An enzyme studied for seventy years has been doing two completely different jobs
For more than seventy years, the enzyme phosphofructokinase was understood as a faithful servant of cellular energy metabolism — a fixed landmark in the biochemistry of life. Researchers at the University of Surrey have now discovered that one of its subunits, Pfk2, quietly performs a second role: binding and unwinding RNA to govern when cells divide. The finding reframes a familiar molecule as a molecular diplomat between energy and growth, and invites the humbling question of how many other long-studied proteins carry secrets we have not yet thought to ask about.
- A cornerstone enzyme of metabolism has been found to moonlight as an RNA regulator, overturning seventy years of assumed understanding in a single study.
- Yeast cells stripped of the Pfk2 subunit grow sluggish and oversized, stalling at the precise threshold where a cell commits to dividing — a disruption that cascades through the entire cell cycle.
- The team traced the mechanism through RNA sequencing, biochemical assays, and polysome profiling, watching key division proteins — including the division-trigger CLN3 — vanish when Pfk2 was absent.
- Crucially, restoring a metabolically inert version of Pfk2 rescued the cell cycle defects, proving the RNA-unwinding role operates entirely apart from the enzyme's energy function.
- The discovery positions PFK as a metabolic switch: abundant energy shifts Pfk2 toward RNA binding and cell division, while energy scarcity redirects it back to glycolysis — a direct molecular vote on whether a cell should grow.
- Scientists now face a wider reckoning: if a molecule this thoroughly studied held a hidden function, the catalogue of enzyme capabilities across biology may be far from complete.
Phosphofructokinase — PFK — has held a settled place in biochemistry for over seventy years, recognized as a key player in glycolysis, the pathway cells use to extract energy from sugar. A new study from the University of Surrey has disturbed that settled picture. One of PFK's two subunits, it turns out, has been performing a second job all along.
The enzyme exists in yeast as two subunits, Pfk1 and Pfk2. Both were long treated as metabolic partners. But researchers found that Pfk2 also binds hundreds of messenger RNA molecules inside living cells, unwinds short stretches of double-stranded RNA, and promotes the translation of genes that drive cell division — a capability normally reserved for specialized RNA helicase enzymes. The work, published in Nucleic Acids Research, was built on RNA sequencing, biochemical assays, and large-scale protein analysis, identifying over eight hundred mRNAs that Pfk2 contacts, many encoding proteins essential to the cell cycle.
The consequences of removing Pfk2 were telling. Yeast cells without it grew more slowly, swelled in size, and struggled to cross from the G1 to S phase — the point where a cell commits to dividing. When the researchers reintroduced a version of Pfk2 incapable of metabolic activity, the cell cycle defects vanished, confirming that the RNA role is independent of energy production. Polysome profiling revealed the mechanism: without Pfk2, messenger RNAs for critical regulators like CLN3 and BUB3 drifted away from the cellular machinery that translates them into proteins, and protein levels fell accordingly.
The team proposes that PFK functions as a metabolic switch. Energy scarcity keeps it locked in glycolytic mode; energy abundance shifts Pfk2 toward RNA binding, licensing cell division. Professor André Gerber, who led the study, described the finding as a challenge to decades of textbook understanding. Beyond its implications for cell cycle disease and potential therapeutics, the discovery poses a quieter, larger question: how many other enzymes, studied for generations through a single lens, are still keeping secrets?
Phosphofructokinase has occupied a secure place in biochemistry textbooks for more than seventy years. The enzyme, known by its abbreviation PFK, sits at a critical junction in glycolysis—the ancient metabolic pathway that cells use to break down sugar and extract energy. Scientists have understood its role thoroughly, or so they thought. A new study from the University of Surrey has upended that assumption, revealing that one of PFK's two subunits possesses an entirely separate capability that has nothing to do with energy production at all.
The enzyme exists in yeast cells as two distinct subunits, Pfk1 and Pfk2. While both have long been treated as metabolic partners working in tandem to fuel cellular energy, researchers discovered that Pfk2 performs a second job: it binds to hundreds of messenger RNA molecules inside cells, unwinds short stretches of double-stranded RNA, and actively promotes the translation of genes that drive cell division. The finding, published in Nucleic Acids Research, suggests that PFK functions as a molecular relay—sensing the cell's energy status and using that information to decide whether conditions are right for growth and division.
