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  3. Nitrogen metabolism profiling reveals cell state-specific pyrimidine synthesis pathway choice

Nitrogen metabolism profiling reveals cell state-specific pyrimidine synthesis pathway choice

  • bioRxiv. 2025 Jul 24:2025.07.23.666448. doi: 10.1101/2025.07.23.666448.
Milan R Savani,  Bailey C Smith,  Wen Gu,  Yi Xiao,  Gerard Baquer,  Bingbing Li,  Skyler S Oken,  Namya Manoj,  Lauren G Zacharias,  Vinesh T Puliyappadamba,  Sylwia A Stopka,  Michael S Regan,  Michael M Levitt,  Charles K Edgar,  William H Hicks,  Soummitra Anand,  Tracey Shipman,  Misty S Martin-Sandoval,  Rainah Winston,  João S Patrício,  Xandria Johnson,  Trevor S Tippetts,  Diana D Shi,  Andrew Lemoff,  Timothy E Richardson,  Pascal O Zinn,  Ashley Solmonson,  Thomas P Mathews,  Nathalie Y R Agar,  Ralph J DeBerardinis,  Kalil G Abdullah,  Samuel K McBrayer
PMID: 40777281 DOI: 10.1101/2025.07.23.666448
Abstract

Conventional stable isotope tracing assays track one or several metabolites. However, cells use an array of nutrients to sustain nitrogen metabolic pathways. This incongruency hampers a system level understanding of cellular nitrogen metabolism. Therefore, we created a platform to simultaneously trace 30 nitrogen Isotope-Labeled Metabolites. This platform revealed that while primitive cells engage both de novo and salvage pyrimidine synthesis pathways, differentiated cells nearly exclusively salvage uridine despite expressing de novo pathway Enzymes. This link between cell state and pyrimidine synthesis routes persisted in physiological contexts, including primary murine and human tissues and tumor xenografts. Mechanistically, we found that Ser1900 phosphorylation of CAD, the first enzyme of the de novo pathway, was enriched in primitive cells and that mimicking this modification in differentiated cells abrogated their preference for pyrimidine salvage. Collectively, we establish a method for nitrogen metabolism profiling and define a mechanism of cell state-specific pyrimidine synthesis pathway choice.

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