Metabolite glues as a means of purine sensing and chemotherapeutic response

  • Nature. 2026 Jul;655(8125):1300-1308. doi: 10.1038/s41586-026-10790-3.
Samuel R Witus  1 ,  Megan M Kober  2 ,  Heegwang Roh  1  3 ,  Zhi Yang  1 ,  Fouad Choueiry  1 ,  Avani S Ghate  1 ,  Denis V Titov  1  2  4 ,  Michael Rapé  5  6  7
Affiliations
  • 1. Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA.
  • 2. Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA, USA.
  • 3. Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA, USA.
  • 4. Center for Computational Biology, University of California, Berkeley, Berkeley, CA, USA.
  • 5. Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA. [email protected].
  • 6. Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA, USA. [email protected].
  • 7. California Institute for Quantitative Biosciences (QB3), University of California, Berkeley, Berkeley, CA, USA. [email protected].
PMID: 42457960 DOI: 10.1038/s41586-026-10790-3
Abstract

Molecular Glues stabilize weak interactions to impart new functionalities to complexes1-3. Although Molecular Glues have been described in plant signalling and as human therapeutics4,5, it is unclear whether this modality provides endogenous regulation in human cells. Here we show that purine nucleotides are Molecular Glues that tether the rate-limiting enzyme in purine biosynthesis-phosphoribosyl pyrophosphate amidotransferase (PPAT)-to its inhibitor NUDT5. This mechanism allows cells to sense the levels of purines and to establish essential feedback control of their synthesis. We refer to such molecules as metabolite glues. Thiopurine chemotherapeutics6, which have been in clinical use since the 1950s, glue the same complex but adopt distinct orientations for enhanced function. Unlike most known glues, the PPAT-NUDT5 metabolite-glue pocket can adjust its conformation to notable compound alterations, enabling increased glue potency and improved on-target activity. We therefore identify Endogenous Metabolite glues as a mode of nutrient sensing that can be exploited for therapeutic benefit.

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