Pathway discovery and engineering of pharmaceuticals from medicinal plants
Abstract/Contents
- Abstract
- It is estimated that a quarter of prescribed medicines from industrialized countries are inspired or directly derived from plant small molecules. Owing to their structural complexity, large-scale synthetic methods do not yet exist for most of these plant-derived pharmaceuticals. Instead, they are extracted directly from natural sources. Industrial farming of medicinal plants, however, is susceptible to pests, diseases, and climate fluctuations, which can result in unreliable supply. In addition, many medicinal plants are difficult to cultivate and are critically endangered. One promising alternative is the engineering of faster growing organisms, such as microbes or the development of chemoenzymatic processes to produce these natural products. However, knowledge about their biosynthetic pathways -- the collection of enzymes required to produce these molecules-- is limited. Traditionally, pathway discovery in plants has been slow due to the complexity and size of their genomes, proteomes, and metabolomes. However, in the last decade, due to recent technological advances, there has been a surge in genomic, transcriptomic, and metabolomic datasets, which have provided valuable insights into plant metabolism. Here, we will present our strategy towards accelerated pathway discovery in medicinal plants, combining these new insights and more recent advances in next-generation sequencing with high-resolution mass spectrometry and a plant (tobacco) heterologous expression platform. First, we will describe our efforts in characterizing the dirigent protein family in Arabidopsis thaliana, which we suspect are involved in the biosynthesis of many unknown plant natural products that may have interesting biological activities. Second, we will describe the discovery of six enzymes from the Himalayan Mayapple for the biosynthesis of the etoposide aglycone, a precursor to the clinically used anticancer agent, etoposide. With these discovered enzymes, we engineered a non-native plant to produce this compound and other non-natural derivatives that cannot be easily accessed by chemical synthesis. Third, we will describe the elucidation of enzymes for the biosynthesis of the ester side chain of homoharringtonine, a drug used in the treatment of chronic myeloid leukemia. Lastly, we present the identification of several biosynthetic enzymes involved in the production of colchicine, a medication for the treatment of gout. This work demonstrates the efficacy of our approach towards pathway discovery in non-model plants, and enables future efforts in the engineering of alternative biological platforms for the biosynthesis of these plant-derived pharmaceuticals.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2017 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Lau, Warren |
|---|---|
| Associated with | Stanford University, Department of Chemical Engineering. |
| Primary advisor | Sattely, Elizabeth |
| Thesis advisor | Sattely, Elizabeth |
| Thesis advisor | Smolke, Christina D |
| Thesis advisor | Spormann, Alfred M |
| Advisor | Smolke, Christina D |
| Advisor | Spormann, Alfred M |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Warren Lau. |
|---|---|
| Note | Submitted to the Department of Chemical Engineering. |
| Thesis | Thesis (Ph.D.)--Stanford University, 2017. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2017 by Warren Lau
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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