Design and evolution of artificial enzyme with in-situ biosynthesized non-canonical amino acid

Wei Huang, Shiping Wang, Ya Wei, Yuting Bai, Zhixi Zhu, Dejing Yin, Tao Liu, Xiang Sheng () and Zhi Zhou ()
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Wei Huang: Jiangnan University
Shiping Wang: Chinese Academy of Sciences
Ya Wei: Jiangnan University
Yuting Bai: Jiangnan University
Zhixi Zhu: Jiangnan University
Dejing Yin: Jiangnan University
Tao Liu: Peking University
Xiang Sheng: Chinese Academy of Sciences
Zhi Zhou: Jiangnan University

Nature Communications, 2025, vol. 16, issue 1, 1-10

Abstract: Abstract The creation of designer enzymes by incorporating genetically encoded non-canonical amino acids (ncAAs) could significantly expand the catalytic repertoire of the enzyme universe for abiological transformations. However, due to the limited availability of ncAAs with potential catalytic functional groups, progress in this field remains relatively slow. Herein, we present an efficient approach for enzyme design with organocatalytic ncAAs by integrating the biosynthesis and genetic incorporation of ncAAs harboring abiological catalytic residues into the protein scaffold. Based on this ncAAs in situ biosynthesis and incorporation system, our designer enzyme with an unnatural mercapto-aniline residue is created efficiently by feeding thiols to E. coli and shows significant catalytic activity for an enantioselective Friedel-Crafts alkylation reaction with excellent enantioselectivity and reactivity after directed evolution. This study provides a universal strategy for designing artificial enzymes with xenobiotic catalytic moieties with diverse biosynthesized ncAAs, thereby expanding the toolbox of biocatalysts for abiological transformations.

Date: 2025
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DOI: 10.1038/s41467-025-63733-3

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