Inhibition of N-acetylglutamate synthase by various monocarboxylic and dicarboxylic short-chain coenzyme A esters and the production of alternative glutamate esters
| Autor: | Lodewijk IJlst, A. G. van Cruchten, Marli Dercksen, F.H. van der Westhuizen, R. J. A. Wanders, Marinus Duran, Lodewyk J. Mienie |
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| Přispěvatelé: | AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Laboratory Genetic Metabolic Diseases |
| Rok vydání: | 2014 |
| Předmět: |
hyperammonemia
N-Acetylglutamate synthase Stereochemistry Coenzyme A Amino-Acid N-Acetyltransferase Carboxylic Acids Glutamic Acid chemistry.chemical_compound Chain (algebraic topology) Tandem Mass Spectrometry Organic chemistry Humans Hyperammonemia Dicarboxylic Acids branched-chain amino acids Molecular Biology Chromatography High Pressure Liquid organic acidemia acyl-CoAs biology Dose-Response Relationship Drug Chemistry Glutamate receptor Esters Branched-chain amino acids N-acetylglutamate synthase Kinetics Acyl-CoAs N-acylglutamates biology.protein Molecular Medicine Acyl Coenzyme A Organic acidemia |
| Zdroj: | BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE, 1842(12 Part A), 2510-2516. Elsevier |
| ISSN: | 0925-4439 |
| DOI: | 10.1016/j.bbadis.2013.04.027 |
| Popis: | Hyperammonemia is a frequent finding in various organic acidemias. One possible mechanism involves the inhibition of the enzyme N-acetylglutamate synthase (NAGS), by short-chain acyl-CoAs which accumulate due to defective catabolism of amino acids and/or fatty acids in the cell. The aim of this study was to investigate the effect of various acyl-CoAs on the activity of NAGS in conjunction with the formation of glutamate esters. NAGS activity was measured in vitro using a sensitive enzyme assay with ultraperformance liquid chromatography– tandem mass spectrometry (UPLC–MS/MS) product analysis. Propionyl-CoA and butyryl-CoA proved to be the most powerful inhibitors of N-acetylglutamate (NAG) formation. Branched-chain amino acid related CoAs (isovaleryl-CoA, 3-methylcrotonyl-CoA, isobutyryl-CoA) showed less pronounced inhibition of NAGS whereas the dicarboxylic short-chain acyl-CoAs (methylmalonyl-CoA, succinyl-CoA, glutaryl-CoA) had the least inhibitory effect. Subsequentwork showed that the most powerful inhibitors also proved to be the best substrates in the formation of N-acylglutamates. Furthermore, we identified N-isovalerylglutamate, N-3-methylcrotonylglutamate and N-isobutyrylglutamate (the latter two in trace amounts), in the urines of patients with different organic acidemias. Collectively, these findings explain one of the contributing factors to secondary hyperammonemia, which lead to the reduced in vivo flux through the urea cycle in organic acidemias and result in the inadequate elimination of ammonia http://www.journals.elsevier.com/bba-molecular-basis-of-disease/ http://dx.doi.org/10.1016/j.bbadis.2013.04.027 Carolina MacGillavry PhD Fellowship awarded by “Koninklijke Nederlandse Akademie van Wetenschappen.” |
| Databáze: | OpenAIRE |
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