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Title: Evolution of diversity in actinobacterial assembly-line biosynthesis
Author: Booth, Thomas
Awarding Body: University of East Anglia
Current Institution: University of East Anglia
Date of Award: 2018
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Actinobacteria are prolific producers of natural products of significant clinical and industrial importance. Among the most common natural product biosynthetic pathways are the type I modular polyketide synthases (PKSs) and the non-ribosomal peptide synthetases (NRPSs); large assembly-line megasynthases. This thesis investigates the biosynthesis and evolution of five families of assembly-line natural products. Firstly, I report the desotamide (dsa) and wollamide (wol) biosynthetic gene clusters (BGCs) from Streptomyes sp. MST-70754 and Streptomyes sp. MST-110588, respectively. The wol BGC was found to encode a unique bifurcated NRPS assembly-line capable of producing both the desotamides and the wollamides. Genomic analysis supports the emergence of the wol BGC through an ancestral intergenic gene duplication followed by an intragenomic recombination event. Secondly, I report the BGC of the β-amino acid containing polyketide macrolactam (βPM) heronamide C and characterise its spontaneous thermal [6π + 4π] and photochemical [6π + 6π] intramolecular cycloadditions. Furthermore, sub-cluster genome mining using conserved genes involved in the incorporation of the β-amino acid identified 40 orphan BGCs putatively belonging to the βPM family. Phylogenetic analysis of these BGCs allowed strains to be prioritised for metabolic analysis, leading to the identification of candidate βPMs from Nocardiopsis gilva DSM44841. Finally, I report the BGCs of the polyketide macrolide pladienolide and the polyketide spirotetronate spirohexenolide and activated their expression in strains of Streptomyces platensis through the overexpression of LAL-family and SARP-family transcriptional activators.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available