Abstract
Electrochemistry is undergoing a resurgence in synthetic chemistry and has compelling advantages1. Repurposing natural enzymes through synthetic chemical strategies holds promise for exploring new chemical space2,3,4,5,6. Elegant strategies, including directed evolution7,8,9,10, artificial enzymes11 and photoenzymatic catalysis12,13, have demonstrated their capacities for expanding the applications of enzymes in both academia and industry. However, the integration of electrochemistry with enzymes has primarily been limited to replicating previously established enzyme functions14,15,16. Key challenges in achieving new enzyme reactivity with electricity include compatibility issues and difficulties in heterogeneous electron transfer. Here we report the reshaping of thiamine-dependent enzymes with ferrocene-mediated electrocatalysis to unlock an unnatural dynamic kinetic oxidation of α-branched aldehydes. This robust electroenzymatic approach yields various bioactive (S)-profens with up to 99% enantiomeric excess; it is applicable with whole cells overexpressing the enzyme and using down to 0.05 mol% enzyme loadings. Mechanistic investigations show multiple functions of the electroenzyme in precise substrate discrimination, accelerating racemization and facilitating kinetically matched electron transfer events.
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Acknowledgements
We thank Y. Yang from NKU, S. Lu and Q. Dai from CIQTEK for their help on pulsed EPR experiments (CIQTEK EPR100); Y.-T. Long, W.-Z. Xie, X. Yang and C. Su from NJU for their help in mechanistic studies; H.-C. Xu, B. Wang and H. Huo from XMU for their discussions; D. Zhu from TIB for the gift of the plasmid for PaBAL; Y. Hao, Y. Zhang and S. Zhang from our group for their assistance with substrate synthesis. We thank the staff members of the Electron Spin Resonance System (https://cstr.cn/31125.02.SHMFF.ESR) at the Steady High Magnetic Field Facility, CAS (https://cstr.cn/31125.02.SHMFF). This work was supported by the National Key Research and Development Program of China 2022YFA0913000 (X.H.), the National Natural Science Foundation of China (22225703 to Y.Z., 22277053 to X.H., 224B2705 to B.Z., 223B2703 to Y.X. and 22437005 to Q.Z.), the Fundamental Research Funds for the Central Universities (0205/14380351 and 0205/14380346 to X.H.), the Strategic Priority Research Program of Chinese Academy of Sciences (XDB0960201 and XDB0540000 to L.Y.) and the Youth Innovation Promotion Association of the Chinese Academy of Sciences (2022455 to L.Y.).
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B.Z. developed the electroenzymatic catalysis. B.Z. and Y.X. performed most of the synthetic and mechanistic experiments. Q.Z. performed molecular dynamics simulations. A.L. and L.Y. contributed to EPR experiments. X.P. and T.Z. performed parts of the synthetic experiments and mechanistic investigations. Y.Z. assisted in mechanistic investigations and data analysis. X.H., Y.X. and B.Z. wrote the paper with input from all authors. X.H. coordinated and conceived the project.
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X.H., B.Z., Y.X., Q.Z., X.P. and T.Z. are inventors of a Chinese patent (application no. 2024117499275) covering the electroenzymatic method reported in this work. The other authors declare no competing interests.
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Zhao, B., Xu, Y., Zhu, Q. et al. Electricity-driven enzymatic dynamic kinetic oxidation. Nature 643, 699–704 (2025). https://doi.org/10.1038/s41586-025-09178-6
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DOI: https://doi.org/10.1038/s41586-025-09178-6
