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Molecular characterization of two members of the glycine N-acyltransferase gene family in human: glycine N-acyl transferase-like 1 (GLYATL1) and glycine N-acyltransferase-like 3 (GLYATL3).
Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
(English)Manuscript (preprint) (Other academic)
Abstract [en]

N-acyl amino acids are a group of endogenous lipid mediators that regulate a variety of cellular physiological functions. The discovery of N-acyl amino acids in many biological systems has allowed research to focus on their functions as well as pathways for production of these signalling lipids.

We have previously identified that human glycine N-acyltransferase-like 2 (hGLYATL2) is involved in the enzymatic formation of N-acyl glycines. hGLYATL2 is localized in a gene cluster with other glycine N-acyltransferase genes. Here, we have characterized human glycine N-acyltransferase-like 1 (hGLYATL1) and human glycine N-acyltransferase-like 3 (hGLYATL3), which are members of this gene family. Our results show that hGLYATL1 is localized to the endoplasmic reticulum (ER) but the intracellular localization of hGLYATL3 remains to be determined. The hGLYATL1 mRNA shows highest expression in liver and kidney, whereas mRNA of hGLYATL3 is expressed in pancreas and liver. Using bioinformatics we determined the overall three-dimensional (3D) structures of hGLYATL1 and hGLYATL3 enzymes, with predicted binding site residues.

In summary, we have characterized novel members of glycine N-acyltransferases that may be involved in the production of lipid signalling molecules, in particular N-acyl glycines.

National Category
Biochemistry and Molecular Biology
Research subject
Genetics; Cell Biology; Biochemistry; Biochemistry towards Bioinformatics
Identifiers
URN: urn:nbn:se:su:diva-75764OAI: oai:DiVA.org:su-75764DiVA: diva2:523861
Available from: 2012-04-26 Created: 2012-04-26 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
Identifiers
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)
Opponent
Supervisors
Note

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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