Copper-dependent halogenase catalyses unactivated C−H bond functionalization

Chen-Yu Chiang, Masao Ohashi (), Jessie Le, Pan-Pan Chen, Qingyang Zhou, Songrong Qu, Undramaa Bat-Erdene, Shabnam Hematian, Jose A. Rodriguez, K. N. Houk, Yisong Guo, Joseph A. Loo and Yi Tang ()
Additional contact information
Chen-Yu Chiang: University of California, Los Angeles
Masao Ohashi: University of California, Los Angeles
Jessie Le: University of California, Los Angeles
Pan-Pan Chen: University of California, Los Angeles
Qingyang Zhou: University of California, Los Angeles
Songrong Qu: University of California, Los Angeles
Undramaa Bat-Erdene: University of California, Los Angeles
Shabnam Hematian: University of North Carolina at Greensboro
Jose A. Rodriguez: University of California, Los Angeles
K. N. Houk: University of California, Los Angeles
Yisong Guo: Carnegie Mellon University
Joseph A. Loo: University of California, Los Angeles
Yi Tang: University of California, Los Angeles

Nature, 2025, vol. 638, issue 8049, 126-132

Abstract: Abstract Carbon–hydrogen (C–H) bonds are the foundation of essentially every organic molecule, making them an ideal place to do chemical synthesis. The key challenge is achieving selectivity for one particular C(sp3)−H bond1–3. In recent years, metalloenzymes have been found to perform C(sp3)−H bond functionalization4,5. Despite substantial progresses in the past two decades6,7, enzymatic halogenation and pseudohalogenation of unactivated C(sp3)−H—providing a functional handle for further modification—have been achieved with only non-haem iron/α-ketoglutarate-dependent halogenases, and are therefore limited by the chemistry possible with these enzymes8. Here we report the discovery and characterization of a previously unknown halogenase ApnU, part of a protein family containing domain of unknown function 3328 (DUF3328). ApnU uses copper in its active site to catalyse iterative chlorinations on multiple unactivated C(sp3)−H bonds. By taking advantage of the softer copper centre, we demonstrate that ApnU can catalyse unprecedented enzymatic C(sp3)−H bond functionalization such as iodination and thiocyanation. Using biochemical characterization and proteomics analysis, we identified the functional oligomeric state of ApnU as a covalently linked homodimer, which contains three essential pairs—one interchain and two intrachain—of disulfide bonds. The metal-coordination active site in ApnU consists of binuclear type II copper centres, as revealed by electron paramagnetic resonance spectroscopy. This discovery expands the enzymatic capability of C(sp3)−H halogenases and provides a foundational understanding of this family of binuclear copper-dependent oxidative enzymes.

Date: 2025
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DOI: 10.1038/s41586-024-08362-4

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