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Here we report the engineering of an amine dehydrogenase (AmDH) from <jats:italic>Jeotgalicoccus aerolatus<\/jats:italic> for the asymmetric synthesis of chiral \u03b1\u2010(hetero)aryl primary amines in excellent conversions (up to 99\u2009%) and enantioselectivities (up to 99\u2009% ee). The best AmDH variant (<jats:italic>Ja<\/jats:italic>\u2010AmDH\u2010M3<jats:sub>3<\/jats:sub>) exhibited high activity and specificity toward alkyl (hetero)aryl ketones, even for those bearing a bulky alkyl chain. An efficient directed evolution approach based on molecular docking was implemented to enlarge the active pocket with a more hydrophobic entrance, which is responsible for the high activity. The <jats:italic>Ja<\/jats:italic>\u2010AmDH\u2010M3<jats:sub>3<\/jats:sub> was also used for preparative\u2010scale synthesis of pharmaceutically relevant amines and a key intermediate of chiral pincer ligands, which highlighted its practical application in synthetic chemistry.<\/jats:p>","DOI":"10.1002\/anie.202202264","type":"journal-article","created":{"date-parts":[[2022,3,14]],"date-time":"2022-03-14T03:04:01Z","timestamp":1647227041000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":46,"title":["Direct Asymmetric Reductive Amination of Alkyl (Hetero)Aryl Ketones by an Engineered Amine Dehydrogenase"],"prefix":"10.1002","volume":"61","author":[{"given":"Weixi","family":"Kong","sequence":"first","affiliation":[{"name":"School of Chemical Engineering and Technology Hebei University of Technology  No. 8 Guangrong Road, Hongqiao District Tianjin 300130 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunting","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Chemical Engineering and Technology Hebei University of Technology  No. 8 Guangrong Road, Hongqiao District Tianjin 300130 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Huang","sequence":"additional","affiliation":[{"name":"School of Chemical Engineering and Technology Hebei University of Technology  No. 8 Guangrong Road, Hongqiao District Tianjin 300130 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liya","family":"Zhou","sequence":"additional","affiliation":[{"name":"School of Chemical Engineering and Technology Hebei University of Technology  No. 8 Guangrong Road, Hongqiao District Tianjin 300130 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Gao","sequence":"additional","affiliation":[{"name":"School of Chemical Engineering and Technology Hebei University of Technology  No. 8 Guangrong Road, Hongqiao District Tianjin 300130 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas J.","family":"Turner","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Manchester Manchester Institute of Biotechnology  131 Princess Street Manchester M1 7DN UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1470-2102","authenticated-orcid":false,"given":"Yanjun","family":"Jiang","sequence":"additional","affiliation":[{"name":"School of Chemical Engineering and Technology Hebei University of Technology  No. 8 Guangrong Road, Hongqiao District Tianjin 300130 China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,3,23]]},"reference":[{"key":"e_1_2_7_1_1","unstructured":"\u00a0"},{"key":"e_1_2_7_2_2","first-page":"12","volume":"94","author":"Jarvis L. 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