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

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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Publication Details

Journal
Universität Zürich, ZORA
Published
2025-11-06
DOI
https://doi.org/10.5167/uzh-283752
Primary Topic
Biochemical and Molecular Research
Type
article
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article

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

Florian Traversi, Ludwig G. Bauer, Marton I. Siklos, Kathrin Runggatscher et al.
Universität Zürich, ZORA
Biochemical and Molecular Research
article

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

Florian Traversi, Ludwig G. Bauer, Marton I. Siklos, Kathrin Runggatscher, Maximilian Fottner, Christoph Klimek, Andreas Reicher, Carol Cheng, Gerald Hofstätter, Anne-Sophie M. C. Marques, Herwig P. Moll, Bettina Guertl, Jung-Ming G. Lin, Pisanu Buphamalai, Jesper S. Hansen, Christoph Bueschl, Ludovica Villanti, Jakob-Wendelin Genger, Maša Bereš, Lorenzo Scrofani, Diana Daum, Sean D. Froese, Yusi Liu, Juan Ignacio Sanchez Avila, Luna D'Angelo Lancellotti Di Durazzo, Monika Malik, Tuan-Anh Nguyen, et al., Nara Marella
article en

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.

Universität Zürich, ZORA
Good health and well-being
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Biochemical and Molecular Research
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