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A combined pseudouridine biomanufacturing platform enabled by a streamlined designer pathway

Author

Listed:
  • Le Yu

    (Wuhan University)

  • Ruyi Chen

    (Wuhan University)

  • Chenyue Zhang

    (Xi’an Jiaotong University)

  • Zhengyuan Wang

    (Wuhan University)

  • Zhuqing Wang

    (Wuhan University)

  • Xinyue Zeng

    (Wuhan University)

  • Han Liang

    (Wuhan University)

  • Yuanyuan He

    (Wuhan University)

  • Yixuan She

    (Wuhan University)

  • Yifei Wang

    (Wuhan University)

  • Rong Gong

    (Wuhan University)

  • Xuemin Song

    (Wuhan University)

  • Zixin Deng

    (Wuhan University
    Wuhan University)

  • Qiang Fei

    (Xi’an Jiaotong University)

  • Wenqing Chen

    (Wuhan University
    Wuhan University)

Abstract

mRNA vaccines, featured by incorporated pseudouridine (Ψ), represent a milestone in combating diseases, thus highlighting Ψ importance in drug development. However, economic and environmental challenges have persisted in sustainable Ψ production. Here, we formulate a streamlined designer Ψ pathway, comprising UMP nucleosidase, ΨMP glycosidase, and ΨMP phosphatase, and realize its gram-scale production by targeted discovery of a prominent UMP-preferred nucleosidase (NmYgdH). The optimized pathway, containing NmYgdH, RjPsuG (ΨMP glycosidase), and HDHD1 (ΨMP-specific phosphatase) is cloned into E. coli and systematic evaluation of multiple strategies achieves a Ψ titer of 44.8 g·L−1. Moreover, a thyA-dependent, tunable, and eco-friendly strategy for sustainable Ψ production is demonstrated in a 5 L bioreactor achieving titer of 45.3 g·L−1. Finally, we establish a simplified-strategy for rapid Ψ purification with a recovery-rate of 71%, and techno-economic analysis is employed to validate the feasibility and advantages of this fermentation platform for Ψ biomanufacturing. Therefore, this study provides a blueprint for industrial-production of nucleoside-related molecules.

Suggested Citation

  • Le Yu & Ruyi Chen & Chenyue Zhang & Zhengyuan Wang & Zhuqing Wang & Xinyue Zeng & Han Liang & Yuanyuan He & Yixuan She & Yifei Wang & Rong Gong & Xuemin Song & Zixin Deng & Qiang Fei & Wenqing Chen, 2025. "A combined pseudouridine biomanufacturing platform enabled by a streamlined designer pathway," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-63906-0
    DOI: 10.1038/s41467-025-63906-0
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    References listed on IDEAS

    as
    1. Elie Dolgin, 2021. "The tangled history of mRNA vaccines," Nature, Nature, vol. 597(7876), pages 318-324, September.
    2. Le Yu & Wenting Zhou & Yixuan She & Hongmin Ma & You-Sheng Cai & Ming Jiang & Zixin Deng & Neil P. J. Price & Wenqing Chen, 2021. "Efficient biosynthesis of nucleoside cytokinin angustmycin A containing an unusual sugar system," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    3. Dwight Koeberl & Andreas Schulze & Neal Sondheimer & Gerald S. Lipshutz & Tarekegn Geberhiwot & Lerong Li & Rajnish Saini & Junxiang Luo & Vanja Sikirica & Ling Jin & Min Liang & Mary Leuchars & Steph, 2024. "Interim analyses of a first-in-human phase 1/2 mRNA trial for propionic acidaemia," Nature, Nature, vol. 628(8009), pages 872-877, April.
    4. Chenyue Zhang & Qiang Fei & Rongzhan Fu & Maximilian Lackner & Yongjin J. Zhou & Tianwei Tan, 2025. "Economic and sustainable revolution to facilitate one-carbon biomanufacturing," Nature Communications, Nature, vol. 16(1), pages 1-10, December.
    5. Martin Pfeiffer & Bernd Nidetzky, 2020. "Reverse C-glycosidase reaction provides C-nucleotide building blocks of xenobiotic nucleic acids," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
    6. Martin Pfeiffer & Andrej Ribar & Bernd Nidetzky, 2023. "A selective and atom-economic rearrangement of uridine by cascade biocatalysis for production of pseudouridine," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    7. Xiongying Yan & Weiwei Bao & Yalun Wu & Chenyue Zhang & Zhitao Mao & Qianqian Yuan & Zhousheng Hu & Penghui He & Qiqun Peng & Mimi Hu & Binan Geng & Hongwu Ma & Shouwen Chen & Qiang Fei & Qiaoning He , 2024. "Paradigm of engineering recalcitrant non-model microorganism with dominant metabolic pathway as a biorefinery chassis," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
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