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Norah Alqahtani -ETD 1.pdf (13.65 MB)

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Synergizing Microbial Culturing, Whole Genome Sequencing, Asymmetric Synthesis and Tandem MS for Reconstruction of Polyketide and Alkaloid Natural Product Biosynthesis in Marine Actinomycete Nocardiopsis sp CMB- M0232

Alqahtani, Norah Faihan
http://rave.ohiolink.edu/etdc/view?acc_num=case1421167765

Abstract Details

2015, Doctor of Philosophy, Case Western Reserve University, Chemistry.
Biosynthetic pathway engineering is rapidly growing by rationally harnessing the enzymatic potential of microbial systems. While marine cyanobacterial genus and a few gram positive bacteria (such as Saccharopolyspora erythraea) have offered an extensive array of promising biocatalysts with unique modular functions as polyketide synthases (PKS), non-ribosomal peptide synthetases (NPRS) or their hybrids, the biosynthetic potential of soil cyanobacteria and marine Nocardiopsis genus largely remain unexplored. Herein we study a marine actinomycete, Nocardiopsis sp. CMB-M0232 isolate as a model organism through an integrated approach involving genome sequencing, metabolic engineering, tandem-MS and asymmetric synthesis to reconstruct multiple biosynthetic pathways leading to PKS, NRPS, alkaloids and their hybrids as potential candidates for clinically relevant drug development. Chapter 1 and Appendix 2 introduce the reader to the significance of marine actinomycetes in the context of drug discovery and development. Chapters 2, 3 and 4 describe multiple recent success stories on the mechanistic investigations of novel biocatalytic systems discovered through this integrated approach applied to Nocardiopsis, for the first time. Specifically, Chapter 2 describes the metabolic pathway to nocardioazines that are candidates for anti-tumor drug development through their participation as inhibitors of p-glycoprotein-mediated efflux. Their biosynthetic pathway is dissected. Chapter 3 builds on the noz gene cluster and NozA as a biocatalyst. Chapter 4 describes the nsn-coded modular megasynthase-based biosynthetic machinery for the assembly of the nocardiopsins. The nocardiopsins are polyketide-non-ribosomal peptide hybrid natural products that are structurally homologous to the rapamycins but are indeed distinct at select positions. Therefore, the nocardiopsin biosynthetic pathway is not only interesting and significant for the potential of creating new mTOR pathway analogs for their biological elucidation. But fundamentally is interesting for biosynthesis of heterocyclic rings such as tetrahydrofurans, pipecolates and proline-containing macrolide architectures. Chapter 5 describes the experimental details, and the corresponding NMR spectra are provided in Appendix 1. Overall, several novel lines of investigations are underway and the data gathered and presented herein constitutes the body of work for three distinct publications.
Rajesh Viswanathan (Advisor)
350 p.
Biochemistry; Chemistry; Organic Chemistry
Asymmetric,Synthesis,Biosynthesis,Marine Natural Product,Polyketide,Alkaloid,Nocardiopsin,Nocardioazine,Actinomycete Nocardiopsis sp CMBM0232,Tandem MS,Microbial Culturing, Genome Sequencing

Recommended Citations

Citations

  • Alqahtani, N. F. (2015). Synergizing Microbial Culturing, Whole Genome Sequencing, Asymmetric Synthesis and Tandem MS for Reconstruction of Polyketide and Alkaloid Natural Product Biosynthesis in Marine Actinomycete Nocardiopsis sp CMB- M0232 [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1421167765

    APA Style (7th edition)

  • Alqahtani, Norah. Synergizing Microbial Culturing, Whole Genome Sequencing, Asymmetric Synthesis and Tandem MS for Reconstruction of Polyketide and Alkaloid Natural Product Biosynthesis in Marine Actinomycete Nocardiopsis sp CMB- M0232. 2015. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1421167765.

    MLA Style (8th edition)

  • Alqahtani, Norah. "Synergizing Microbial Culturing, Whole Genome Sequencing, Asymmetric Synthesis and Tandem MS for Reconstruction of Polyketide and Alkaloid Natural Product Biosynthesis in Marine Actinomycete Nocardiopsis sp CMB- M0232." Doctoral dissertation, Case Western Reserve University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=case1421167765

    Chicago Manual of Style (17th edition)

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© 2014, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.