Engineering of biosynthetic pathways to the type II polyketides frenolicin B and A-74528
Abstract/Contents
- Abstract
- Polyketides are a large class of structurally diverse natural products which posses a wide range of biological activities. Unfortunately, despite the potential utility of these compounds in the clinic, large scale production of many of these natural products from their native hosts remains a challenge. Additionally, due to their complexity, engineering better pharmacokinetic properties by traditional synthetic means is often challenging. A better understanding of the biosynthetic machinery which produces polyketides allows for optimization of their production and paves the way for bioactivity-based pathway reengineering. This work begins with an introduction detailing attempts to unravel the biosynthetic underpinnings of two key natural product families, the tetracyclines and the thiostreptons, with an eye toward ultimately reengineering the pathways. Then, our efforts to reconstruct and reengineer the biosynthesis and biological activity of the type II polyketides frenolicin and A-74528 are detailed. Successful reconstruction of a chimeric biosynthetic pathway to frenolicin B and subsequent reengineering of that pathway to produce novel frenolicin analogs is described. Then, the biological activity of these compounds both in vitro against the parasites Toxoplasma gondii and Plasmodium falciparum is discussed. Additional studies against Plasmodium berghi in mice show that frenolicin B is an effective antiparastic agent in vivo. Following this, engineering of a biosynthetic pathway to the novel antiviral agent A-74528 from S. sp. SANK 61196 is presented and the impact of various tailoring enzymes on metabolite production are explored.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2012 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Fitzgerald, Jay Thomas |
|---|---|
| Associated with | Stanford University, Department of Chemistry |
| Primary advisor | Khosla, Chaitan, 1964- |
| Thesis advisor | Khosla, Chaitan, 1964- |
| Thesis advisor | Chen, James |
| Thesis advisor | Kool, Eric T |
| Advisor | Chen, James |
| Advisor | Kool, Eric T |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Jay Thomas Fitzgerald. |
|---|---|
| Note | Submitted to the Department of Chemistry. |
| Thesis | Thesis (Ph.D.)--Stanford University, 2012. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2012 by Jay Thomas Fitzgerald
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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