Biosynthesis of plant tetrahydroisoquinoline alkaloids through an imine reductase route

Lu Yang; Jinmei Zhu; Chenghai Sun; Zixin Deng; Xudong Qu

doi:10.1039/c9sc03773j

Biosynthesis of plant tetrahydroisoquinoline alkaloids through an imine reductase route

Chem Sci. 2019 Nov 18;11(2):364-371. doi: 10.1039/c9sc03773j. eCollection 2020 Jan 14.

Authors

Lu Yang^{1

2}, Jinmei Zhu², Chenghai Sun², Zixin Deng¹, Xudong Qu^{1

2}

Affiliations

¹ State Key Laboratory of Microbial Metabolism , School of Life Sciences and Biotechnology , Shanghai Jiao Tong University , Shanghai 200240 , China . Email: quxd@whu.edu.cn.
² Key Laboratory of Combinatorial Biosynthesis and Drug Discovery Ministry of Education , School of Pharmaceutical Sciences , Wuhan University , Wuhan 430071 , China.

Abstract

Herein, we report a biocatalytic approach to synthesize plant tetrahydroisoquinoline alkaloids (THIQAs) from dihydroisoquinoline (DHIQ) precursors using imine reductases and N-methyltransferase (NMT). The imine reductase IR45 was engineered to significantly expand its substrate specificity, enabling efficient and stereoselective conversion of 1-phenyl and 1-benzyl 6,7-dimethoxy-DHIQs into the corresponding (S)-tetrahydroisoquinolines (S-THIQs). Coclaurine N-methyltransferase (CNMT) was able to further efficiently convert these (S)-THIQ intermediates into (S)-THIQAs. By assembling IRED, CNMT, and glucose dehydrogenase (GDH) in one reaction, we effectively constituted two artificial biosynthetic pathways in Escherichia coli and successfully applied them to the production of five (S)-THIQAs. This highly efficient (100% yield from DHIQs) and easily tailorable (adding other genes) biosynthetic approach will be useful for producing a variety of plant THIQAs.