A yeast platform for high-level synthesis of natural and unnatural tetrahydroisoquinoline alkaloids

The tetrahydroisoquinoline (THIQ) moiety is a privileged substructure of many bioactive natural products and semi-synthetic analogues. The plant kingdom manufactures more than 3,000 THIQ alkaloids, including the opioids morphine and codeine. While microbial species have been engineered to synthesize...

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Bibliographic Details
Published inbioRxiv
Main Authors Pyne, Michael E, Kaspar Kevvai, Grewal, Parbir S, Narcross, Lauren, Choi, Brian, Bourgeois, Leanne, Dueber, John E, Martin, Vincent Jj
Format Paper
LanguageEnglish
Japanese
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 05.12.2019
Subjects
Alkaloids
Amino acids
Codeine
Morphine
Narcotics
Natural products
Opioids
Tetrahydroisoquinoline
Yeast
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Summary:The tetrahydroisoquinoline (THIQ) moiety is a privileged substructure of many bioactive natural products and semi-synthetic analogues. The plant kingdom manufactures more than 3,000 THIQ alkaloids, including the opioids morphine and codeine. While microbial species have been engineered to synthesize a few compounds from the benzylisoquinoline alkaloid (BIA) family of THIQs, low product titers impede industrial viability and limit access to the full chemical space. Here we report a THIQ platform by increasing yeast production of the central BIA intermediate (S)-reticuline to more than 3 g L-1, a 38,000-fold improvement over our first-generation strain. Gains in BIA output coincided with the formation of several substituted THIQs derived from host amino acid catabolism. Enabled by this activity, we repurposed the yeast Ehrlich pathway and demonstrate the synthesis of an array of unnatural THIQ scaffolds. This work provides a blueprint for synthesizing new privileged structures and will enable the targeted overproduction of thousands of THIQ products, including natural and semi-synthetic opioids.
DOI:10.1101/863506