Endogenous Metabolite Glues Can Be Therapeutically Exploited

Cells tightly regulate metabolic processes, balancing energy conservation and biosynthetic demand. In a recent study, Witus and colleagues describe a metabolite glue that regulates purine biosynthesis, with implications for clinical utility. Although molecular glues have been identified in other species and are of active interest for therapeutic development, whether molecular glues represent an endogenous mode of regulation within human cells has not been well-characterized. To investigate mechanisms of metabolic control, a targeted genetic screen was performed in which around 3,000 metabolic enzymes and transporters were knocked out and assessed for differential responses to disrupted biosynthetic pathway regulation via inhibition of cullin-RING E3 ligases (CRL). While loss of purine synthesis enzymes sensitized cells to CRL inhibition, the opposite was true for pyrimidines. Notably, depletion of the protein NUDT5 also protected against CRL inhibitor sensitivity. Affinity purification and mass spectrometry demonstrated that NUDT5 interacts with the rate-limiting enzyme of de novo purine synthesis, phosphoribosyl pyrophosphate amidotransferase (PPAT). In concordance with the potential role of AMP in modulating PPAT stability, cryo-electron microscopy revealed the structure of a PPAT–AMP–NUDT5 complex, with an AMP binding pocket between PPAT and NUDT5 molecules that has flexibility to accommodate other purines. This structure and subsequent biochemical analyses suggested that AMP may function as a molecular glue that tethers the metabolic enzyme PPAT to its inhibitor NUDT5. The PPAT substrate phosphoribosyl diphosphate (PRPP) was shown to bind at the same site as AMP but resulted in dissociation of the complex. These opposing functions of AMP and PRPP align with cellular demands for increased purine synthesis in the setting of elevated PRPP and low AMP and decreased pathway activation with abundant AMP, supported by an observed reduction in flux through de novo synthesis in the presence of ample purines. Extending the implications of these findings to therapeutic settings, thiopurine chemotherapeutics were shown to also act through a glue mechanism to bridge PPAT and NUDT5. Thiopurines more strongly inhibited purine synthesis than endogenous nucleotides, and structural studies with bulkier molecules demonstrated the striking flexibility of the pocket region to fit an array of ligands, without compromising glue-like properties. Initial characterization of a modified thiopurine, 6-ethylthioinosine-5′-monophosphate, showed greater PPAT inhibition and more favorable selectivity, highlighting the potential of translating these insights into improved chemotherapeutics. Overall, these data identify metabolite glues as endogenous regulators of purine biosynthesis, a mechanism that may be repurposed for clinical benefit.Witus SR, Kober MM, Roh H, Yang Z, Choueiry F, Ghate AS, et al. Metabolite glues as a means of purine sensing and chemotherapeutic response. Nature 2026;655:1300–8.Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at https://aacrjournals.org/cdnews.