Activation and Stabilization of Engineered Amine Dehydrogenase by Fatty Acids for Bioprocess Intensification of Asymmetric Reductive Amination
Weixi Kong (Hebei Vocational University of Technology and Engineering, Hebei University of Technology)
Jiawang Zhang (Hebei University of Technology)
Liya Zhou (Hebei University of Technology)
Guanhua Liu (Hebei University of Technology)
Ying He (Hebei University of Technology)
Li Ma (Hebei University of Technology)
Frank Hollmann (TU Delft - BT/Biocatalysis)
Lihui Wang (Tianjin Modern Vocational Technology College)
Yunting Liu (Hebei University of Technology)
Yanjun Jiang (Hebei University of Technology)
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Abstract
In this study, we present a significant advancement in the field of enzymatic asymmetric reductive amination (ARA) of ketones, a pivotal reaction for chiral amine synthesis. Through a combination of semirational enzyme design and bioprocess development, we achieve the dual activation and stabilization of amine dehydrogenase (AmDH) to meet industrial demands. The engineered AmDH exhibits remarkable catalytic efficiency (turnover number, TON >1,000,000) and exceptional stability (half-life >7 days at 50 °C), with a broadened substrate scope including various aryl alkyl ketones and fatty ketones. Leveraging biobased oleic acid as an activator and stabilizer, we achieved kilogram-scale synthesis of chiral amines. Furthermore, the integration of AmDH with chemical catalysts in chemoenzymatic cascades has enabled the synthesis of a wide array of pharmaceutically relevant amines from diverse substrates, demonstrating the enzyme’s versatility and potential to transform synthetic chemistry.