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Charting unknown metabolic reactions by mass spectrometry-resolved stable-isotope tracing metabolomics

Author

Listed:
  • Yang Gao

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Mingdu Luo

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Hongmiao Wang

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Zhiwei Zhou

    (Chinese Academy of Sciences)

  • Yandong Yin

    (Chinese Academy of Sciences)

  • Ruohong Wang

    (Chinese Academy of Sciences)

  • Beizi Xing

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Xiaohua Yang

    (Chinese Academy of Sciences)

  • Yuping Cai

    (Chinese Academy of Sciences)

  • Zheng-Jiang Zhu

    (Chinese Academy of Sciences
    Shanghai Key Laboratory of Aging Studies)

Abstract

Metabolic reactions play important roles in organisms such as providing energy, transmitting signals, and synthesizing biomacromolecules. Charting unknown metabolic reactions in cells is hindered by limited technologies, restricting the holistic understanding of cellular metabolism. Using mass spectrometry-resolved stable-isotope tracing metabolomics, we develop an isotopologue similarity networking strategy, namely IsoNet, to effectively deduce previously unknown metabolic reactions. The strategy uncovers ~300 previously unknown metabolic reactions in living cells and mice. Specifically, we elaborately chart the metabolic reaction network related to glutathione, unveiling three previously unreported reactions nestled within glutathione metabolism. Among these, a transsulfuration reaction, synthesizing γ-glutamyl-seryl-glycine directly from glutathione, underscores the role of glutathione as a sulfur donor. Functional metabolomics studies systematically characterize biochemical effects of previously unknown reactions in glutathione metabolism, showcasing their diverse functions in regulating cellular metabolism. Overall, these newly uncovered metabolic reactions fill gaps in the metabolic network maps, facilitating exploration of uncharted territories in cellular biochemistry.

Suggested Citation

  • Yang Gao & Mingdu Luo & Hongmiao Wang & Zhiwei Zhou & Yandong Yin & Ruohong Wang & Beizi Xing & Xiaohua Yang & Yuping Cai & Zheng-Jiang Zhu, 2025. "Charting unknown metabolic reactions by mass spectrometry-resolved stable-isotope tracing metabolomics," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60258-7
    DOI: 10.1038/s41467-025-60258-7
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    References listed on IDEAS

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    1. Yang Gao & Mingdu Luo & Hongmiao Wang & Zhiwei Zhou & Yandong Yin & Ruohong Wang & Beizi Xing & Xiaohua Yang & Yuping Cai & Zheng-Jiang Zhu, 2025. "Charting unknown metabolic reactions by mass spectrometry-resolved stable-isotope tracing metabolomics," Nature Communications, Nature, vol. 16(1), pages 1-16, December.

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