Microbial synthesis of natural,semisynthetic, and new-to-nature tetrahydroisoquinoline alkaloids

The tetrahydroisoquinoline (THIQ) moiety forms the backbone of several natural, synthetic, and semisynthetic drugs approved for the treatment of cancer, pain, gout, and various neurodegenerative diseases. Plants synthesize up to 3000 THIQ structures constituting the benzylisoquinoline, phenethylisoquinoline, Amaryllidaceae, and ipecac alkaloid classes. This review outlines the ongoing surge in activity surrounding the production of natural, semisynthetic, and new-to-nature THIQ metabolites in engineered microbial systems. These efforts have accelerated THIQ pathway discovery and engineering, unlocked new domains of chemical space, and spurred the development of highly productive microbial strains synthesizing unprecedented yields of THIQ precursors. Consolidating these advancements into a single bioprocess holds potential to outcompete crop-based manufacturing and total synthesis for the production of high-value THIQ pharmaceuticals at scale.