MassIVE MSV000101706

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Metabolite glues as a means of purine sensing and chemotherapeutic response

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Description

Molecular glues stabilize weak interactions to impart novel functionalities onto complexes. While molecular glues have been described in plant signaling and human therapeutics, it remains to be established whether this modality provides endogenous regulation in human cells. Here, we show that purine nucleotides are molecular glues that tether the rate-limiting enzyme of purine biosynthesis, phosphoribosyl pyrophosphate amidotransferase (PPAT), to its inhibitor NUDT5. This mechanism allows cells to sense purine levels and establish essential feedback control of their synthesis. We refer to such molecules as metabolite glues. Thiopurine chemotherapeutics, in clinical use since the 1950s, target the same complex, but adopt unique orientations for enhanced function. Distinct from most known glues, the PPAT-NUDT5 metabolite glue pocket can adjust its conformation to significant compound alterations, enabling increased glue potency and enhanced on-target activity. We therefore identify endogenous metabolite glues as a mode of nutrient sensing that can be exploited for therapeutic benefit. [doi:10.25345/C5V40KC9Z] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: purine metabolism ; NUDT5 ; PPAT ; metabolomics ; DatasetType:Metabolomics

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Principal Investigators:
(in alphabetical order) 		Michael Rape, University of California, Berkeley, United States of America
Submitting User: switus
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