Researchers from the University of Seville and cicCartuja take part in the discovery of new chemical marks that regulate pyruvate kinase activity, opening the door to a better understanding of the metabolic reprogramming of cancer cells.
Researchers from the University of Seville and the Institute for Chemical Research have participated in a study aimed at identifying the molecular details of the regulation of an enzyme essential for sugar metabolism and closely linked to cell proliferation and growth: pyruvate kinase.
The results, arising from a long-standing collaboration between the team led by Professor Irene Díaz Moreno of the University of Seville, affiliated with the IIQ, and that of Prof. Eyal Arbely from Ben-Gurion University of the Negev, have recently been published in a research article in the scientific journal Proceedings of the National Academy of Sciences of the United States of America (PNAS) of the U.S. National Academy of Sciences.
In this work, the researchers show how acetylation, a reversible chemical modification that acts as a fine cellular regulatory mechanism, affects the dynamics and function of pyruvate kinase. In normal cells, these marks allow metabolism to be precisely adjusted in response to cellular environmental conditions. However, in pathological situations such as cancer, the loss of this control mechanism can divert metabolic flux and favor uncontrolled cell proliferation.
“Understanding the molecular mechanisms that finely and precisely regulate the function of pyruvate kinase brings us closer to deciphering the metabolic changes that drive the proliferation of cancer cells,” explains Professor Irene Díaz-Moreno of the Institute of Chemical Research at the Isla de la Cartuja Scientific Research Center (US–CSIC).
Pyruvate kinase has two variants: PKM1, associated with adult tissues, and PKM2, linked to both adult and embryonic tissues. By combining biochemical, biophysical, and structural techniques with computational simulations, the authors of the article demonstrate that acetylation at specific positions of pyruvate kinase inhibits its function and decreases the stability of the enzyme. In addition, the researchers discovered that certain acetylations affect each variant differently, revealing isoform-specific regulatory mechanisms.
Taken together, these findings help to clarify how this key metabolic enzyme is regulated at the molecular level and provide essential information to interpret its functional behavior in contexts such as cancer, where the loss of control over pyruvate kinase activity promotes cell proliferation.
Bibliographic reference:
D. Pavlenko, J. Tamargo-Azpilicueta, H. Nudelman, Y. Ankri, A. Shahar, I. Díaz-Moreno & E. Arbely (2025). Isoform-specific regulation of PKM by acetylation. Proc. Natl. Acad. Sci. U.S.A. 122: e2527086122. https://doi.org/10.1073/pnas.2527086122