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A yeast platform for high-level synthesis of tetrahydroisoquinoline alkaloids.

Author(s): Pyne ME, Kevvai K, Grewal PS, Narcross L, Choi B, Bourgeois L, Dueber JE, Martin VJJ

Nat Commun. 2020 Jul 03;11(1):3337 Authors: Pyne ME, Kevvai K, Grewal PS, Narcross L, Choi B, Bourgeois L, Dueber JE, Martin VJJ

Article GUID: 32620756
A Highly Characterized Synthetic Landing Pad System for Precise Multicopy Gene Integration in Yeast.

Author(s): Bourgeois L, Pyne ME, Martin VJJ

ACS Synth Biol. 2018 Nov 16;7(11):2675-2685 Authors: Bourgeois L, Pyne ME, Martin VJJ

Article GUID: 30372609
Microbial Factories for the Production of Benzylisoquinoline Alkaloids.

Author(s): Narcross L, Fossati E, Bourgeois L, Dueber JE, Martin VJJ

Trends Biotechnol. 2016 Mar;34(3):228-241 Authors: Narcross L, Fossati E, Bourgeois L, Dueber JE, Martin VJJ

Article GUID: 26775900
Reconstituting Plant Secondary Metabolism in Saccharomyces cerevisiae for Production of High-Value Benzylisoquinoline Alkaloids.

Author(s): Pyne ME, Narcross L, Fossati E, Bourgeois L, Burton E, Gold ND, Martin VJ

Methods Enzymol. 2016;575:195-224 Authors: Pyne ME, Narcross L, Fossati E, Bourgeois L, Burton E, Gold ND, Martin VJ

Article GUID: 27417930
Mining Enzyme Diversity of Transcriptome Libraries through DNA Synthesis for Benzylisoquinoline Alkaloid Pathway Optimization in Yeast.

Author(s): Narcross L, Bourgeois L, Fossati E, Burton E, Martin VJ

ACS Synth Biol. 2016 12 16;5(12):1505-1518 Authors: Narcross L, Bourgeois L, Fossati E, Burton E, Martin VJ

Article GUID: 27442619
Title:A yeast platform for high-level synthesis of tetrahydroisoquinoline alkaloids.
Authors:Pyne ME,  Kevvai K,  Grewal PS,  Narcross L,  Choi B,  Bourgeois L,  Dueber JE,  Martin VJJ
Link:https://www.ncbi.nlm.nih.gov/pubmed/32620756?dopt=Abstract
DOI:10.1038/s41467-020-17172-x
Category:Nat Commun
PMID:32620756
Dept Affiliation: BIOLOGY
1 Department of Biology, Concordia University, Montréal, QC, Canada.
2 Centre for Applied Synthetic Biology, Concordia University, Montréal, QC, Canada.
3 Department of Chemical and Biomolecular Engineering, University of California, Berkeley, Berkeley, CA, USA.
4 Department of Bioengineering, University of California, Berkeley, Berkeley, CA, USA.
5 Biological Systems & Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
6 Department of Biology, Concordia University, Montréal, QC, Canada. vincent.martin@concordia.ca.
7 Centre for Applied Synthetic Biology, Concordia University, Montréal, QC, Canada. vincent.martin@concordia.ca.

Description:

A yeast platform for high-level synthesis of tetrahydroisoquinoline alkaloids.

Nat Commun. 2020 Jul 03;11(1):3337

Authors: Pyne ME, Kevvai K, Grewal PS, Narcross L, Choi B, Bourgeois L, Dueber JE, Martin VJJ

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.

PMID: 32620756 [PubMed - as supplied by publisher]