Characterization and Analysis of Biosynthetic Systems from Nostoc sp. ATCC 53789 and Selected Fungal Natural Product Pathways.
dc.contributor.author | Ding, Yousong | en_US |
dc.date.accessioned | 2010-06-03T17:43:06Z | |
dc.date.available | 2010-06-03T17:43:06Z | |
dc.date.issued | 2010 | en_US |
dc.identifier.uri | https://hdl.handle.net/2027.42/76020 | |
dc.description.abstract | Complex secondary metabolites display diverse biological activities and together with their derivatives have provided over two-thirds of new pharmaceutical agents introduced during the past two decades. However, limitations in isolation and in rapid structural determination continue to be inherent hurdles for using natural products as leads in drug discovery and design. My dissertation research focused on selected biosynthetic pathways with the hope to overcome some of these limitations. Three projects are described in this dissertation thesis. The first project demonstrates my efforts to generate natural product analogs using the biocatalysts, a strategy that provides significant advantages in catalytic specificity, efficiency, and impacts on the environment. Several natural and synthetic anticancer agent analogs were produced with a single P450 epoxidase and an excised thioesterase involved in the production of cryptophycin in Nostoc sp. Moreover, the homotropic and heterotropic cooperativity of the bacterial P450 epoxidase toward its substrates was characterized in details. This enzyme may serve as a more operable model to study the same features in several human P450s involving in xenobiotcs metabolism. The second project describes how unique prenylated indole alkaloids are biosynthesized in various fungal genera. These biosynthetic pathways were extensively investigated by isolation and characterization of several key biosynthetic intermediates from Penicillium, Aspergillus, and Malbranchea sp. Subsequently, these pathways were examined at the first time through the elucidation of the biosynthetic gene cluster for stephacidin/notoamide from a marine Aspergillus strain and biochemical characterization of two critical aromatic prenyltransferases catalyzing two committed steps. Finally, one trichothecene macrolide gene cluster was cloned from a marine Myrothecium verrucaria strain and validated with biochemical characterization of a sesquiterpene synthase and a multifunctional P450, representing the latest understanding of the biosynthesis of structurally complex mycotoxins. With the identification and characterization of natural product gene clusters, more new fungal secondary metabolite analogs may be generated through metabolic engineering and heterologous production. | en_US |
dc.format.extent | 5821997 bytes | |
dc.format.extent | 1373 bytes | |
dc.format.mimetype | application/pdf | |
dc.format.mimetype | text/plain | |
dc.language.iso | en_US | en_US |
dc.subject | Natural Product | en_US |
dc.subject | Biosynthesis | en_US |
dc.subject | Chemoenzymatic Synthesis | en_US |
dc.subject | Genome Mining | en_US |
dc.subject | Enzyme Characterization | en_US |
dc.title | Characterization and Analysis of Biosynthetic Systems from Nostoc sp. ATCC 53789 and Selected Fungal Natural Product Pathways. | en_US |
dc.type | Thesis | en_US |
dc.description.thesisdegreename | PhD | en_US |
dc.description.thesisdegreediscipline | Medicinal Chemistry | en_US |
dc.description.thesisdegreegrantor | University of Michigan, Horace H. Rackham School of Graduate Studies | en_US |
dc.contributor.committeemember | Sherman, David H. | en_US |
dc.contributor.committeemember | Ballou, David P. | en_US |
dc.contributor.committeemember | Gestwicki, Jason E. | en_US |
dc.contributor.committeemember | Mapp, Anna K. | en_US |
dc.contributor.committeemember | Wang, Shaomeng | en_US |
dc.subject.hlbsecondlevel | Biological Chemistry | en_US |
dc.subject.hlbtoplevel | Science | en_US |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/76020/1/dingyous_1.pdf | |
dc.owningcollname | Dissertations and Theses (Ph.D. and Master's) |
Files in this item
Remediation of Harmful Language
The University of Michigan Library aims to describe library materials in a way that respects the people and communities who create, use, and are represented in our collections. Report harmful or offensive language in catalog records, finding aids, or elsewhere in our collections anonymously through our metadata feedback form. More information at Remediation of Harmful Language.
Accessibility
If you are unable to use this file in its current format, please select the Contact Us link and we can modify it to make it more accessible to you.