通过研究由亚甲基四氢叶酸脱氢酶、环水解酶和甲酰四氢叶酸合成酶1 （MTHFD1）突变引起的化学和遗传依赖性，课题组研究人员发现Nudix水解酶5 （NUDT5）在调节嘌呤从头合成中起关键作用。遗传耗竭和选择性化学降解表明，是脚手架作用而不是NUDT5酶活性主导了这种表型。NUDT5与嘌呤从头合成的限速酶磷酸核糖基焦磷酸氨基转移酶（PPAT）相互作用，以抑制嘌呤丰度增加的途径。通过这一机制，在癌症治疗中，NUDT5的缺失介导了对嘌呤类似物的耐药性，并防止MTHFD1缺乏时的腺苷毒性。
研究人员表示，叶酸代谢通过将叶酸衍生的单碳单位并入嘌呤支架而与嘌呤从头合成密切相关。
附：英文原文
Title: A non-enzymatic role of Nudix hydrolase 5 in repressing purine de novo synthesis
Author: Tuan-Anh Nguyen, Jung-Ming G. Lin, Anne-Sophie M. C. Marques, Maximilian Fottner, Ludwig G. Bauer, Andreas Reicher, Diana Daum, Lorenzo Scrofani, Yusi Liu, Carol Cheng, Luna D’Angelo L.d.D., Juan Sanchez, Christoph Bueschl, Nara Marella, Pisanu Buphamalai, Florian Traversi, Maa Bere, Herwig P. Moll, Marton Siklos, Jakob-Wendelin Genger, Gerald Hofstaetter, Ludovica Villanti, Monika Malik, Christoph Klimek, Kathrin Runggatscher, Bettina Guertl, Jesper S. Hansen, Sarah Dobner, Olga Babosova, Tina Becirovic, Laura P. M. H. de Rooij, Emilio Casanova, Anna Koren, D. Sean Froese, David S. Rosenblatt, Kristaps Klavins, Andreas Bergthaler, Jrg Menche, J. Thomas Hannich, Miriam Abele, Sara Sdelci, Kathrin Lang, Kilian V. M. Huber, Stefan Kubicek
Issue&Volume: 2025-11-06
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.
DOI: adv4257
Source: https://www.science.org/doi/10.1126/science.adv4257