Reference

Latorre-Muro, P., Baeza, J., Armstrong, E. A., Hurtado-Guerrero, R., Corzana, F., Wu, L.E., Sinclair, D.A., López-Buesa, P., Carrodeguas, J.A., Denu, J.M. (2018). Dynamic acetylation of cytosolic phosphoenolpyruvate carboxykinase toggles enzyme activity between gluconeogenic and anaplerotic reactions. Mol. Cell 71, 718-732. doi: 10.1016/j.molcel.2018.07.031. Portada MOL CELL

Authors

Latorre-Muro, Pedro, Baeza, Josue, Armstrong, Eric A., Hurtado-Guerrero, Ramón, Corzana, Francisco, Wu, Lindsay E., Sinclair, David A., López-Buesa, Pascual, Carrodeguas, José A., Denu, John M.

Abstract

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 GSK3β-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 hyperacetylated PCK1 to promote anaplerotic activity, and the intersection of post-translational control of PCK1 involving acetylation, phosphorylation, and ubiquitination.

Description

La fosfoenolpiruvato carboxiquinasa citosólica (PCK1) se encuentra en un cruce de camino de numerosas rutas metabólicas y cataliza una reacción reversible. El papel biológico de PCK1 ha estado asociado al de la gluconeogénesis (una de las reacciones), sin embargo, el papel de la reacción reversa en mamíferos es desconocido. Latorre y cols. describen los mecanismos por los que diversas modificaciones post-traduccionales (PTMs) son capaces de regular tanto la actividad como la estabilidad de la PCK1. En condiciones de alta glucosa, la acetilación de PCK1 favorece la reacción reversa de la enzima que permite suministrar metabolitos al ciclo de Krebs. En estas mismas condiciones, la fosforilación de PCK1 es mediada por GSK3β y favorece la ubiquitinación y degradación de la enzima no acetilada. Por otro lado, en condiciones de baja glucosa, SIRT1 deacetila PCK1 y restaura las propiedades cinéticas de la enzima favoreciendo la ruta gluconeogénica. Esta reacción de deacetilación se ve facilitada por la fosforilación de ciertos residuos. En conjunto, la acetilación, fosforilación y ubiquitinación de PCK1 interactúan con el fin de controlar la estabilidad y el sentido de la reacción de la enzima en función de las condiciones energéticas de las células.

 

 

Latorre Carrodeguas

 

REFERENCIA DEL GRUPO INVESTIGADOR

El grupo de investigación se formó al regresar a España el Dr. Carrodeguas como investigador Ramón y Cajal. Inicialmente dedicado a la biología molecular de la mitocondria, trabajó en líneas de investigación sobre Alzheimer, apoptosis, células madre y metabolismo. En éste último campo realizó estudios con el Dr. López Buesa relacionados con la producción animal. De ahí surgió la semilla de este trabajo, que se consolidó gracias a una estancia del Dr. Latorre Muro en el Wisconsin Institute for Discovery con el Dr. John Denu, completándose en el Instituto de Biocomputación y Física de Sistemas Complejos (BIFI) de la Universidad de Zaragoza.

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