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Rivastigmine is one of the several pharmaceuticals widely prescribed for the treatment of Alzheimer's disease. However, its practical synthesis still faces many issues, such as the involvement of toxic metals and harsh reaction conditions. Herein, we report a chemo-enzymatic synthesis of Rivastigmine. The key chiral intermediate was synthesized by an engineered alcohol dehydrogenase from Lactobacillus brevis (LbADH). A semi-rational 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-immobilized on nanoparticles. By integrating enzymatic and chemical steps, Rivastigmine was successfully synthesized with an overall yield of 66 %. This study offers an efficient chemo-enzymatic route for Rivastigmine and provides several efficient LbADH variants with a broad range of potential applications.

Titel:	Directed Evolution and Immobilization of Lactobacillus brevis Alcohol Dehydrogenase for Chemo-Enzymatic Synthesis of Rivastigmine.
Autor/in / Beteiligte Person:	Su, G ; Ran, L ; Liu, C ; Qin, Z ; Teng, H ; Wu, S
Link:	Zum Volltext
Zeitschrift:	Chemistry (Weinheim an der Bergstrasse, Germany), Jg. 30 (2024-06-06), Heft 32, S. e202400454
Veröffentlichung:	Weinheim, Germany : Wiley-VCH, 2024
Medientyp:	academicJournal
ISSN:	1521-3765 (electronic)
DOI:	10.1002/chem.202400454
Schlagwort:	Biocatalysis Acetophenones chemistry Acetophenones metabolism Protein Engineering Rivastigmine chemistry Levilactobacillus brevis enzymology Alcohol Dehydrogenase metabolism Alcohol Dehydrogenase chemistry Enzymes, Immobilized chemistry Enzymes, Immobilized metabolism
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Grant Information: 32101229 National Natural Science Foundation of China; 22071072 National Natural Science Foundation of China; 2662021JC006 Fundamental Research Funds for the Central Universities; LongYun Program 2.0 Huazhong Agricultural University Contributed Indexing: Keywords: Rivastigmine; alcohol dehydrogenase; co-immobilization; directed evolution; enzyme engineering Substance Nomenclature: PKI06M3IW0 (Rivastigmine) ; EC 1.1.1.1 (Alcohol Dehydrogenase) ; 0 (Enzymes, Immobilized) ; 0 (Acetophenones) ; RK493WHV10 (acetophenone) Entry Date(s): Date Created: 20240403 Date Completed: 20240607 Latest Revision: 20240607 Update Code: 20240607

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Directed Evolution and Immobilization of Lactobacillus brevis Alcohol Dehydrogenase for Chemo-Enzymatic Synthesis of Rivastigmine.