Purine nucleotides and their derivatives play crucial roles in many cellular processes, making them essential metabolites for all living organisms. Purine nucleotides are synthesized through salvage or de novo pathways. De novo purine synthesis (DPS) is up-regulated under conditions of high purine demand to ensure the production of genetic materials and chemical energy, thereby supporting cell proliferation. However, the regulatory mechanisms governing DPS remain unclear. We herein show that PRPP amidotransferase (PPAT), the rate-limiting enzyme in DPS, forms dynamic and motile condensates in cells under a purine-depleted environment. The formation and maintenance of condensates requires phase separation, which is driven by target of rapamycin complex 1-induced ribosome biosynthesis. The self-assembly of PPAT molecules facilitates condensate formation, with intracellular PRPP and purine nucleotides both regulating this self-assembly. Moreover, molecular dynamics simulations suggest that clustering-mediated PPAT activation occurs through intermolecular substrate channeling. Cells unable to form PPAT condensates exhibit growth defects, highlighting the physiological importance of condensation. Disorders in the regulation of purine metabolism are associated with various diseases, such as cancer and hyperuricemia (gout). Therefore, detailed examinations of DPS, including this study, will provide insights into the molecular mechanisms underlying these diseases.

・PLOS Biology　
・2025/04/10
・Phase separation of the PRPP amidotransferase into dynamic condensates promotes de novo purine synthesis in yeast

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