A non-enzymatic role of Nudix hydrolase 5 in repressing purine de novo synthesis

  • Science. 2025 Dec 11;390(6778):1143-1150. doi: 10.1126/science.adv4257.
Tuan-Anh Nguyen  #  1 ,  Jung-Ming G Lin  #  1 ,  Anne-Sophie M C Marques  #  2  3 ,  Maximilian Fottner  4 ,  Ludwig G Bauer  2  3 ,  Andreas Reicher  1 ,  Diana Daum  1 ,  Lorenzo Scrofani  1 ,  Yusi Liu  2  3 ,  Carol Cheng  2  3 ,  Luna D'Angelo L D D  1 ,  Juan Sanchez  1 ,  Christoph Bueschl  1 ,  Nara Marella  1 ,  Pisanu Buphamalai  1  5 ,  Florian Traversi  6 ,  Maša Bereš  7 ,  Herwig P Moll  7 ,  Marton Siklos  1 ,  Jakob-Wendelin Genger  1 ,  Gerald Hofstaetter  1 ,  Ludovica Villanti  1 ,  Monika Malik  1 ,  Christoph Klimek  1 ,  Kathrin Runggatscher  1 ,  Bettina Guertl  1 ,  Jesper S Hansen  2  3 ,  Sarah Dobner  1 ,  Olga Babosova  1 ,  Tina Becirovic  1 ,  Laura P M H de Rooij  1 ,  Emilio Casanova  7  8 ,  Anna Koren  1 ,  D Sean Froese  6 ,  David S Rosenblatt  9 ,  Kristaps Klavins  1 ,  Andreas Bergthaler  1  10 ,  Jörg Menche  1  5 ,  J Thomas Hannich  1 ,  Miriam Abele  1 ,  Sara Sdelci  1  11 ,  Kathrin Lang  4 ,  Kilian V M Huber  2  3 ,  Stefan Kubicek  1
Affiliations
  • 1. CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
  • 2. Centre for Medicines Discovery, Nuffield Department of Medicine, Oxford, UK.
  • 3. Target Discovery Institute, Nuffield Department of Medicine, Oxford, UK.
  • 4. Laboratory for Organic Chemistry (LOC), Department of Chemistry and Applied Biosciences (D-CHAB), ETH Zurich, Zurich, Switzerland.
  • 5. Department of Structural and Computational Biology, Max Perutz Labs, University of Vienna, Vienna, Austria.
  • 6. Division of Metabolism and Children's Research Center, University Children's Hospital, University of Zurich, Zurich, Switzerland.
  • 7. Institute of Pharmacology, Center of Physiology and Pharmacology & Comprehensive Cancer Center (CCC), Medical University of Vienna, Vienna, Austria.
  • 8. Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria.
  • 9. Department of Human Genetics, McGill University, Montreal, Canada.
  • 10. Institute for Hygiene and Applied Immunology, Center of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
  • 11. Center for Genomic Regulation, Barcelona, Spain.
  • # Contributed equally.
PMID: 41196952 DOI: 10.1126/science.adv4257
Abstract

Folate metabolism is intricately linked to purine de novo synthesis through the incorporation of folate-derived one-carbon units into the purine scaffold. By investigating chemical and genetic dependencies caused by mutations in methylenetetrahydrofolate dehydrogenase, cyclohydrolase, and formyltetrahydrofolate synthetase 1 (MTHFD1), we discovered a key role for Nudix hydrolase 5 (NUDT5) in regulating purine de novo synthesis. Genetic depletion and selective chemical degradation showed that a scaffolding role, rather than NUDT5 enzymatic activity, was causing this phenotype. NUDT5 interacted with phosphoribosyl pyrophosphate amidotransferase (PPAT), the rate-limiting enzyme of purine de novo synthesis, to repress the pathway in response to increased purine abundance. Through this mechanism, loss of NUDT5 mediates resistance to purine analogs in Cancer treatment and prevents adenosine toxicity in MTHFD1 deficiency.

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