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Dissecting Natural Product Biosynthetic Enzymes Using Siderophore Systems
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| 자료유형 | 학위논문 |
|---|---|
| 서명/저자사항 | Dissecting Natural Product Biosynthetic Enzymes Using Siderophore Systems. |
| 개인저자 | Vinnik, Vladimir. |
| 단체저자명 | The University of Wisconsin - Madison. Microbiology ALS. |
| 발행사항 | [S.l.]: The University of Wisconsin - Madison., 2019. |
| 발행사항 | Ann Arbor: ProQuest Dissertations & Theses, 2019. |
| 형태사항 | 122 p. |
| 기본자료 저록 | Dissertations Abstracts International 81-03B. Dissertation Abstract International |
| ISBN | 9781085672825 |
| 학위논문주기 | Thesis (Ph.D.)--The University of Wisconsin - Madison, 2019. |
| 일반주기 |
Source: Dissertations Abstracts International, Volume: 81-03, Section: B.
Advisor: Thomas, Michael G. |
| 이용제한사항 | This item must not be sold to any third party vendors.This item must not be added to any third party search indexes. |
| 요약 | Nonribosomal peptides (NRPs) and polyketides are medically and industrially vital natural products of diverse biological function, including many of the most commonly used antibiotics. These natural products are biosynthesized by nonribosomal peptide synthetases (NRPSs) and polyketide synthases (PKSs), respectively. The rising threat of antibiotic drug resistance is further exacerbated by the dramatic downturn in conventional drug discovery efforts. Combinatorial biosynthesis of NRPSs and PKSs is a promising approach for producing new antibiotics and other pharmaceuticals by engineering these biosynthetic enzymes. This thesis examines the use of NRPS and PKS-produced siderophores to study natural product biosynthesis through directed evolution approaches. In particular, the substrate specificity of the adenylation (A) domain of the NRPS EntF, from enterobactin biosynthesis in E. coli, is investigated using multi-site saturation mutagenesis of the substrate binding pocket. This work provided key insights into how the gatekeeper A domains recognize their substrates. Additionally, the structures of two new hybrid NRPS/PKS-produced siderophore analogs, fabrubactin (FBN) A and B, made by Agbrobacterium fabrum strain C58, were solved and the core biosynthetic enzymes were characterized. Determining the structures of FBN A and B allows for the use of directed evolution approaches to study aspects of the NRPS and PKS enzymology involved in the formation of these siderophores. Additionally, our data revealed the presence of unique structural moieties suggesting the involvement of unusual enzymology. The fundamentals learned from these directed evolution approaches can be applied to engineering enzymes involved in the biosynthesis of molecules that are important for medicine, industry, and agriculture. |
| 일반주제명 | Microbiology. |
| 언어 | 영어 |
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