Efficient Synthesis of Tetrahydroisoquinoline Alkaloids from Dopamine and Natural Phenolic Acids by Whole-Cell Biocatalysis

Abstract

Plant-derived tetrahydroisoquinoline alkaloids (THIQAs) are an important class of natural products for various biological purposes. However, their preparation still relies on phytoextraction, which remains challenging due to low production yields. Notably, biocatalysis has shown the potential to address this challenge. Herein, through overexpressing a carboxylate reductase (CAR), an old yellow enzyme (OYE), and a norcoclaurine synthase (NCS) in Escherichia coli, two whole-cell biocatalytic systems were constructed to synthesize eight THIQAs, including three benzylisoquinoline alkaloids (BIAs) and five phenethylisoquinoline alkaloids (PEIAs), from dopamine and different natural phenolic acids, including phenylacetic and cinnamic acids. The synthesis of BIAs was achieved with excellent enantioselectivity (≥97% ee) and titers of up to 4.34 g L^–1. PEIAs could be produced with ee values ranging from 80% to 94%, and most had titers greater than 1 g L^–1. Moreover, lignocellulosic hydrolyzate was also used as the substrate to investigate the synthesis of a 1-phenethylisoquinoline scaffold, in which 1.14 g L^–1 product was produced in 73.1% yield. This work not only provides a new strategy for the efficient synthesis of diverse THIQAs, but also serves as a reference for the high-value utilization of lignocellulosic biomass in the synthesis of valuable natural products.