A yeast platform for high-level synthesis of tetrahydroisoquinoline alkaloids

Michael E. Pyne, Kaspar Kevvai, Parbir S. Grewal, Lauren Narcross, Brian Choi, Leanne Bourgeois, John E. Dueber and Vincent J. J. Martin ()
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Michael E. Pyne: Concordia University
Kaspar Kevvai: Concordia University
Parbir S. Grewal: University of California, Berkeley
Lauren Narcross: Concordia University
Brian Choi: University of California, Berkeley
Leanne Bourgeois: Concordia University
John E. Dueber: University of California, Berkeley
Vincent J. J. Martin: Concordia University

Nature Communications, 2020, vol. 11, issue 1, 1-10

Abstract: Abstract The tetrahydroisoquinoline (THIQ) moiety is a privileged substructure of many bioactive natural products and semi-synthetic analogs. Plants manufacture 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 yeast THIQ platform by increasing production of the central BIA intermediate (S)-reticuline to 4.6 g L−1, a 57,000-fold improvement over our first-generation strain. We show that gains in BIA output coincide with the formation of several substituted THIQs derived from amino acid catabolism. We use these insights to repurpose the Ehrlich pathway and synthesize an array of THIQ structures. This work provides a blueprint for building diverse alkaloid scaffolds and enables the targeted overproduction of thousands of THIQ products, including natural and semi-synthetic opioids.

Date: 2020
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DOI: 10.1038/s41467-020-17172-x

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