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However, the potential of merging these two strategies remains underdeveloped for enantiocontrolled biotransformations. Herein, we develop a synergistic metalloenzymatic and photoredox catalysis platform to enable enantiodivergent radical alkylation of 2\u2010acyl imidazoles. Specifically, cupin proteins are redesigned to function as copper(II)\u2010based Lewis\u2010acid\u2010enzymes (LAses), which, in synergy with tripyridinyl\u2010ruthenium\u2010based photoredox catalysis, precisely control the generation, reactivity, and selectivity of abiological radicals, thereby unlocking non\u2010natural enzyme reactivity. Powered by protein engineering, repurposed photo\u2010LAses facilitate the green and efficient synthesis of diverse enantioenriched \u03b1\u2010chiral ketones in high enantioselectivity (both enantiomers accessible, up to 97% yield and 98.5:1.5 enantiomeric ratio [er]). Detailed mechanistic studies suggest a radical addition to the metalloenzymatic enolate pathway and explain the switched selectivity from dark to photoconditions.<\/jats:p>","DOI":"10.1002\/anie.202500338","type":"journal-article","created":{"date-parts":[[2025,4,10]],"date-time":"2025-04-10T10:03:31Z","timestamp":1744279411000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Enantiodivergent Radical Alkylation by Synergistic Lewis\u2010Acid\u2010Enzyme and Photoredox Catalysis"],"prefix":"10.1002","volume":"64","author":[{"given":"Jiawei","family":"Zhang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Coordination Chemistry Chemistry and Biomedicine Innovation Center (ChemBIC) Frontier Interdisciplinary Science Research Center School of Chemistry and Chemical Engineering Nanjing University  Nanjing 210023 P.R. 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