Divergent Protein Engineering of Transaminase for the Synthesis of Chiral Rivastigmine and Apremilast Precursors

Author:

Tang Langyu12,Yang Xinjie13,Sun Ningning1,Wu Guojiao1,Wu Yuzhou1,Zhong Fangrui12

Affiliation:

1. Hubei Engineering Research Center for Biomaterials and Medical Protective Materials, Hubei Key Laboratory of Bioinorganic Chemistry & Materia Medica, School of Chemistry and Chemical Engineering, Huazhong University of Science and Technology 1037 Luoyu Road Wuhan Hubei 430074 China

2. Shenzhen Huazhong University of Science and Technology Research Institute Shenzhen Guangdong 518000 China

3. Longgang Institute of Zhejiang Sci‐Tech University Wenzhou Zhejiang 325802 China

Abstract

Comprehensive SummaryThe implementation of divergent protein engineering on the natural transaminase Vf‐ω‐TA led to the development of two effective mutants (M2 and M8), enabling the enzymatic synthesis of chiral amine precursors of Rivastigmine and Apremilast, respectively. The evolution of the enzymes was guided by crystal structures and a focused mutagenesis strategy, allowing them to effectively address the challenging ketone substrates with significant steric hindrance. Under the optimized reaction parameters, transamination proceeded smoothly in good conversions and with perfect stereochemical control (> 99% ee). These processes utilize inexpensive α‐methylbenzylamine as an amine donor and avoid the continuous acetone removal and costly LDH/GDH/NADH systems.

Funder

National Key Research and Development Program of China

Huazhong University of Science and Technology

Publisher

Wiley

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