The sulfur containing vitamin, <I>biotin</I> has a cofactorial role for a number of carboxylation enzymes responsible for a variety of essential metabolic processes. Biotin is produced in minute quantities by micro-organisms and plants via a similar biosynthetic route that has few parallels in mammalian biochemistry, making it an attractive target for inhibition studies. This thesis describes the development of synthetic strategies for intermediates of the biotin biosynthetic pathway, and some structurally related compounds. An early step in biotin biogenesis is the decarboxylative condensation of pimeloyl-CoA and L-alanine to give 8-amino-7-oxononanoic acid (AON), catalysed by the <I>bio</I>F gene product, 8-amino-7-oxononanoate synthase (AONS). A novel preparation of AON is described here, along with a description of various alternative strategies which have been employed in the synthesis of this, and related compounds. Dethiobiotin synthetase (DTBS), the penultimate enzyme in the biotin biosynthetic pathway, catalyses the incorporation of a carbonyl moiety between the adjacent amino groups of 7,8-diaminononanoic acid (DAN), in a process utilising ATP and carbon dioxide. A phosphorus containing structural analogue of a postulated intermediate in this process has been synthesised. The study of the interactions between these compounds and the purified enzymes will enable the design and development of mechanism-based enzyme-inhibitors.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:663570 |
| Date | January 1998 |
| Creators | Watt, Rory Munro |
| Publisher | University of Edinburgh |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://hdl.handle.net/1842/11527 |
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