Engineering Saccharomyces cerevisiae for the production of plant-derived pharmaceuticals
Abstract/Contents
- Abstract
- Natural products and their derivatives comprise over 60% of all drugs currently on the market, and natural product pharmaceuticals have been the subject of renewed interest to revitalize drug discovery pipelines. Plant secondary metabolites are a significant source of bioactive compounds. The discovery and screening of new natural products from plants is difficult, however, because many compounds exist only in trace amounts and the methods for isolating and purifying these compounds from the native plant hosts are generally inefficient. Microbial biosynthesis of plant metabolites is an exciting alternative production platform that provides several distinct advantages over the native plant hosts, including well-developed genetic tools for pathway expression and manipulation, fast growth rates, and established large-scale culture methods. Here we describe engineering Saccharomyces cerevisiae as a microbial production platform for the benzylisoquinoline alkaloids (BIAs), a large class of plant secondary metabolites that exhibit a wide range of pharmacological activities, including anti-HIV, anticancer, and antimicrobial activities. We engineered strains capable of producing protoberberine, protopine, benzophenanthridine and bisbenzylisoquinoline alkaloids. The number and types of chemical transformation steps achieved in this work represent one of the most complex examples in the field of metabolic engineering. In addition, we have developed strategies for the microbial expression of plant cytochrome P450s including expression methods and culture condition optimizations. Through engineering BIA biosynthetic pathways in yeast we have sought to create a reliable and scalable source of valuable drugs and drug candidates and develop generalizable optimization strategies that will broadly advance the development of microbial production platforms for plant natural products.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2014 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Trenchard, Isis Jean |
|---|---|
| Associated with | Stanford University, Department of Bioengineering. |
| Primary advisor | Smolke, Christina D |
| Thesis advisor | Smolke, Christina D |
| Thesis advisor | Endy, Andrew D |
| Thesis advisor | Swartz, James R |
| Advisor | Endy, Andrew D |
| Advisor | Swartz, James R |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Isis Jean Trenchard. |
|---|---|
| Note | Submitted to the Department of Bioengineering. |
| Thesis | Thesis (Ph.D.)--Stanford University, 2014. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2014 by Isis Jean Trenchard
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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