Purines: essential components of DNA
Purines are molecules that are one of the building blocks of DNA. Cells can create purines by recycling old materials or by manufacturing them from scratch via a process that requires a lot of energy and is driven by an enzyme called PPAT. If this manufacture process is not controlled, purines can build up in the cell. This becomes a problem if someone is taking a cancer treatment that mimics purines; the purines manufactured by the cell effectively out-compete the drug, stopping it from working.
Now, scientists have worked out how an enzyme called NUDT5 acts as a ‘handbrake’ on PPAT, preventing it from triggering excess purine production. The work, published in the prestigious journal Science, was funded in part by the Innovative Medicines Initiative (IMI) via the EUbOPEN project.
While NUDT5 was known to be involved in cells’ energy metabolism and signalling, the fact it plays a role in purine production is a revelation. The discovery came about when EUbOPEN scientists at the University of Oxford developed a molecular degrader called dNUDT5 that removes NUDT5 from cells entirely. They found that eliminating NUDT5 from cells in this way removed the brake on purine synthesis, allowing it to spiral out of control. Further experiments revealed that NUDT5 works by physically attaching itself to the PPAT enzyme and so stopping it from driving purine production.
A molecule that moonlights as a scaffold
‘This discovery was a big surprise, in the best possible way,’ said Kilian Huber of the University of Oxford, a senior author of the paper. ‘An enzyme long thought to have a single, well-defined role turned out to moonlight as a molecular scaffold - something never seen before in this enzyme family. It challenges the textbook view of how cells regulate the production of DNA building blocks and offers a fundamental insight into cellular control. It’s also a reminder that in science, you should never take anything for granted - even familiar proteins can still surprise us.’
The result could inform the development of new and better cancer treatments, as understanding how NUDT5 acts as a ‘handbrake’ on purine manufacture sheds new light on how cancer cells respond to drugs that target DNA such as thiopurines. Crucially, it could result in new biomarkers to guide thiopurine therapy, and new therapeutic strategies targeting the NUDT5-PPAT interaction, for example. The findings could also advance the treatment of rare genetic disorders and inflammatory diseases where purine metabolism plays a role.
‘It’s a clear demonstration of how fundamental discovery can lead to more personalised and effective therapies,’ said Professor Huber.
The work also underlines the importance of the work taking place in EUbOPEN, which is developing high-quality chemical probes like the NUDT5 degrader and making them available to the scientific community.
‘By developing the NUDT5 degrader (dNUDT5), we generated a potent, selective tool that reveals how this protein functions in cells - in this case, uncovering a completely new, non-enzymatic role,’ explained Professor Huber. ‘The study demonstrates how such chemical tools can transform our understanding of disease biology and accelerate the identification of new therapeutic opportunities.’
The public-private partnership model – bridging basic research and real-world drug development
According to Professor Huber, the public-private nature of EUbOPEN is essential for its success. ‘For me, this structure enables academic groups to pursue fundamental discovery science while drawing on the drug discovery experience and quality standards of the pharmaceutical sector - including the rigorous criteria required to turn chemical probes into credible starting points for therapeutics,’ he said. ‘This collaborative framework helps bridge the gap between basic research and real-world drug development, ultimately ensuring that discoveries meet the highest standards of scientific and translational quality.’
Next steps for NUDT5
Looking to the future, the team wants to explore in more detail how the NUDT5-PPAT handbrake mechanism works in cancer and immune cells. They will also assess whether the enzymes could work as a marker of treatment response, and will continue developing molecules that could be the starting points of future treatments that would work either by degrading NUDT5 or stabilising the NUDT5-PPAT pairings.
In parallel, they will apply a similar experimental approach other well-known enzymes, in the hope of discovering further hidden functions that could shed new light on other diseases and their treatments.
EUbOPEN is supported by the Innovative Medicines Initiative, a partnership between the European Union and the European pharmaceutical industry.