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

• 成果类型: Article
• 署名作者: Nguyen, Tuan-Anh; Lin, Jung-Ming G.; Marques, Anne-Sophie M. C.; Fottner, Maximilian; Bauer, Ludwig G.; Reicher, Andreas; Daum, Diana; Scrofani, Lorenzo; Liu, Yusi; Cheng, Carol; D'Angelo, L. d. D. Luna; Sanchez, Juan; Bueschl, Christoph; Marella, Nara; Buphamalai, Pisanu; Traversi, Florian; Beres, Masa; Moll, Herwig P.; Siklos, Marton; Genger, Jakob-Wendelin; Hofstaetter, Gerald; Villanti, Ludovica; Malik, Monika; Klimek, Christoph; Runggatscher, Kathrin; Guertl, Bettina; Hansen, Jesper S.; Dobner, Sarah; Babosova, Olga; Becirovic, Tina; de Rooij, Laura P. M. H.; Casanova, Emilio; Koren, Anna; Froese, D. Sean; Rosenblatt, David S.; Klavins, Kristaps; Bergthaler, Andreas; Menche, Jorg; Hannich, J. Thomas; Abele, Miriam; Sdelci, Sara; Lang, Kathrin; Huber, Kilian V. M.; Kubicek, Stefan
• 署名单位: Austrian Academy of Sciences; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences; University of Oxford; University of Oxford; Swiss Federal Institutes of Technology Domain; ETH Zurich; University of Zurich; University Children's Hospital Zurich; University Children's Hospital Zurich; University of Zurich; Medical University of Vienna; Medical University of Vienna; Medical University of Vienna; Ludwig Boltzmann Institute; McGill University; Medical University of Vienna; Pompeu Fabra University; Barcelona Institute of Science & Technology; Centre de Regulacio Genomica (CRG)
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8075; 1095-9203
• DOI: 10.1126/science.adv4257
• 发表日期: 2025-12-11
• 页码: 1143-1150
• 关键词: GLUTAMINE PHOSPHORIBOSYLPYROPHOSPHATE; cell-growth; HUMAN NUDT5; cancer; folate; MTHFD1; dehydrogenase; nucleotide; mutations; reveals

摘要

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.