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Title: Aspects of the biosynthesis of chloroeremomycin
Author: Barton, S. J.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2003
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In recent years, the glycopeptide antibiotics have emerged as the drugs of choice in the treatment of potentially life-threatening infections caused by Gram-positive pathogens such as Staphylococcus aureus and Enterococi faeium. However, with the global emergence of glycopeptide-resistant bacteria over the past decade, there are few effective antibiotic treatments remaining and the development of novel therapeutic agents it vital. As a result of the structural complexity of glycopeptide antibiotics, chemical modification often proves difficult, and consequently their biosynthesis is of great interest. Characterisation of the biosynthetic pathways producing these antibiotics could form the basis for the design and synthesis of novel antibiotics with potentially increased antibacterial activity. Chloroeremomycin is comprised of a core, which consists of mainly non-proteinogenic amino acids. The heptapeptide backbone is further modified by cross-linking, chlorination and glycosylation. The work presented in this thesis describes the study of proteins putatively involved in the biosynthesis of the unusual amino acid b-hydroxytyrosine and the 4-epi-vancosamine deoxysugar components of chloroeremomycin. The investigation of the function of a putative peptide synthetase potentially involved in the biosynthesis of b-hydroxytyrosine is described. Mass spectrometry was used to detect and assign peptide fragments generated by the digestion of the peptide synthetase in an effort to identify the peptide loaded with the 4’-phosphopantetheine prosthetic group and subsequently L-tyrosine. In addition, analysis of the function of a putative cytochrome P-450 monooxygenase as the enzyme responsible for catalysing the β-hydroxylation of L-tyrosine whilst it is covalently-bound to the peptide synthetase is described. Lastly, the function of an enzyme responsible for catalysing the 2,3-dehydration of TDP-4-keto-6-deoxyglucose, the first step in the biosynthetic pathway producing the deoxysugar 4-epi-vancosamine, is confirmed.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available