Unveiling the Enzyme's Surprising Role: A New Twist in DNA Production Control
Imagine a finely tuned orchestra, where each musician plays a crucial part in creating a harmonious melody. Now, picture a conductor who, when the music reaches its peak, suddenly steps in to silence a specific instrument, ensuring the balance and beauty of the composition. This is akin to the fascinating discovery made by researchers at CeMM and the University of Oxford, who have identified an enzyme with an unexpected role in cellular metabolism.
The Unseen Conductor: NUDT5's Secret Mission
Inside every cell, a complex metabolic network decides when to create, recycle, or halt the production of essential molecules. At the heart of this network is folate metabolism, a process that provides the building blocks for DNA, RNA, and amino acids. When this delicate system is disrupted, the consequences can be severe, ranging from developmental disorders to cancer.
But here's where it gets controversial... Researchers have uncovered a new player in this metabolic balance: the enzyme NUDT5. Their study, published in Science, reveals that NUDT5 acts as a regulator, switching off the production of purines - the essential molecules that form the backbone of DNA and RNA. However, NUDT5 doesn't rely on its enzymatic activity to do so; instead, it acts as a molecular scaffold, physically restraining a key biosynthetic step when purine levels are high.
An Old Enzyme, a New Function
Purines are vital molecules, used by cells to construct DNA and RNA and store energy. They can be recycled or produced from scratch through the energy-intensive de novo pathway, a process that requires tight control.
The researchers explored this control mechanism by studying cells with mutations in the MTHFD1 gene, a crucial enzyme in the folate cycle. Folate metabolism provides the one-carbon units necessary for purine synthesis, and defects in this pathway can lead to rare genetic diseases and influence cancer risk.
Through a combination of genetic screening, metabolomics, and chemical biology, the team discovered that NUDT5 interacts with another enzyme, PPAT, which catalyzes the first step of purine synthesis. When purine levels rise, NUDT5 binds to PPAT, likely locking it into an inactive state, thus telling the cell to stop producing more purines.
The surprising part? This function of NUDT5 doesn't depend on its enzymatic activity. Even when its catalytic site was blocked or disabled, the protein continued to regulate purine synthesis. It's only when NUDT5 is completely removed that cells lose this control mechanism.
Metabolic Control and Its Medical Impact
This discovery sheds light on how cells sense and respond to changes in their metabolic environment. "NUDT5 has been classified as an enzyme that hydrolyzes metabolites," says Stefan Kubicek, Principal Investigator at CeMM and senior author of the study. "But our work reveals a different role - it acts as a structural regulator, determining whether the cell continues producing purines or not."
This mechanism could also explain why some cells become resistant to certain cancer drugs. "Many chemotherapies work by mimicking purine molecules and blocking DNA synthesis," explains Tuan-Anh Nguyen, co-first author of the study. "However, we found that cells without functional NUDT5-PPAT interaction were less sensitive to these treatments, suggesting that mutations in NUDT5 could contribute to drug resistance in tumors."
The key role of NUDT5 in controlling cancer drug sensitivity is further supported by findings from Ralph DeBerardinis' laboratory, also published in the same issue of Science.
Additionally, this research connects folate metabolism, purine synthesis, and diseases caused by MTHFD1 deficiency, a rare genetic disorder affecting immune and neurological development. "Understanding this regulatory network could lead to new therapeutic approaches," adds Jung-Ming George Lin, co-first author of the study.
The collaborators in Kilian Huber's lab in Oxford developed a chemical degrader called dNUDT5, which selectively eliminates NUDT5 from cells. This tool will enable scientists to study the pathway in greater detail and may offer future possibilities for protecting healthy cells from chemotherapy side effects.
"Our findings highlight that enzymes can act not only through the chemical reactions they catalyze but also through their structure," concludes Kubicek. "Sometimes, it's the physical presence of a protein that makes all the difference."
Reference: Nguyen TA, Lin JMG, Marques ASMC, et al. A non-enzymatic role of Nudix hydrolase 5 in repressing purine de novo synthesis. Science. 2025:eadv4257. doi:10.1126/science.adv4257 (https://doi.org/10.1126/science.adv4257)
