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Identification of glycine N-acyltransferase-like 2 (GLYATL2) as a transferase that produces N-acyl glycines in humans.
Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
2010 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 24, no 8, 2795-2803 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2010. Vol. 24, no 8, 2795-2803 p.
Keyword [en]
N-oleoyl glycine, N-arachidonoyl glycine, endocannabinoids, N-acyl amino acids, endoplasmic reticulum
National Category
Biochemistry and Molecular Biology
Research subject
Biochemistry; Molecular Cellbiology; Molecular Genetics
URN: urn:nbn:se:su:diva-75625DOI: 10.1096/fj.09-148551OAI: diva2:517488
Swedish Research Council
Available from: 2012-04-23 Created: 2012-04-23 Last updated: 2012-05-02Bibliographically approved
In thesis
1. Biosynthesis and physiological functions of N-acyl amino acids
Open this publication in new window or tab >>Biosynthesis and physiological functions of N-acyl amino acids
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

N-acyl amino acids are lipid signalling molecules that have recently been identified in biological systems. These lipids are structurally related to the endocannabinoids, although they do not activate cannabinoid receptors. In 2001, N-arachidonoyl glycine was the first signalling lipid in this group to be identified in bovine and rat brain and since then, about 50 novel N-acyl amino acids have been identified in mammalian systems. These N-acyl amino acids are involved in regulating pain processes, are anti-inflammatory and regulate body temperature, but the metabolic pathways for production and metabolism remain poorly understood.

This thesis focussed on the identification of pathways for production and regulation of N-acyl amino acids, in particular N-acyl glycines, and in identifying physiological functions for N-acyl amino acids (particularly N-acyl taurines). Our results identified an enzymatic pathway for production of N-acyl glycines in human and we identified that the human glycine N-acyltransferase-like 2 (hGLYATL2) conjugates (amidates) medium- and long-chain, saturated and unsaturated acyl-CoAs with glycine, to produce N-acyl glycines, with the preferential production of N-oleoyl glycine. Furthermore, we have characterized two other members of the gene family of glycine N-acyltransferases (GLYATs) in human, the hGLYATL1 and hGLYATL3 that may be involved in the production of N-acyl amino acids.

As N-acyl glycines are bioactive signalling molecules, it is likely their production requires a rapid on/off switch. The post-translational modification of proteins can result in enzyme regulation, without the need for transcriptional regulation. We have identified that hGLYATL2 is regulated by acetylation/deacetylation on lysine 19, and using mutation analysis, we show that deacetylation of lysine 19 is important for full enzyme activity.

The physiological functions of N-acyl amino acids are not well studied to date. In this thesis, we have identified that N-arachidonoyl taurine and N-oleoyl taurine trigger insulin secretion by increasing the calcium flux in pancreatic b-cells via the activation of transient receptor potential vanilloid subfamily 1 (TRPV1).

This work on N-acyl amino acids has led us to identify new pathways and physiological functions for these lipid signalling molecules, which advances our knowledge of the importance of these lipids in mammalian systems.

Place, publisher, year, edition, pages
Stockholm: Department of Genetics, Microbiology and Toxicology, Stockholm University, 2012. 62 p.
National Category
Cell Biology Biochemistry and Molecular Biology Genetics
Research subject
Molecular Genetics
urn:nbn:se:su:diva-75766 (URN)978-91-7447-523-4 (ISBN)
Public defence
2012-06-01, sal G, Arrheniuslaboratorierna, Svante Arrhenius väg 20 C, Stockholm, 10:00 (English)

At the time of doctoral defence the following papers were unpublished and had a status as follows:Paper 2: Accepted; Paper 3: Manuscript; Paper 4; Manuscript

Available from: 2012-05-10 Created: 2012-04-26 Last updated: 2013-04-09Bibliographically approved

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Waluk, Dominik P.Schultz, Niklas
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