Harnessing Fe(II)/α-ketoglutarate-dependent oxygenases for sustainable synthesis

Fe(II)/α-ketoglutarate-dependent oxygenases (αKG OXs) have emerged as versatile biocatalysts for selective C–H functionalization, offering sustainable routes to complex molecules under mild conditions. Recent advances in data-driven enzyme discovery, machine learning (ML)-guided enzyme engineering, and computational design have significantly improved their substrate scope, stability, and scalability for pharmaceutical synthesis. Beyond native oxidative modifications, repurposed αKG OXs mediate new-to-nature transformations, including site‐selective azidation, Mukaiyama hydration, Conia-ene cyclization, and photoenzymatic cross-coupling. Their integration into chemoenzymatic cascades has enabled concise and green syntheses of complex natural products and drug intermediates. This review highlights recent advances in studies that establish αKG OXs as key enzymes for sustainable biocatalytic synthesis. • αKG OXs enable selective C–H functionalization under mild conditions. • Data-driven and computational designs expand reaction diversity and enzyme stability. • Repurposed enzymes catalyze new-to-nature transformations. • Chemoenzymatic cascades streamline syntheses of natural products and drugs.