Multiple oxidative post-translational modifications of human glutamine synthetase mediate peroxynitrite-dependent enzyme inactivation and aggregation.
| Autor: | Campolo N; Departamento de Bioquímica and Centro de Investigaciones Biomédicas (CEINBIO), Facultad de Medicina, Universidad de la República, Montevideo, Uruguay., Mastrogiovanni M; Departamento de Bioquímica and Centro de Investigaciones Biomédicas (CEINBIO), Facultad de Medicina, Universidad de la República, Montevideo, Uruguay., Mariotti M; Department of Biomedical Sciences, Panum Institute, University of Copenhagen, Copenhagen, Denmark., Issoglio FM; CONICET-Universidad de Buenos Aires, Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN), Buenos Aires, Argentina; Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa (ITQB NOVA), Oeiras, Portugal., Estrin D; CONICET-Universidad de Buenos Aires, Instituto de Química Física de los Materiales, Medio Ambiente y Energía (INQUIMAE), Buenos Aires, Argentina; Departamento de Química Inorgánica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Analítica y Química Física, Buenos Aires, Argentina., Hägglund P; Department of Biomedical Sciences, Panum Institute, University of Copenhagen, Copenhagen, Denmark., Grune T; Department of Molecular Toxicology, German Institute of Human Nutrition, Potsdam-Rehbrücke, Nuthetal, Germany; German Center for Cardiovascular Research (DZHK), Berlin, Germany; Department of Physiological Chemistry, Faculty of Chemistry, University of Vienna, Vienna, Austria., Davies MJ; Department of Biomedical Sciences, Panum Institute, University of Copenhagen, Copenhagen, Denmark., Bartesaghi S; Departamento de Bioquímica and Centro de Investigaciones Biomédicas (CEINBIO), Facultad de Medicina, Universidad de la República, Montevideo, Uruguay., Radi R; Departamento de Bioquímica and Centro de Investigaciones Biomédicas (CEINBIO), Facultad de Medicina, Universidad de la República, Montevideo, Uruguay. Electronic address: rradi@fmed.edu.uy. |
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| Jazyk: | angličtina |
| Zdroj: | The Journal of biological chemistry [J Biol Chem] 2023 Mar; Vol. 299 (3), pp. 102941. Date of Electronic Publication: 2023 Jan 23. |
| DOI: | 10.1016/j.jbc.2023.102941 |
| Abstrakt: | Glutamine synthetase (GS), which catalyzes the ATP-dependent synthesis of L-glutamine from L-glutamate and ammonia, is a ubiquitous and conserved enzyme that plays a pivotal role in nitrogen metabolism across all life domains. In vertebrates, GS is highly expressed in astrocytes, where its activity sustains the glutamate-glutamine cycle at glutamatergic synapses and is thus essential for maintaining brain homeostasis. In fact, decreased GS levels or activity have been associated with neurodegenerative diseases, with these alterations attributed to oxidative post-translational modifications of the protein, in particular tyrosine nitration. In this study, we expressed and purified human GS (HsGS) and performed an in-depth analysis of its oxidative inactivation by peroxynitrite (ONOO - ) in vitro. We found that ONOO - exposure led to a dose-dependent loss of HsGS activity, the oxidation of cysteine, methionine, and tyrosine residues and also the nitration of tryptophan and tyrosine residues. Peptide mapping by LC-MS/MS through combined H Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the content of this article. (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.) |
| Databáze: | MEDLINE |
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