Date of Award
9-2013
Document type
dissertation
Access Type
Open Access Dissertation
Degree Name
Doctor of Philosophy (PhD)
Degree Program
Chemistry
First Advisor
Nathan A. Schnarr
Second Advisor
Vincent M. Rotello
Third Advisor
Richard W. Vachet
Subject Categories
Chemistry
Abstract
Polyketides are a class of natural products that exhibit remarkable structural and functionally diversity and are highly sought after due to their medicinally important activities. For many decades now, polyketide synthases (PKSs), the mega-enzymes responsible for biosynthesis of polyketides have been the focus of extensive investigation to make new polyketides by polyketide engineering strategies. While there are many established methods to investigate polyketide enzymes and biosynthesis mechanisms, they have substantial shortcomings that have limited the extent of success with polyketide engineering efforts.
This thesis focuses on developing simple, flexible yet powerful tools for examining polyketide biosynthesis by overcoming some deficiencies in currently used techniques. Reactive heterocylces have been designed for direct labeling of key polyketide synthase enzymes to provide a direct insight into its functions and mechanisms. First β-lactones and then β-lactams have been used as small molecule probes to perform site-specific labeling of acyl carrier proteins and further used for mechanistic interrogation of key steps in polyketide biosynthesis. The utility of these probes has been demonstrated by comparison to traditional probes and has been successfully applied to examine substrate selectivity of keto synthases, key enzymes in polyketide biosynthesis. The applications of the tools described in this manuscript only scratch the surface of their capabilities and are expected to significantly aid in the study of new and existing PKS systems leading to improved understanding of how these extraordinary biosynthetic machines function.
DOI
https://doi.org/10.7275/36k0-5s91
Recommended Citation
Prasad, Gitanjeli, "Reactive Heterocycles for Examining Polyketide Biosynthesis" (2013). Open Access Dissertations. 817.
https://doi.org/10.7275/36k0-5s91
https://scholarworks.umass.edu/open_access_dissertations/817