Engineering a norcoclaurine synthase for one-step synthesis of (S)-1-aryl-tetrahydroisoquinolines

Abstract Tetrahydroisoquinoline alkaloids (THIQAs) are ubiquitous compounds with important pharmaceutical and biological activity. Their key N -heterocyclic structural motifs synthesised via Pictet–Spengler (P–S) reaction by norcoclaurine synthases (NCS) in plants. The synthesis of 1-aryl-tetrahydroisoquinoline has attracted increasing attention due to their antitumor antivirus activities. Herein, the L68T/M97V mutant NCS from Thalictrum flavum improved activity was developed semi-rational design. This not only showed higher catalytic performance (> 96% conversion) toward benzaldehyde dopamine over wild-type enzyme, but also catalysed P–S bulky substrate 4-biphenylaldehyde high conversion 99%) for effective 1-aryl-THIQA. In terms stereoselectivity, all products optical purity (92–99% enantiomeric excess). Graphical