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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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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2020
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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. |
format | Online Article Text |
id | pubmed-7529995 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT srinivasanprashanth biosynthesisofmedicinaltropanealkaloidsinyeast AT smolkechristinad biosynthesisofmedicinaltropanealkaloidsinyeast |