Loss of metabolic control mechanisms promotes uncontrolled cancer cell proliferation

Researchers from the University of Seville have participated in research to identify 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, the fruit of an extensive collaboration between the team led by Professor Irene Díaz Moreno of the University of Seville and that of Professor Eyal Arbely of 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).

In this paper, the researchers demonstrate 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 markers 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 flow and promote uncontrolled cell proliferation.

Understanding the molecular mechanisms that finely and precisely regulate the functioning of pyruvate kinase brings us closer to deciphering the metabolic changes that drive the proliferation of cancer cells."

Irene Díaz-Moreno, Professor, Institute of Chemical Research at the Isla de la Cartuja Scientific Research Centre (US-CSIC)

Pyruvate kinase has two variants: PKM1, associated with adult tissues, and PKM2, linked to both adult and embryonic tissues. Using a combination of biochemical, biophysical, structural and computational simulation techniques, the authors of the paper demonstrate that acetylation at certain positions on pyruvate kinase inhibits the function and decreases the stability of the enzyme. In addition, the researchers discovered that certain acetylations affect each variant differently, revealing specific regulatory mechanisms.

Taken together, these findings help to understand how this key metabolic enzyme is regulated at molecular level and provide essential information for interpreting its functional behaviour in contexts such as cancer, where loss of control over the action of pyruvate kinase promotes cell proliferation.