biostudies-literatureChiang CYNIAID NIH HHSNIGMS NIH HHS126-132https://www.ebi.ac.uk/biostudies/studies/S-EPMC12145154biostudies-literatureUnknown638(8049)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 bond^1-3. In recent years, metalloenzymes have been found to perform C(sp³)-H bond functionalization^4,5. Despite substantial progresses in the past two decades^6,7, 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 unknNatureCopper-dependent halogenase catalyses unactivated C-H bond functionalization.PMC12145154R35 GM150762R01 AI141481R35 GM118056R35 GM145286Zhou QGuo YLe JOhashi MChen PPHouk KNHematian SBat-Erdene UQu SRodriguez JALoo JAChiang CYTang YfalseCopper-dependent halogenase catalyses unactivated C-H bond functionalization.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 bond^1-3. In recent years, metalloenzymes have been found to perform C(sp³)-H bond functionalization^4,5. Despite substantial progresses in the past two decades^6,7, 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 unkn2025-01-01T00:00:00Z2025 Feb2026-03-18T13:29:21.721Z2025-08-18T09:54:10.971ZS-EPMC121451543988094410.1038/s41586-024-08362-4