Published in Science, the study reveals that the enzyme NUDT5, long known for its enzymatic role in metabolism, also acts as a molecular scaffold that regulates another enzyme, PPAT, which controls the rate of de novo purine synthesis - the pathway that produces the building blocks of DNA and RNA.
By binding and restraining PPAT, NUDT5 functions as a molecular handbrake, fine-tuning nucleotide production and helping cells maintain balance. When this brake is released - through mutation, disease, or chemical removal - cells overproduce purines, which can out-compete thiopurine-type cancer drugs, such as 6-thioguanine, reducing their effectiveness.
 Dr Anne-Sophie Marques
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The CMD Oxford team discovered this unexpected role using a combination of chemical biology and proteomics, developing a highly selective NUDT5 degrader (dNUDT5) that completely removes the protein from cells. Unlike classical enzyme inhibitors, the degrader revealed a non-enzymatic scaffolding function for NUDT5 and uncovered its interaction with PPAT - the rate-limiting enzyme in purine synthesis. |
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“This discovery was a big surprise, in the best possible way,” said Professor Kilian Huber, who led the research at CMD. “It challenges the textbook view of how cells control the production of DNA building blocks and shows how chemistry can reveal new biology.” The findings have important implications for personalised cancer therapy and drug discovery, identifying a new molecular switch that could be used to predict or overcome drug resistance. The research was led by Oxford in collaboration with the CeMM Research Center for Molecular Medicine (Vienna) and supported by EU Horizon Europe/IMI and Wellcome. |
 Professor Kilian Huber
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The paper, “A non-enzymatic role of Nudix hydrolase 5 in repressing purine de novo synthesis,” appears in Science (6 November 2025).
🔗 Read the full University of Oxford press release
Releasing the Brake on Purine Metabolism. NUDT5 binds and restrains PPAT, acting as a cellular handbrake to limit the production of DNA building blocks. Loss or mutation of NUDT5 releases the brake, boosting purine synthesis and giving cancer cells the fuel to resist treatment.