The evidence emerged through a combination of RNA sequencing, biochemical assays, and large-scale protein analysis. The team identified over eight hundred mRNA molecules that Pfk2 binds in living cells, many of them coding for proteins essential to the mitotic cell cycle. Using real-time optical tracking, they demonstrated that Pfk2—but not its partner Pfk1—can unwind short double-stranded RNA molecules with a specific directionality, a capability normally associated with specialized RNA helicase enzymes whose primary function is precisely this kind of molecular unwinding.
The functional consequence became clear when researchers examined what happens when Pfk2 is absent. Yeast cells lacking the subunit grew more slowly, became significantly larger, and struggled to progress from the G1 to S phase of the cell cycle—a critical transition point where cells commit to division. Crucially, when the team reintroduced a version of Pfk2 that could no longer perform its metabolic function, the defects disappeared. This proved that the enzyme's role in cell division operates independently of its energy-production machinery.
Polysome profiling—a technique that reveals which messenger RNAs are actively being converted into proteins—showed the mechanism at work. In cells lacking Pfk2, messenger RNAs for critical cell cycle regulators, including CLN3 (a protein that triggers the start of division) and BUB3 (a protein that ensures chromosomes separate correctly), shifted dramatically away from the cellular machinery that translates them into proteins. Protein analysis confirmed that levels of these cell cycle regulators dropped significantly in cells without Pfk2.
The researchers propose a model in which PFK acts as a metabolic switch. When cellular energy runs low, PFK adopts an enzymatically active state and focuses on glycolysis. When energy is abundant, Pfk2 shifts to a low-activity configuration that enhances its ability to bind and unwind RNA, promoting the translation of cell cycle genes and enabling cell division. This creates a direct molecular link between how much energy a cell has available and whether it should divide.
Professor André Gerber, who led the study, noted that the discovery challenges decades of textbook understanding. "Phosphofructokinase has been studied intensively for its role in metabolism since the 1950s," he said. "What we have found is that one of its subunits also functions as an RNA regulator that helps coordinate when cells divide." The implications extend beyond basic science. Understanding how cells coordinate energy status with division decisions could illuminate diseases involving cell cycle misregulation and potentially lead to new therapeutic approaches. The discovery also raises a broader question: how many other enzymes, long studied for a single function, harbor hidden capabilities waiting to be found?
Citações Notáveis
Phosphofructokinase has been studied intensively for its role in metabolism since the 1950s. What we have found is that one of its subunits also functions as an RNA regulator that helps coordinate when cells divide.— Professor André Gerber, University of Surrey
For decades, PFK has been described in every biochemistry textbook as a unifunctional enzyme acting solely in glycolysis. The discovery of this dual function opens up new avenues and raises an important question—how many more hidden functions are there in other enzymes?— Waleed Albihlal, first author of the study
A Conversa do Hearth Outra perspectiva sobre a história
So this enzyme has been studied for seventy years and nobody noticed it was doing two completely different things?
Not quite. The metabolic function was so dominant, so well-characterized, that the RNA work went undetected. It's like having a tool that's been used for one purpose so effectively that nobody thought to check if it could do something else.
But the RNA unwinding—that's a pretty significant capability. How did it stay hidden?
The subunit that does it, Pfk2, is part of a larger protein complex focused on energy. The RNA work happens at a different scale, with different binding partners. You'd need to look specifically for it, using techniques that didn't exist or weren't applied to this enzyme until now.
The study mentions a molecular relay. What does that actually mean in practical terms?
Imagine a cell sensing that energy is plentiful. Instead of just burning sugar faster, the enzyme shifts shape and starts promoting the genes needed for division. It's the cell saying: we have enough fuel, now we can afford to grow and split.
And if you remove Pfk2 entirely?
Cells slow down, get bigger, and get stuck at a critical checkpoint. They can't commit to dividing. But here's the key: if you put back a version that can't do the metabolic work, the cells recover. That proves the division function is separate.
What happens next? Is this heading toward treatment?
Not immediately. But understanding how cells link energy status to division decisions could help explain cancers, where that link breaks down. It's foundational knowledge that might eventually lead somewhere therapeutic.