A yeast platform for high-level synthesis of natural and unnatural tetrahydroisoquinoline alkaloids
| Autor: | Parbir Grewal, Lauren Narcross, Martin Vjj, Michael E. Pyne, Leanne Bourgeois, Kaspar Kevvai, Bernard Choi, John E. Dueber |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
chemistry.chemical_classification
0303 health sciences 010405 organic chemistry Chemistry Tetrahydroisoquinoline Stereochemistry Alkaloid 01 natural sciences Yeast Chemical space 0104 chemical sciences Amino acid 03 medical and health sciences chemistry.chemical_compound THIQ medicine Moiety Benzylisoquinoline 030304 developmental biology medicine.drug |
| DOI: | 10.1101/863506 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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