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Published on: February 16, 2018
An Engineered Enzyme Catalyzing Tandem Reductive Aminations for Synthesizing Tertiary Amines
Yaqing Ma1,2, Han Zhang1,3, Jinping Bao1,2
1State Key Laboratory of Engineering Biology For Low-Carbon Manufacturing, Chinese Academy of Sciences, Tianjin Institute of Industrial Biotechnology, Tianjin, China.
Abstract:
Tertiary amines are privileged motifs in bioactive molecules. However, their chemical synthesis lacks sustainability, and biocatalytic alternatives remain underdeveloped. Therefore, there is an urgent need to develop innovative catalytic strategies. We herein disclose the engineering of a wild-type imine reductase into a tandem aminase for consecutive intermolecular reductive aminations, designated AHTanAm. The tandem aminase and its variants exhibit dual catalytic advantages, enabling one-pot synthesis of hundreds of tertiary amines from broadly available primary amine precursors, and exerting precise stereochemical control over multiple stereocenters. Mechanistic dissection via x-ray crystallography and mutagenesis revealed that enzyme-pocket alterations amplify the second-step amination's activity, which serves as the driving force for successful tandem catalysis. In summary, this study bridges the critical synthetic challenge in accessing tertiary amines by creating the first tandem aminase, to the best of our knowledge, via imine-reductase redesign.
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