A new study led by the University of Oxford has identified a previously unknown function for the enzyme NUDT5, revealing its role as a regulator in the production of DNA building blocks. The findings, published in Science, show that NUDT5 acts as a molecular “handbrake” on another enzyme, PPAT, which is responsible for controlling purine synthesis. Purines are essential components of DNA and RNA.
The research demonstrates that when NUDT5’s regulatory function is lost—due to genetic variation, disease, or chemical removal—cells begin to overproduce purines. This surplus can interfere with cancer drugs such as thiopurines, including 6-thioguanine used in leukemia and autoimmune diseases, reducing their effectiveness.
Professor Kilian Huber from Oxford’s Centre for Medicines Discovery said: "This discovery was a big surprise, in the best possible way. 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. This work shows what can be achieved when curiosity-driven research meets international collaboration."
The team developed dNUDT5, described as a first-in-class small-molecule degrader that removes NUDT5 from human cells. Unlike traditional inhibitors that block enzymes’ activity chemically, this method eliminates the protein entirely and revealed its scaffolding role in restraining PPAT.
Dr Anne-Sophie Marques, co-first author on the study, commented: "In this study we have shown an unprecedented role of NUDT5 in repressing the purine de novo biosynthetic pathway. In addition to proving that the scaffolding role of NUDT5 is essential in this phenotype, we have demonstrated that the interaction between NUDT5 and PPAT, the rate-limiting enzyme of purine de novo synthesis, acts like a switch to repress the pathway.
"It is undeniable that our results pave the way for future discoveries around the NUDT5 protein and its role in cancer."
The researchers also found through proteomics analysis that NUDT5 physically interacts with PPAT and influences metabolism through structural means rather than just chemical reactions. They showed that removing NUDT5 could rescue adenosine-induced toxicity in patient-derived fibroblasts from individuals with MTHFD1 deficiency.
Multiple independent teams validated these preclinical findings—including researchers at University of Texas Southwestern Medical Center—supporting evidence for using NUDT5-PPAT as a potential biomarker for personalized therapy and drug development targeting cancer and metabolic disorders.
The collaborative project included contributions from ETH Zurich and University of Zurich (Switzerland), McGill University (Canada), and was supported by funding from the EU Innovative Medicines Initiative programme.
"Our team is now evaluating NUDT5-PPAT as a potential biomarker in clinical samples, advancing NUDT5 degraders through preclinical testing, and exploring whether other enzymes might have similar hidden scaffold roles in cell metabolism," Professor Huber added.