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Harnessing photoenzymatic reactions for unnatural biosynthesis in microorganisms

Yuan, Yujie1; Li, Maolin1; Harrison, Wesley1; Zhang, Zhengyi1; Zhao, Huimin1

Published Dec 10, 2025 on Dryad. https://doi.org/10.5061/dryad.ns1rn8q54

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Abstract

Photoenzymatic catalysis enables new-to-nature transformations, but its scalability is limited by high enzyme loading, costly cofactors, and radical-induced instability. Here we report the integration of light-driven photoenzymatic reactions into the cellular metabolism of Escherichia coli, bridging flavin-based photobiocatalysis with biosynthesis. Using synthetic biology strategies, we engineered microbial cells to continuously produce olefin substrates and ene-reductase photoenzyme while regenerating cofactors directly from glucose. By externally supplying radical precursors or by introducing synthetic pathways for their in situ production, we enabled fermentation-based microbial photobiosynthesis, achieving high titers and demonstrating its feasibility for scale-up in bioreactor. This approach extends photobiocatalysis from in vitro applications to in vivo semi-biosynthesis and complete biosynthesis, revealing its full potential for integrating light-driven reactions into cellular metabolism.