Purine nucleotides act as endogenous molecular glues to regulate purine biosynthesis and thiopurine response (nature.com)

• Purine monophosphates (AMP, IMP, GMP) act as endogenous molecular glues tethering PPAT to NUDT5, enabling nutrient sensing and feedback control of purine synthesis.
• Thiopurine chemotherapeutics (6-MP, 6-TG) function as enhanced molecular glues at the same interface, with 6-meTIMP inhibiting PPAT ~70-fold more potently than AMP.
• The PPAT–NUDT5 glue pocket exhibits conformational flexibility, allowing rational design of improved thiopurines: 6-ethylTIMP shows greater on-target cytotoxicity in leukemia cells.

"Researchers at UC Berkeley discovered that purine nucleotides (AMP, IMP, GMP) function as endogenous molecular glues that tether the rate-limiting enzyme PPAT to its inhibitor NUDT5, enabling cells to sense purine levels and feedback-control synthesis. Thiopurine chemotherapeutics like 6-mercaptopurine and 6-thioguanine exploit this same glue mechanism with enhanced potency. The PPAT–NUDT5 glue pocket shows remarkable conformational flexibility, allowing rational design of more potent thiopurine derivatives. This work identifies metabolite glues as a mode of nutrient sensing and provides a starting point for therapeutic glue discovery."