like the perception of pain and body temperature and also have anti-inflammatory properties (15)(16)(17).…”

Redetermination of the crystal structure of N-acetyl glycine (2-acetamidoacetic acid), C4H7NO3

“…It is used as the starting material for the synthesis of oxazalones and aryl methyl triazinones [1,2]. The biological activities of N-acyl glycine derivatives include antinociceptive, anti-inflammatory and antiproliferative effects as well as the ability of activating G-protein-coupled receptors [3]. The crystal structure of N-acetyl glycine was originally determined by Carpenter and Donhue by means of neutron radiation in 1950 but no atomic coordinates were determined [4].…”