Overview: A Surprising Discovery in Cell Biology
For over seven decades, scientists studied phosphofructokinase (PFK) as a key metabolic enzyme. Now, a groundbreaking new study from the University of Surrey reveals that PFK has a remarkable hidden second function. Specifically, one of its subunits controls when and how cells divide. This discovery fundamentally challenges what biochemistry textbooks have long described. Moreover, it opens exciting new doors for understanding disease and developing novel therapies.
What Is Phosphofructokinase?
Phosphofructokinase, or PFK, acts as the “gatekeeper” of glycolysis — the ancient metabolic pathway that breaks down sugar to produce energy. In yeast (Saccharomyces cerevisiae), PFK consists of two subunits: Pfk1 (α) and Pfk2 (β). Traditionally, researchers understood both subunits purely as metabolic partners working together in energy production. However, the new Surrey-led research has uncovered something entirely different about Pfk2.
The Dual Function of Pfk2
The study, published in Nucleic Acids Research, demonstrates that Pfk2 possesses a completely separate capability beyond glycolysis. It binds hundreds of messenger RNAs (mRNAs) inside living cells. Furthermore, it unwinds short double-stranded RNA in a specific direction. Most importantly, it actively promotes the translation of genes that drive cell division.
Without Pfk2, yeast cells show clear defects. They grow more slowly, become significantly larger, and struggle to advance from the G1 to S phase of the cell cycle. This transition is a critical checkpoint where cells commit to dividing. Crucially, researchers reintroduced a version of Pfk2 that cannot perform glycolysis at all. Yet, this version still rescued the cell cycle defects. Therefore, the enzyme’s role in cell division operates entirely independently of its metabolic function.
As Professor André Gerber, corresponding author from Surrey’s School of Biosciences, explained: Pfk2 acts as “a molecular relay, sensing the cell’s energy status and using that information to decide whether to promote growth.”
How Researchers Proved the Second Role
RNA Binding and Unwinding Activity
The research team combined RNA sequencing, biochemical assays, and proteomics to build a compelling case. They identified over 800 mRNAs that Pfk2 binds inside living cells. Many of these encode proteins involved in controlling the mitotic cell cycle. Additionally, using real-time light-signal tracking tests, the team showed that Pfk2 — but not Pfk1 — can unwind short double-stranded RNA molecules with directional specificity. This function is normally associated only with dedicated RNA helicase enzymes.
Impact on Cell Cycle Regulators
The team applied polysome profiling to reveal which mRNAs were actively producing proteins. In cells lacking Pfk2, mRNAs for critical cell cycle regulators shifted dramatically away from ribosomes. As a result, these mRNAs were no longer efficiently translated. Affected targets included the G1 cyclin CLN3, which triggers the start of cell division, and the spindle checkpoint protein BUB3, which ensures chromosomes separate correctly. Proteomics analysis confirmed significantly reduced levels of cell cycle proteins in Pfk2 deletion mutants.
The Molecular Relay Switch Model
Based on their findings, the researchers propose a “molecular relay switch” model. When cellular energy is low, PFK adopts its enzymatically active state and focuses on glycolysis. Conversely, when energy is abundant, Pfk2 shifts to a low-activity shape. In that state, it enhances its ability to bind and unwind RNA, thereby promoting the translation of cell cycle genes. Consequently, this creates a direct molecular link between a cell’s metabolic state and its decision to proliferate.
This elegant model explains how a single enzyme can serve two completely distinct biological purposes depending on the cell’s energy environment.
Why This Discovery Matters
First author Waleed Albihlal noted that PFK has been described as a unifunctional enzyme in every biochemistry textbook for decades. This discovery challenges that assumption entirely. Beyond advancing basic science, the findings carry significant clinical implications. Misregulation of the cell cycle underlies many cancers and other diseases. Thus, understanding how PFK links metabolism to cell division could lead to novel therapeutic targets.
Additionally, this study raises a broader question: how many other well-studied enzymes harbor undiscovered secondary functions? The research was funded by the Biotechnology and Biological Sciences Research Council (BBSRC), Cancer Research UK, and the Engineering and Physical Sciences Research Council (EPSRC). International collaborators included teams from the Cancer Research UK Scotland Institute, the University of Osnabrück, the University of Basel, and Ulm University.
Conclusion
This landmark study by the University of Surrey transforms our understanding of the PFK enzyme. Rather than acting solely as a metabolic gatekeeper, Pfk2 also functions as a powerful RNA regulator that links a cell’s energy status to its decision to divide. As scientists continue exploring such hidden enzyme functions, entirely new approaches to treating cancer and cell-cycle disorders may emerge.
