130445 20240125162930.0 doi 10.1016/j.molcel.2018.07.031 sideral 108074 ART-2018-108074 eng Latorre-Muro, Pedro Universidad de Zaragoza (orcid)0000-0002-6794-3535 Dynamic Acetylation of Phosphoenolpyruvate Carboxykinase Toggles Enzyme Activity between Gluconeogenic and Anaplerotic Reactions 2018 Cytosolic phosphoenolpyruvate carboxykinase (PCK1) is considered a gluconeogenic enzyme; however, its metabolic functions and regulatory mechanisms beyond gluconeogenesis are poorly understood. Here, we describe that dynamic acetylation of PCK1 interconverts the enzyme between gluconeogenic and anaplerotic activities. Under high glucose, p300-dependent hyperacetylation of PCK1 did not lead to protein degradation but instead increased the ability of PCK1 to perform the anaplerotic reaction, converting phosphoenolpyruvate to oxaloacetate. Lys91 acetylation destabilizes the active site of PCK1 and favors the reverse reaction. At low energy input, we demonstrate that SIRT1 deacetylates PCK1 and fully restores the gluconeogenic ability of PCK1. Additionally, we found that GSK3 beta-mediated phosphorylation of PCK1 decreases acetylation and increases ubiquitination. Biochemical evidence suggests that serine phosphorylation adjacent to Lys91 stimulates SIRT1-dependent deacetylation of PCK1. This work reveals an unexpected capacity of hyper-acetylated PCK1 to promote anaplerotic activity, and the intersection of post-translational control of PCK1 involving acetylation, phosphorylation, and ubiquitination. Access copy available to the general public Unrestricted info:eu-repo/grantAgreement/ES/MEC/BFU2016-75633-P info:eu-repo/grantAgreement/ES/MEC/CTQ2013-44367-C2-2-P info:eu-repo/grantAgreement/ES/MINECO/AGL2015-66177 info:eu-repo/grantAgreement/ES/UZ-IBERCAJA-CAI/CM1-16 info:eu-repo/grantAgreement/ES/UZ/UZ2014-CIE-03 info:eu-repo/grantAgreement/ES/UZ/UZ2015-BIO-01 info:eu-repo/semantics/openAccess by-nc-nd http://creativecommons.org/licenses/by-nc-nd/3.0/es/ 14.548 2018 CELL BIOLOGY 11 / 191 = 0.058 2018 Q1 T1 BIOCHEMISTRY & MOLECULAR BIOLOGY 6 / 294 = 0.02 2018 Q1 T1 12.076 2018 Molecular Biology 2018 Q1 Cell Biology 2018 Q1 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Baeza, J. Armstrong, E.A. Hurtado-Guerrero, Ramón Universidad de Zaragoza (orcid)0000-0002-3122-9401 Corzana, F. Wu, L.E. Sinclair, D.A. López-Buesa, Pascual Universidad de Zaragoza (orcid)0000-0001-5992-2913 Carrodeguas, José A. Universidad de Zaragoza (orcid)0000-0003-0062-1029 Denu, J.M. 1002 060 Universidad de Zaragoza Dpto. Bioq.Biolog.Mol. Celular Área Bioquímica y Biolog.Mole. 2008 780 Universidad de Zaragoza Dpto. Produc.Animal Cienc.Ali. Área Tecnología de Alimentos 71, 5 (2018), 718-732.e1–e8 Mol. cell Molecular Cell 1097-2765 5375242 http://zaguan.unizar.es/record/130445/files/texto_completo.pdf Versión publicada 1660441 http://zaguan.unizar.es/record/130445/files/texto_completo.jpg?subformat=icon icon Versión publicada oai:zaguan.unizar.es:130445 articulos driver 2024-01-25-15:11:09 ARTICLE