title: Reversible lysine acetylation regulates activity of human glycine N-acyltransferase-like 2 (hGLYATL2): implications for production of glycine-conjugated signaling molecules.
abstract: Lysine acetylation is a major post-translational modification of proteins and regulates many physiological processes such as metabolism, cell migration, aging, and inflammation. Proteomic studies have identified numerous lysine-acetylated proteins in human and mouse models (Kim, S. C., Sprung, R., Chen, Y., Xu, Y., Ball, H., Pei, J., Cheng, T., Kho, Y., Xiao, H., Xiao, L., Grishin, N. V., White, M., Yang, X. J., and Zhao, Y. (2006) Mol. Cell 23, 607-618). One family of proteins identified in this study was the murine glycine N-acyltransferase (GLYAT) enzymes, which are acetylated on lysine 19. Lysine 19 is a conserved residue in human glycine N-acyltransferase-like 2 (hGLYATL2) and in several other species, showing that this residue may be important for enzyme function. Mutation of lysine 19 in recombinant hGLYATL2 to glutamine (K19Q) and arginine (K19R) resulted in a 50-80% lower production of N-oleoyl glycine and N-arachidonoylglycine, indicating that lysine 19 is important for enzyme function. LC/MS/MS confirmed that Lys-19 is not acetylated in wild-type hGLYATL2, indicating that Lys-19 requires to be deacetylated for full activity. The hGLYATL2 enzyme conjugates medium- and long-chain saturated and unsaturated acyl-CoA esters to glycine, resulting in the production of N-oleoyl glycine and also N-arachidonoyl glycine. N-Oleoyl glycine and N-arachidonoyl 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. In conclusion, acetylation of lysine(s) in hGLYATL2 regulates the enzyme activity, thus linking post-translational modification of proteins with the production of biological signaling molecules, the N-acyl glycines.
authors.affiliation: Department of Genetics, Microbiology, and Toxicology, Stockholm University Svante Arrhenius väg 20C, 106 91 Stockholm, Sweden.
authors.forename: Dominik P
authors.initials: DP
authors.lastname: Waluk
authors.forename: Filip
authors.initials: F
authors.lastname: Sucharski
authors.forename: Laszlo
authors.initials: L
authors.lastname: Sipos
authors.forename: Jerzy
authors.initials: J
authors.lastname: Silberring
authors.forename: Mary C
authors.initials: MC
authors.lastname: Hunt
mesh_terms: D000107:Acetylation; D000217:Acyltransferases / Q000235:genetics / Q000378:metabolism*; D019943:Amino Acid Substitution; D000818:Animals; D001095:Arachidonic Acids / Q000096:biosynthesis* / Q000235:genetics; D005998:Glycine / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000235:genetics; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D020125:Mutation, Missense; D009829:Oleic Acids / Q000096:biosynthesis* / Q000235:genetics; D011499:Protein Processing, Post-Translational / Q000502:physiology*
chemical_list: D001095:Arachidonic Acids; C465623:N-arachidonylglycine; C516666:N-oleoylglycine; D009829:Oleic Acids; D000217:Acyltransferases; C020680:glycine acyltransferase; D005998:Glycine