A binuclear copper enzyme platform for enantioconvergent radical (pseudo)halogenation
- 1Purdue University
Abstract
Despite their intriguing native metalloenzymology, naturally occurring copper enzymes remain largely underexploited for new-to-nature biocatalytic reactions. Herein, we report the systematic investigation and reprogramming of natural copper enzymes to catalyze unnatural free radical (pseudo)halogenation reaction in a highly enantioselective fashion. Evaluating Cu enzymes in the decarboxylative azidation of redox-active esters revealed activity across multiple Cu enzyme families, with type III binuclear Cu enzymes, particularly the Bacillus megaterium tyrosinase (BmTyr), exhibiting superior activity and enantioselectivity across both stabilized and unstabilized alkyl radicals upon further engineering. The strong halide binding affinity of the binuclear Cu system also enabled challenging enantioconvergent bromination, chlorination and isothiocyanation reactions, which remained inaccessible to repurposed nonheme Fe enzymes. Further EPR and UV-visible spectroscopic analyses confirmed the coupled binuclear nature of wild-type and engineered bacterial tyrosinases and provided insights into the origin of their enhanced activity. Collectively, this study establishes binuclear copper enzymes as a powerful platform for new-to-nature stereoselective radical reactions, expanding the scope of metalloenzyme catalysis beyond mononuclear systems.
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BibTeX
@misc{chen2026binuclear,
title = {{A binuclear copper enzyme platform for enantioconvergent radical (pseudo)halogenation}},
author = {X. Chen and O. M. Adeyemo and H. Chen and H. Chen and N. Nguyen and J. Palazzo and L. Zhao and K. Lin and B. K. Mai and P. Liu and S. Tian and Y. Yang},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.20.753013},
url = {https://www.biorxiv.org/content/10.64898/2026.09.20.753013v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - A binuclear copper enzyme platform for enantioconvergent radical (pseudo)halogenation
AU - X. Chen
AU - O. M. Adeyemo
AU - H. Chen
AU - H. Chen
AU - N. Nguyen
AU - J. Palazzo
AU - L. Zhao
AU - K. Lin
AU - B. K. Mai
AU - P. Liu
AU - S. Tian
AU - Y. Yang
PY - 2026
DA - 2026/09/20
PB - bioRxiv
DO - 10.64898/2026.09.20.753013
UR - https://www.biorxiv.org/content/10.64898/2026.09.20.753013v1
AB - Despite their intriguing native metalloenzymology, naturally occurring copper enzymes remain largely underexploited for new-to-nature biocatalytic reactions. Herein, we report the systematic investigation and reprogramming of natural copper enzymes to catalyze unnatural free radical (pseudo)halogenation reaction in a highly enantioselective fashion. Evaluating Cu enzymes in the decarboxylative azidation of redox-active esters revealed activity across multiple Cu enzyme families, with type III binuclear Cu enzymes, particularly the Bacillus megaterium tyrosinase (BmTyr), exhibiting superior activity and enantioselectivity across both stabilized and unstabilized alkyl radicals upon further engineering. The strong halide binding affinity of the binuclear Cu system also enabled challenging enantioconvergent bromination, chlorination and isothiocyanation reactions, which remained inaccessible to repurposed nonheme Fe enzymes. Further EPR and UV-visible spectroscopic analyses confirmed the coupled binuclear nature of wild-type and engineered bacterial tyrosinases and provided insights into the origin of their enhanced activity. Collectively, this study establishes binuclear copper enzymes as a powerful platform for new-to-nature stereoselective radical reactions, expanding the scope of metalloenzyme catalysis beyond mononuclear systems.
ER -