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Title: Biosynthesis of the natural and novel structural variants of calcium-dependent antibiotic produced by streptomyces coelicolor A3(2)
Author: Gordon, Lynsey
ISNI:       0000 0004 2679 0346
Awarding Body: The University of Manchester
Current Institution: University of Manchester
Date of Award: 2006
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The aims of this project are to better understand the biosynthesis of CDA and then use that knowledge to genetically manipulate Streptomyces to produce novel compounds. The natural structural variants of CDA which have been characterised contain several unusual amino acids residues. CDA contains both D-figured and non-proteinogenic residues within its structure. In all of the CDA structures isolated so far, position six is occupied by a D-figured hydroxyphenylglycine residue (D-4-HPG). The precursor biosynthetic pathway for HPG has been elucidated in A. orientalis and it has been shown previously that the cda cluster contains homologues to these genes. A mutant strain of S. coelicolor in which the hmaS (4-hydroxymandelic acid synthase) gene had been disrupted had previously been created and shown to be deficient in CDA production. During this study the proposed intermediates of the HPG biosynthetic pathway were fed into the mutant and CDA production re-established thus proving the pathway for HPG biosynthesis in S. coelicolor mirrors that seen in other organisms. Feeding analogues of the pathway intermediates to the mutants resulted in the mutasynthesis of novel lipopeptides with modified arylglycine residues. This study also identified a gene from the cda cluster, hasP, which in silico analysis predicted to encode a 3-hydroxyasparaginyl phosphotransferase responsible for the biosynthesis of 3-phosphohydroxyasparagine sometimes found at position nine in the CDA structure. Deletion of the majority of the gene resulted in only non-phosphorylated CDA variants being produced.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available