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|Title: ||Studies and application of the enzymes of fluorometabolite biosynthesis in Streptomyces cattleya|
|Authors: ||Onega, Mayca|
|Supervisors: ||O'Hagan, David|
|Issue Date: ||2009|
|Abstract: ||This thesis focuses on studies investigating the structure of intermediates involved in
fluorometabolite biosynthesis, and the potential applications of the fluorinase enzyme in
positron emission tomography (PET).
Chapter 1 introduces the rare natural occurrence of fluorinated compounds. The bacterium
Streptomyces cattleya is known to biosynthesise two fluorinated secondary metabolites: the
toxin fluoroacetate (FAc) and the antibiotic 4-fluorothreonine (4-FT). The enzymes and
intermediates identified on this fluorometabolite biosynthetic pathway in S. cattleya, prior to
this research, are discussed in detail.
Chapter 2 presents studies towards the unambiguous structural identification of (3R,4S)-5-
deoxy-5-fluoro-D-ribulose-1-phosphate (5-FRulP) as the third fluorinated intermediate on the
biosynthetic pathway to fluoroacetate and 4-fluorothreonine in S. cattleya.
Chapter 3 describes the synthetic routes to key molecules, necessary as reference
compounds and substrates, to underpin the subsequent studies in this thesis. In particular,
synthetic routes to 5'-deoxy-5'-fluoroadenosine (5'-FDA), 5'-deoxy-5'-fluoroinosine (5'-FDI),
5-deoxy-5-fluoro-D-ribose (5-FDR) and 5-deoxy-5-fluoro-D-xylose (5-FDX) are described.
Chapter 4 describes the use of the fluorinase enzyme from S. cattleya as a tool for the
synthesis of new [¹⁸F]-labelled sugars with potential application in positron emission
tomography (PET). A new route to 5-deoxy-5-[¹⁸F]fluoro-D-ribose ([¹⁸F]FDR) is developed
in a two-step enzymatic synthesis. A total of three potential radiotracers ([¹⁸F]FDA,
[¹⁸F]FDR and [¹⁸F]FDI) are synthesised using fluorinase-coupled enzyme reactions.
In addition, in vitro studies are reported with these [¹⁸F]-labelled sugars to investigate their
uptake and potential as PET radiotracers in cancer cells. A preliminary rat imaging study with
[¹⁸F]FDA is reported.
Chapter 5 details the experimental procedures for the compounds synthesised in this
research and the biological procedures for chemo-enzymatic syntheses and protein
|Publisher: ||University of St Andrews|
|Appears in Collections:||Chemistry Theses|
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