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Harnessing photoenzymatic reactions for unnatural biosynthesis in microorganisms

Nature Catalysis volume 9, pages 62–72 (2026)Cite this article

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Abstract

Photobiocatalysis provides a powerful strategy for integrating light and biological catalysts to drive abiological transformations. However, its scalability is hindered by high enzyme loading, reliance on costly cofactors and instability under radical-generating conditions. Here we report the integration of light-driven enzymatic 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 while regenerating cofactors directly from glucose. By externally supplying radical precursors or introducing synthetic pathways for their in situ production, we enabled fermentation-based microbial photobiosynthesis, achieving high titres and demonstrating feasibility for scale-up in a bioreactor. This approach extends photobiocatalysis from in vitro applications to in vivo semi- and complete biosynthesis, revealing its full potential for integrating light-driven reactions into cellular metabolism.

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Fig. 1: Integration of in vitro new-to-nature enzymatic reactions into in vivo biosynthetic pathways.
Fig. 2: Design and optimization of an in vivo photobiosynthesis platform.
Fig. 3: Expanding the scope of the in vivo photobiosynthesis platform.
Fig. 4: Coupling photoenzymatic reactions into metabolic networks.

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Data availability

The DNA sequences of plasmids used in this study are provided in the Supplementary Information. The SnapGene files for the key plasmids can be accessed at https://doi.org/10.5061/dryad.ns1rn8q54 (ref. 50). Source data are provided with this paper. The remaining data are available in the main text or Supplementary Information, or from the corresponding author upon reasonable request.

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Acknowledgements

We thank L. Burrus and T. Martin for assistance with the fed-batch fermentation experiments. This work was funded by the DOE Center for Advanced Bioenergy and Bioproducts Innovation, under the auspices of the US Department of Energy, Office of Science, Office of Biological and Environmental Research (award DE-SC0018420 to H.Z.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Author information

Author notes

  1. Maolin Li

    Present address: Frontier Science Center for the Creation of New Organic Substances, Nankai University, Tianjin, China

  2. These authors contributed equally: Yujie Yuan, Maolin Li.

Authors and Affiliations

  1. DOE Center for Advanced Bioenergy and Bioproducts Innovation, University of Illinois Urbana-Champaign, Urbana, IL, USA

    Yujie Yuan, Maolin Li, Wesley Harrison, Zhengyi Zhang & Huimin Zhao

  2. Department of Chemical and Biomolecular Engineering, University of Illinois Urbana-Champaign, Urbana, IL, USA

    Yujie Yuan, Maolin Li, Wesley Harrison, Zhengyi Zhang & Huimin Zhao

  3. Carl R. Woese Institute for Genomic Biology, University of Illinois Urbana-Champaign, Urbana, IL, USA

    Yujie Yuan, Maolin Li, Wesley Harrison, Zhengyi Zhang & Huimin Zhao

  4. NSF Molecule Maker Lab Institute, University of Illinois Urbana-Champaign, Urbana, IL, USA

    Huimin Zhao

  5. NSF iBioFoundry, University of Illinois Urbana-Champaign, Urbana, IL, USA

    Huimin Zhao

Authors
  1. Yujie Yuan
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Contributions

H.Z. coordinated the project. H.Z., Y.Y. and M.L. jointly conceptualized the project and designed the research experiments. Y.Y., M.L. and H.Z. wrote the paper with input from all authors. Y.Y. executed the strain construction, biosynthesis and fed-batch fermentation experiments. Y.Y. and M.L. constructed the plasmids. M.L. synthesized the product standards. W.H. contributed to construction of the mutant library. W.H. and Z.Z. were responsible for synthesizing radical precursors.

Corresponding author

Correspondence to Huimin Zhao.

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Yuan, Y., Li, M., Harrison, W. et al. Harnessing photoenzymatic reactions for unnatural biosynthesis in microorganisms. Nat Catal 9, 62–72 (2026). https://doi.org/10.1038/s41929-025-01470-y

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