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Biosynthetic Study of CcsA and a Polyketide Synthase with Homology to Carnitine Acyltransferase Open Access


Other title
Type of item
Degree grantor
University of Alberta
Author or creator
Larade, Sean
Supervisor and department
Vederas, John (Chemistry)
Examining committee member and department
Clive, Derrick (Chemistry)
Lundgren, Rylan (Chemistry)
Department of Chemistry

Date accepted
Graduation date
2017-11:Fall 2017
Master of Science
Degree level
Polyketides are a class of natural products with large structural and biochemical diversity. Polyketides are assembled by the polymerization of short-chain fatty acids by enzymes named polyketide synthases. Fungal iterative polyketide synthases are notable in that they contain multiple active sites that are used in a cyclical fashion to construct their natural product. There is potential for competing reactions on the growing substrate, and how these enzymes are programmed to synthesize only one final product is not well understood. Cytochalasin E is a fungal polyketide that is currently utilized as an angiogenesis inhibitor in cellular assays. The enzyme responsible for production of cytochalasin E is named CcsA. CcsA is a polyketide synthase that is fused to a non-ribosomal peptide synthetase domain, and both work in tandem to create cytochalasin E. The biosynthetic pathway in the production of cytochalasin E has been proposed, but the pathway has only been partially elucidated. This thesis will first outline the synthetic effort undertaken toward the synthesis of compounds that will be used to study the biosynthesis of cytochalasin E. Progress made toward the synthesis of the proposed octaketide late-stage product of the polyketide synthase will be described. This thesis will then illustrate the discovery of a novel polyketide system that may help to answer pressing questions the polyketide community has concerning enzymatic control of methylation and reduction events. The product of this polyketide system contains an interesting pattern of methylation and reduction, and the enzyme responsible contains a domain with homology to carnitine acyltransferase instead of the standard thioesterase domain for off-loading of the polyketide product. It is hoped that by understanding this fungal polyketide system, the results can be translated to other polyketides assembled by fungal iterative polyketide synthases. The carnitine acyltransferase domain also represents a new mode of polyketide off-loading by polyketide synthases, and adds to the already broad diversity of polyketide natural products.
This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for the purpose of private, scholarly or scientific research. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
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