Directed evolution of an amine transaminase for the synthesis of an Apremilast intermediate via kinetic resolution. (1st August 2021)

• Record Type: Journal Article
• Authors: Xiang, Chao; Wu, Shuke; Bornscheuer, Uwe T.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 43(2021)
• Publication Date: 2021-08-01
• Subjects: Biocatalysis -- Chiral amine -- Directed evolution -- Kinetic resolution -- Transaminase; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2021.116271
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Apremilast is an important active pharmaceutical ingredient that relies on a resolution to produce the key chiral amine intermediate. To provide a new catalytic and enzymatic process for Apremilast, we performed the directed evolution of the amine transaminase from Vibrio fluvialis . Six rounds of evolution resulted in the VF-8M-E variant with > 400-fold increase specific activity over the wildtype enzyme. A homology model of VF-8M-E was built and a molecular docking study was performed to explain the increase in activity. The purified VF-8M-E was successfully applied to produce the key chiral amine intermediate in enantiopure form and 49% conversion via a kinetic resolution, representing a new enzymatic access towards Apremilast.