Modular multi-enzyme cascades enable green and sustainable synthesis of non-canonical amino acids from glycerol

Shuai Xu, Shu-hong Wang, Long-wei Lou, Yu Ji, Ulrich Schwaneberg, Zhi-min Li (), Feng Cheng () and Zong-lin Li ()
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Shuai Xu: East China University of Science and Technology
Shu-hong Wang: East China University of Science and Technology
Long-wei Lou: East China University of Science and Technology
Yu Ji: Beijing University of Chemical Technology
Ulrich Schwaneberg: Worringerweg 3
Zhi-min Li: East China University of Science and Technology
Feng Cheng: Zhejiang University of Technology
Zong-lin Li: East China University of Science and Technology

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: Abstract Non-canonical amino acids (ncAAs) bearing diverse functional groups hold transformative potential in drug discovery, protein engineering, and biomaterial science. However, their industrial-scale production remains constrained by the inefficiency, high cost, and environmental burden of conventional chemical and enzymatic methods. Here, we present a modular multi-enzyme cascade platform that leverages glycerol—an abundant and sustainable byproduct of biodiesel production—as a low-cost substrate for ncAAs synthesis. Directed evolution of O-phospho-l-serine sulfhydrylase (OPSS) enhances the catalytic efficiency of C–N bond formation by 5.6-fold, enabling the efficient synthesis of triazole-functionalized ncAAs. By integrating a plug-and-play enzymatic strategy, our system enables gram- to decagram-scale production of 22 ncAAs with C–S, C–Se, and C–N side chains and can be readily scaled up to a 2 liter reaction system. Notably, water is the sole byproduct, and all products exhibit an atomic economy of >75%, highlighting the environmental compatibility of this platform. This work establishes a green, cost-effective, and industrially viable approach to expanding amino acid diversity, providing a versatile toolkit for applications in pharmaceuticals, synthetic biology, and next-generation biomaterials.

Date: 2025
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DOI: 10.1038/s41467-025-63341-1

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