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A robust platform streamlining aromatic noncanonical amino acid biosynthesis and genetic code expansion in Escherichia coli

Author

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  • Jingxuan Zhang

    (Chinese Academy of Sciences
    Tianjin University)

  • Keying Yu

    (Chinese Academy of Sciences
    Nanjing University of Chinese Medicine)

  • Yali Xu

    (Chinese Academy of Sciences)

  • Wushuang Zhao

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

  • Yulian Li

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

  • Ying Wang

    (Tianjin University)

  • Florian P. Seebeck

    (University of Basel)

  • Xiao-Hua Chen

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

  • Cangsong Liao

    (Chinese Academy of Sciences
    Nanjing University of Chinese Medicine
    University of Chinese Academy of Sciences)

Abstract

Genetic code expansion (GCE) has significantly enhanced the diversity of proteins in the biological world, leading to a wide range of applications. Despite the advances in GCE, the cost of noncanonical amino acids (ncAAs) remains one of the major obstacles for large-scale production. In situ biosynthesis of ncAAs from commercial precursors offers a promising solution to this challenge, yet only a few biosynthetic pathways have been reported. Here, we present a platform that couples the biosynthesis of aromatic ncAAs with genetic code expansion in E. coli, enabling the production of proteins and peptides containing ncAAs. Forty ncAAs are synthesized from aryl aldehydes by the biosynthetic pathway, while nineteen ncAAs are incorporated into superfolder GFP using three orthogonal translation systems. The platform’s versatility is demonstrated by the production of macrocyclic peptides and antibody fragments. We envision that the platform will facilitate the production of peptides, enzymes, and antibody fragments containing ncAAs.

Suggested Citation

  • Jingxuan Zhang & Keying Yu & Yali Xu & Wushuang Zhao & Yulian Li & Ying Wang & Florian P. Seebeck & Xiao-Hua Chen & Cangsong Liao, 2025. "A robust platform streamlining aromatic noncanonical amino acid biosynthesis and genetic code expansion in Escherichia coli," Nature Communications, Nature, vol. 16(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-63679-6
    DOI: 10.1038/s41467-025-63679-6
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    References listed on IDEAS

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    1. Lars Longwitz & Reuben B. Leveson-Gower & Henriëtte J. Rozeboom & Andy-Mark W. H. Thunnissen & Gerard Roelfes, 2024. "Boron catalysis in a designer enzyme," Nature, Nature, vol. 629(8013), pages 824-829, May.
    2. Yuda Chen & Shikai Jin & Mengxi Zhang & Yu Hu & Kuan-Lin Wu & Anna Chung & Shichao Wang & Zeru Tian & Yixian Wang & Peter G. Wolynes & Han Xiao, 2022. "Unleashing the potential of noncanonical amino acid biosynthesis to create cells with precision tyrosine sulfation," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    3. Daniel L. Dunkelmann & Carlos Piedrafita & Alexandre Dickson & Kim C. Liu & Thomas S. Elliott & Marc Fiedler & Dom Bellini & Andrew Zhou & Daniele Cervettini & Jason W. Chin, 2024. "Adding α,α-disubstituted and β-linked monomers to the genetic code of an organism," Nature, Nature, vol. 625(7995), pages 603-610, January.
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