代谢物胶作为嘌呤感知和化疗反应的手段，这一成果由加州大学Michael Rapéel课题组经过不懈努力而取得。这一研究成果于2026年7月15日发表在国际顶尖学术期刊《自然》上。

在这里，研究团队发现嘌呤核苷酸是将嘌呤生物合成中的限速酶-磷酸核糖基焦磷酸氨基转移酶（PPAT）连接到其抑制剂NUDT5的分子胶。这种机制允许细胞感知嘌呤的水平，并建立必要的反馈控制它们的合成。该课题组研究人员把这种分子称为代谢物胶。自20世纪50年代以来，硫嘌呤化疗一直是临床主题，它将相同的复合物粘合在一起，但采用不同的方向以增强功能。与大多数已知的胶水不同，PPAT-NUDT5代谢物胶袋可以调整其构象以适应显着的化合物变化，从而提高胶水效力和改善靶向活性。因此，课题组研究人员确定内源性代谢物胶作为一种可以用于治疗益处的营养感知模式。

据悉，分子胶稳定弱相互作用，赋予复合物新的功能。尽管分子胶已经在植物信号传导和人类治疗中被描述，但尚不清楚这种方式是否在人类细胞中提供内源性调节。

附：英文原文

Title: Metabolite glues as a means of purine sensing and chemotherapeutic response

Author: Witus, Samuel R., Kober, Megan M., Roh, Heegwang, Yang, Zhi, Choueiry, Fouad, Ghate, Avani S., Titov, Denis V., Rap, Michael

Issue&Volume: 2026-07-15

Abstract: Molecular glues stabilize weak interactions to impart new functionalities to complexes1,2,3. 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.

DOI: 10.1038/s41586-026-10790-3

Source: https://www.nature.com/articles/s41586-026-10790-3