Enzyme Unveils a Surprising Role in Cellular Metabolism
(Vienna, 6 November 2025) Within the intricate cellular machinery, a delicate metabolic network orchestrates the production, recycling, and cessation of essential molecules. At the heart of this network lies folate metabolism, a process that supplies the building blocks for DNA, RNA, and amino acids. When this intricate system is disrupted, whether by genetic mutations or inadequate dietary folates, the consequences can be severe, ranging from developmental disorders to cancer.
In a groundbreaking discovery, researchers from CeMM, the Research Center for Molecular Medicine of the Austrian Academy of Sciences, in collaboration with scientists from the University of Oxford, have identified an unexpected player in this metabolic symphony: the enzyme NUDT5. Their study, published in the prestigious journal Science, reveals that NUDT5 plays a crucial role in shutting down purine production, the chemical pathway responsible for DNA's building blocks, but it does so without relying on its traditional enzymatic function.
NUDT5's Unconventional Role
Purines are essential molecules that cells utilize for DNA and RNA synthesis and energy storage. They can be recycled from existing materials or synthesized de novo, a resource-intensive process demanding tight regulation.
The researchers delved into this regulatory mechanism by examining cells with mutations in the gene MTHFD1, a key enzyme in the folate cycle. Folate metabolism provides the essential one-carbon units for purine synthesis, and disruptions 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 uncovered that NUDT5 interacts with another enzyme, PPAT, which catalyzes the initial step of purine synthesis. When purine levels surge, NUDT5 binds to PPAT, potentially rendering it inactive and signaling the cell to halt purine production.
The surprising revelation was that NUDT5's regulatory function doesn't hinge on its known enzymatic activity, which typically breaks down nucleotide derivatives. Even when its catalytic site was chemically blocked or genetically disabled, NUDT5 continued to regulate purine synthesis. It was only when NUDT5 was entirely removed, either through genetic knockout or a novel molecule that selectively degrades it, that cells lost this control mechanism.
Metabolic Regulation with Medical Implications
This discovery sheds new light on how cells perceive and respond to metabolic changes. Stefan Kubicek, Principal Investigator at CeMM and senior author of the study, emphasizes, "NUDT5 has long been categorized as an enzyme that hydrolyzes metabolites. However, our findings unveil a distinct role—it acts as a structural regulator, determining whether cells continue producing purines or not."
This mechanism may also explain the resistance of certain cells to cancer drugs. Many chemotherapies, such as 6-thioguanine, mimic purine molecules to block DNA synthesis. The study found that cells lacking functional NUDT5-PPAT interaction were less sensitive to these treatments, suggesting that NUDT5 mutations could contribute to tumor drug resistance. This finding is further supported by similar research from Ralph DeBerardinis' laboratory, also published in Science.
Additionally, the research connects folate metabolism, purine synthesis, and diseases caused by MTHFD1 deficiency, a rare genetic disorder affecting immune and neurological development. Jung-Ming George Lin, co-first author of the study, notes, "Given the tight linkage between folate and purine pathways, understanding this regulatory network could pave the way for novel therapeutic approaches."
The collaborators in Kilian Huber's lab at Oxford also developed a chemical degrader called dNUDT5, which selectively eliminates NUDT5 from cells. This tool will enable scientists to delve deeper into the pathway's intricacies and may offer future avenues for shielding healthy cells from chemotherapy side effects.
Kubicek concludes, "Our findings underscore that enzymes can exert influence not only through the chemical reactions they catalyze but also through their structural presence. Sometimes, it's the physical presence of a protein that makes the crucial difference."
