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Biosynthesis of medicinal tropane alkaloids in yeast

Tropane alkaloids (TAs) from nightshade plants are neurotransmitter inhibitors used for treating neuromuscular disorders and are classified as essential medicines by the World Health Organization(1,2). Global supply challenges have resulted in frequent drug shortages(3,4). Further supply-chain vulne...

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Autores principales: Srinivasan, Prashanth, Smolke, Christina D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529995/
https://www.ncbi.nlm.nih.gov/pubmed/32879484
http://dx.doi.org/10.1038/s41586-020-2650-9
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author Srinivasan, Prashanth
Smolke, Christina D.
author_facet Srinivasan, Prashanth
Smolke, Christina D.
author_sort Srinivasan, Prashanth
collection PubMed
description Tropane alkaloids (TAs) from nightshade plants are neurotransmitter inhibitors used for treating neuromuscular disorders and are classified as essential medicines by the World Health Organization(1,2). Global supply challenges have resulted in frequent drug shortages(3,4). Further supply-chain vulnerabilities are revealed by events like the Australian wildfires(5) and the COVID-19 pandemic(6). Rapidly deployable production strategies that are robust to environmental and socioeconomic upheaval(7,8) are needed. Here, we engineered baker’s yeast to produce the medicinal TAs hyoscyamine and scopolamine starting from simple sugars and amino acids. We combined functional genomics to identify a missing pathway enzyme, protein engineering to enable functional acyltransferase expression via trafficking to the vacuole, heterologous transporters to facilitate intracellular routing, and strain optimization to improve titers. Our integrated system positions >20 proteins adapted from yeast, bacteria, plants, and animals across six sub-cellular locations to recapitulate the spatial organization of TA biosynthesis in plants. Microbial biosynthesis platforms can facilitate discovery of TA derivatives as novel therapeutics for neurological disease and, once scaled, enable robust and agile supply of these essential medicines.
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spelling pubmed-75299952021-03-02 Biosynthesis of medicinal tropane alkaloids in yeast Srinivasan, Prashanth Smolke, Christina D. Nature Article Tropane alkaloids (TAs) from nightshade plants are neurotransmitter inhibitors used for treating neuromuscular disorders and are classified as essential medicines by the World Health Organization(1,2). Global supply challenges have resulted in frequent drug shortages(3,4). Further supply-chain vulnerabilities are revealed by events like the Australian wildfires(5) and the COVID-19 pandemic(6). Rapidly deployable production strategies that are robust to environmental and socioeconomic upheaval(7,8) are needed. Here, we engineered baker’s yeast to produce the medicinal TAs hyoscyamine and scopolamine starting from simple sugars and amino acids. We combined functional genomics to identify a missing pathway enzyme, protein engineering to enable functional acyltransferase expression via trafficking to the vacuole, heterologous transporters to facilitate intracellular routing, and strain optimization to improve titers. Our integrated system positions >20 proteins adapted from yeast, bacteria, plants, and animals across six sub-cellular locations to recapitulate the spatial organization of TA biosynthesis in plants. Microbial biosynthesis platforms can facilitate discovery of TA derivatives as novel therapeutics for neurological disease and, once scaled, enable robust and agile supply of these essential medicines. 2020-09-02 2020-09 /pmc/articles/PMC7529995/ /pubmed/32879484 http://dx.doi.org/10.1038/s41586-020-2650-9 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Srinivasan, Prashanth
Smolke, Christina D.
Biosynthesis of medicinal tropane alkaloids in yeast
title Biosynthesis of medicinal tropane alkaloids in yeast
title_full Biosynthesis of medicinal tropane alkaloids in yeast
title_fullStr Biosynthesis of medicinal tropane alkaloids in yeast
title_full_unstemmed Biosynthesis of medicinal tropane alkaloids in yeast
title_short Biosynthesis of medicinal tropane alkaloids in yeast
title_sort biosynthesis of medicinal tropane alkaloids in yeast
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529995/
https://www.ncbi.nlm.nih.gov/pubmed/32879484
http://dx.doi.org/10.1038/s41586-020-2650-9
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