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However, its practical synthesis still faces many issues, such as the involvement of toxic metals and harsh reaction conditions. Herein, we report a chemo\u2010enzymatic synthesis of Rivastigmine. The key chiral intermediate was synthesized by an engineered alcohol dehydrogenase from <jats:italic>Lactobacillus brevis<\/jats:italic> (LbADH). A semi\u2010rational approach was employed to improve its catalytic activity and thermal stability. Several LbADH variants were obtained with a remarkable increase in activity and melting temperature. Exploration of the substrate scope of these variants demonstrated improved activities toward various ketones, especially acetophenone analogs. To further recycle and reuse the biocatalyst, one LbADH variant and glucose dehydrogenase were co\u2010immobilized on nanoparticles. By integrating enzymatic and chemical steps, Rivastigmine was successfully synthesized with an overall yield of 66\u2009%. This study offers an efficient chemo\u2010enzymatic route for Rivastigmine and provides several efficient LbADH variants with a broad range of potential applications.<\/jats:p>","DOI":"10.1002\/chem.202400454","type":"journal-article","created":{"date-parts":[[2024,4,3]],"date-time":"2024-04-03T12:54:45Z","timestamp":1712148885000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Directed Evolution and Immobilization of <i>Lactobacillus brevis<\/i> Alcohol Dehydrogenase for Chemo\u2010Enzymatic Synthesis of Rivastigmine"],"prefix":"10.1002","volume":"30","author":[{"given":"Guorong","family":"Su","sequence":"first","affiliation":[{"name":"National Key Laboratory of Agricultural Microbiology College of Life Science and Technology Huazhong Agricultural University  1 Shizishan Street Wuhan 430070 P.R. 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