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Identification and enzyme studies of rare amino acid biosynthesis from Streptomyces cattleya

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JasonChanPhDThesis.pdf (41.51Mb)
Date
2013
Author
Chan, K. K. Jason
Supervisor
O'Hagan, David
Keywords
Streptomyces cattleya
Fluorometabolite
Organofluorine natural products
Isomerase
Fluorinase
Protein crystallography
Ethynylserine
Rare amino acids
Click chemistry
Acetylenic amino acid
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Abstract
This thesis is focussed on the biosynthesis of three toxins: fluoroacetate, 4-fluoro-L-theronine and β-ethynyl-L-serine which are biosynthesised by the soil bacteria Streptomyces cattleya. The two fluorinated metabolites originate from a common biosynthetic pathway and the thesis describes studies carried out on an aldose-ketose isomerase enzyme of the pathway. The biosynthetic origin of β-ethynyl-L-serine is not known. A total synthesis of this acetylenic amino acid is descibed along with the development of a new analytical method for identifying the metabolite and for future isotope-labelling based biosynthetic studies. Chapter 1 presents the background of this research. It is focussed on the biosynthesis of fluoroacetate and 4-fluoro-L-threonine by S. cattleya and it also introduces alkyne-containing natural products and their biosynthesis. Chapter 2 describes the work carried out on crystallisation of the aldose-ketose isomerase of the fluorometabolite pathway in S. cattleya. Crystals of the isomerase were obtained and they were diffracted by X-ray, however a structure could not be solved. Chapter 3 contains site-directed mutagenesis studies of the isomerase from S. cattleya. Chapter 4 describes an enantioselective total synthesis of β-ethynyl-L-serine. A robust analytical technique based on derivatisation using 'Click' chemistry and LC-MS was developed for the detection of this amino acid directly from the fermentation broth. Chapter 5 details the experimental procedures for compounds synthesised in this thesis and the biological procedures for gene cloning and protein purification.
Type
Thesis, PhD Doctor of Philosophy
Collections
  • Chemistry Theses
URI
http://hdl.handle.net/10023/4478

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