Researchers have uncovered a surprising new function for the enzyme NUDT5, demonstrating it helps control the production of DNA building blocks not through its typical enzymatic activity, but through its structural properties. This discovery significantly expands our understanding of how cells regulate essential metabolic processes and has implications for cancer treatment and rare genetic disorders.
Understanding Folate Metabolism and Purine Synthesis
Every cell maintains a meticulously balanced metabolic network that dictates when to create, recycle, or stop producing vital molecules. A critical component of this network is folate metabolism, a process that provides key chemical units needed to synthesize DNA, RNA, and amino acids. Disruptions to this system—whether due to genetic mutations or a lack of dietary folates—can lead to developmental problems or even contribute to the development of cancer.
At the heart of this process lies purine production. Purines are essential molecules used by cells to construct DNA and RNA and store energy. Cells can recycle these molecules or create them from scratch through a process called the de novo pathway. This pathway is energy-intensive and needs to be tightly controlled.
A New Discovery: NUDT5’s Structural Role
A recent study, published in Science, reveals that the enzyme NUDT5 participates in this control mechanism in an unexpected way. Researchers from CeMM and the University of Oxford discovered that NUDT5 helps to shut down purine production without using its enzymatic activity, which normally breaks down nucleotide derivatives. Instead, NUDT5 acts as a molecular scaffold, physically restraining a key enzyme called PPAT – which catalyzes the first step of purine synthesis. When purine levels become too high, NUDT5 binds to PPAT, essentially telling the cell to stop producing more purines.
Surprising Findings About Enzyme Function
The team’s research involved studying cells with mutations in the MTHFD1 gene, crucial to folate metabolism. Through a combination of genetic screening, metabolomics, and chemical biology, they found that NUDT5 interacts with PPAT. Remarkably, even when NUDT5’s catalytic site was chemically blocked or genetically disabled, the protein continued to regulate purine synthesis. Only when NUDT5 was completely removed—through genetic knockout or the use of a newly developed molecule that selectively degrades it—did cells lose this control mechanism.
Implications for Cancer Treatment and Genetic Disorders
This discovery has significant implications. It highlights that enzymes aren’t solely defined by the chemical reactions they catalyze but also by their structural properties. Furthermore, it may explain why some cells develop resistance to certain cancer drugs, such as 6-thioguanine, which work by mimicking purine molecules and blocking DNA synthesis. Cells lacking a functional NUDT5-PPAT interaction were found to be less sensitive to these treatments.
“NUDT5 has long been classified as an enzyme that hydrolyzes metabolites,” says Stefan Kubicek, Principal Investigator at CeMM. “But our work reveals a completely different role—it acts as a structural regulator that determines whether the cell keeps producing purines or not.”
The research also connects folate metabolism, purine synthesis, and diseases caused by MTHFD1 deficiency, a rare genetic disorder affecting immune and neurological development. Researchers have developed a chemical degrader called dNUDT5 to selectively eliminate NUDT5 from cells, allowing for more detailed study of this pathway and potentially offering ways to protect healthy cells from chemotherapy side effects.
In conclusion, this study demonstrates that enzymes can play a crucial role not just through their enzymatic actions but also through their physical structure, offering new avenues for therapeutic intervention in cancer and shedding light on the intricate workings of cellular metabolism. It’s a reminder that our understanding of biological processes is constantly evolving, revealing unexpected functionalities in established players like NUDT5.
