Repurposing Enzymes through Light, Electricity and Engineering

The growing demand for green and sustainable manufacturing has driven increasing interest in biosynthesis using nature’s catalysts: enzymes. Although enzymes mediate numerous biochemical transformations essential to life, their catalytic repertoire remains far more limited than that of small-molecule chemocatalysts, thereby restricting the scope of biomanufacturing. Our research focuses on developing versatile biocatalysts with tailored, new-to-nature functions that are difficult to achieve through conventional chemocatalysis. Specifically, we harness visible-light-catalysis and electrochemical methods to generate highly reactive radical intermediates within enzymatic systems, thereby unlocking non-natural enzyme reactivity. In parallel, we employ directed evolution to remodel protein structures and fine-tune both reactivity and selectivity. Recently, we have repurposed: (1) flavoproteins as visible-light-excitable enzymes for oxidation-triggered biotransformations; and (2) thiamine-dependent enzymes as radical acyl/alkyl/alkenyl transferases for unprecedented asymmetric radical–radical cross-couplings; (3) copper-binding proteins as Lewis-acid enzymes; (4) imine-reductases as radical-type aminases.

De novo design of Artificial Enzymes

The core innovation in asymmetric synthesis lies in the development of novel chiral catalysts. To expand the catalytic repertoire of enzymes, we integrate concepts and techniques from organic chemistry, synthetic biology, and artificial intelligence to establish a “design–reaction–mechanism–application” framework for artificial photoenzymes.

PhotoBioManufacturing

Biomanufacturing uses living organisms or their components to produce a wide range of products, including pharmaceuticals, vaccines, foods, and biofuels. By harnessing the capabilities of the unnatural enzymatic functions we have developed, we aim to construct sunlight-driven microbial cell factories, thereby laying the foundation for an emerging field: photobiomanufacturing. We anticipate that photobiomanufacturing will enable efficient and scalable production, offer new opportunities for renewable manufacturing, help address environmental challenges, and contribute to the development of a bio-based economy. 

1. Electricity-Driven Enzymatic Dynamic Kinetic Oxidation. Zhao, B.; Xu, Y.; Zhu, Q.; Liu, A.; Peng, X.; Zhang, T.; Yu, L.; Zhang, Y.; Huang, X.* Nature 2025, 643, 699-704.

2. Synergistic Photobiocatalysis for Enantioselective Triple Radical Sorting. Xing, Z.; Liu, F.; Feng, J.; Yu, L.; Wu, Z.; Zhao, B.; Chen, B.; Ping, H.; Xu, Y.; Liu, A.; Zhao, Y.; Wang, C.; Wang, B.*; Huang, X.* Nature 2025, 637, 1118-1123.

3. A Light-Driven Enzymatic Enantioselective Radical Acylation. Xu, Y.; Chen, H.; Yu, L.; Peng, X.; Zhang, J.; Xing, Z.; Bao, Y.; Liu, A.; Zhao, Y.; Tian, C.*; Liang, Y.*; Huang, X.* Nature 2024, 625, 74-78.

4. Enantioselective C(sp³)-C(sp³) Bond Formation by Synergistic Thiamine-Dependent Radical Biocatalysis and Photoredox Catalysis. Chun, J.; Bao, Y.; Zhang, Q.; Hou, X.; Wu, Z.; Sun, H.; Xing, Z.; Chen, B.; Zhang, Z.; Zhao, Y.; Zhou, J.*; Wang, B.*; Huang, X.* Nat. Catal. 2026, 9, 414-423.

5. Steering Oxygen-Centred Radicals with Ground-State Ene-Reductases for Enantioselective Intermolecular Hydroalkoxylations. Chen, B.; Zhang, Q.; Yu, J.; Zhao, B.; Ge, R.; Zhang, Z.; Luo, D.; Wang, B.*; Huang, X.* Nat. Catal. 2025, 8, 740-748.