Charting unknown metabolic reactions by mass spectrometry-resolved stable-isotope tracing metabolomics
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 m...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-60258-7 |
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| author | Yang Gao Mingdu Luo Hongmiao Wang Zhiwei Zhou Yandong Yin Ruohong Wang Beizi Xing Xiaohua Yang Yuping Cai Zheng-Jiang Zhu |
| author_facet | Yang Gao Mingdu Luo Hongmiao Wang Zhiwei Zhou Yandong Yin Ruohong Wang Beizi Xing Xiaohua Yang Yuping Cai Zheng-Jiang Zhu |
| author_sort | Yang Gao |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-019a9fdcb4bb4f6792ea13f5ff6cea46 |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-019a9fdcb4bb4f6792ea13f5ff6cea462025-08-20T03:16:41ZengNature PortfolioNature Communications2041-17232025-05-0116111610.1038/s41467-025-60258-7Charting unknown metabolic reactions by mass spectrometry-resolved stable-isotope tracing metabolomicsYang Gao0Mingdu Luo1Hongmiao Wang2Zhiwei Zhou3Yandong Yin4Ruohong Wang5Beizi Xing6Xiaohua Yang7Yuping Cai8Zheng-Jiang Zhu9Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of SciencesInterdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of SciencesInterdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of SciencesInterdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of SciencesInterdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of SciencesInterdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of SciencesInterdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of SciencesInterdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of SciencesInterdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of SciencesInterdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of SciencesAbstract 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.https://doi.org/10.1038/s41467-025-60258-7 |
| spellingShingle | Yang Gao Mingdu Luo Hongmiao Wang Zhiwei Zhou Yandong Yin Ruohong Wang Beizi Xing Xiaohua Yang Yuping Cai Zheng-Jiang Zhu Charting unknown metabolic reactions by mass spectrometry-resolved stable-isotope tracing metabolomics Nature Communications |
| title | Charting unknown metabolic reactions by mass spectrometry-resolved stable-isotope tracing metabolomics |
| title_full | Charting unknown metabolic reactions by mass spectrometry-resolved stable-isotope tracing metabolomics |
| title_fullStr | Charting unknown metabolic reactions by mass spectrometry-resolved stable-isotope tracing metabolomics |
| title_full_unstemmed | Charting unknown metabolic reactions by mass spectrometry-resolved stable-isotope tracing metabolomics |
| title_short | Charting unknown metabolic reactions by mass spectrometry-resolved stable-isotope tracing metabolomics |
| title_sort | charting unknown metabolic reactions by mass spectrometry resolved stable isotope tracing metabolomics |
| url | https://doi.org/10.1038/s41467-025-60258-7 |
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