A yeast platform for high-level synthesis of tetrahydroisoquinoline alkaloids
| Autor: | Kaspar Kevvai, Leanne Bourgeois, Brian Choi, John E. Dueber, Parbir Grewal, Vincent J. J. Martin, Lauren Narcross, Michael E. Pyne |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Science General Physics and Astronomy Saccharomyces cerevisiae Benzylisoquinolines 01 natural sciences Article General Biochemistry Genetics and Molecular Biology Applied microbiology 03 medical and health sciences chemistry.chemical_compound Alkaloids Tetrahydroisoquinolines medicine Moiety Benzylisoquinoline lcsh:Science chemistry.chemical_classification Biological Products Multidisciplinary Molecular Structure 010405 organic chemistry Chemistry Tetrahydroisoquinoline Alkaloid General Chemistry Combinatorial chemistry Yeast Chemical space Biosynthetic Pathways 0104 chemical sciences Amino acid Analgesics Opioid 030104 developmental biology Models Chemical THIQ Natural product synthesis lcsh:Q Genetic Engineering Metabolic engineering medicine.drug |
| Zdroj: | Nature Communications, Vol 11, Iss 1, Pp 1-10 (2020) Nature Communications |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-020-17172-x |
| Popis: | 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. Plants synthesize more than 3000 tetrahydroisoquinoline (THIQ) alkaloids, but only a few of them have been produced by engineered microbes and titers are very low. Here, the authors increase (S)-reticuline titer to 4.6 g/L and repurpose the yeast Ehrlich pathway to synthesize a diverse array of THIQ scaffolds. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|