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Title: The biosynthesis of some bacterial and fungal polyketide metabolites
Author: Rogers, Sarah Victoria
Awarding Body: Durham University
Current Institution: Durham University
Date of Award: 1994
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Methylmalonyl-CoA is a key building block in the biosynthesis of propionate derived polyketide metabolites. There are several known metabolic sources of methylmalonyl-CoA, e.g. succinyl-CoA (citric acid cycle), valine and isoleudne. An objective of this research was to investigate the role of the DNA base, thymine, as a source of methyhnalonyl-CoA in Streptomyces and hence probe the link between primary and secondary metabolism. Feeding key intermediates of the thymine and valine cataboHc pathways, i.e. [(^13)C(^2)H(_3)-methyl]-thymine, [(^13)C-methyl]- and [l-(613)c]-β- aminoisobutyric acid, sodium [3-(^13)C]-isobutyrate, sodium [(^13)C-methyl]- methacrylate and sodium [l-(^13)C]-methacrylate, to the monensin A producer, Streptomyces cinnamonensis, provided evidence of the reductive catabolism of thymine occurring in Streptomyces, analogous to mammals. The results also provided evidence which supports the existence of a novel deaminase enzyme mediating the transformation of β-aminoisobutyric add and methacrylyl-CoA. Cubensic add, isolated from Xylaria cubensis, is a long chain fungal metabolite possessing eight pendant methyl groups. Its biosynthesis from acetate and L-methionine units was demonstrated with the aid of feeding experiments, proving a classical fungal mode of assembly. Attempts to incorporate an advanced methylated precursor into cubensic add were unsuccessful. Biological intramolecular Diels-Alder reactions are implicated in the biosynthesis of a wide range of polyketide metabolites, e.g. nargenicin, solanapyrones. Attempts to demonstrate, by feeding an isotopically labelled precursor, an intramolecular Diels-Alder mechanism for the formation of the sbc membered ring in cytochalasin D, proved inconclusive. In the event, the precursor was degraded to acetate. This degradation was suppressed in the second attempt by the addition of a β-oxidation inhibitor, but still no incorporation of labelled precursor was evident.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Metabolism Chemistry, Organic Microbiology