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Title: The biogenesis of terrestrial and marine polycyclic ethers
Author: Gallimore, A. R.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2007
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The widely accepted hypothetical model for polyether biosynthesis involves a polyene intermediate that undergoes an oxidative cyclisation via the corresponding polyepoxide. Recently, a triene shunt metabolite from monensin-producing Streptomyces cinnamonensis lent great support to this model. Sequencing of the gene cluster also supported this model. However, the role of two novel genes, monBI and monBII, was unclear. Deletion of these genes resulted in the production of a number of apparent monensin analogues, whilst abolishing monensin production itself. By isolating and characterising novel epimers of monensin, from one of these mutants, a role of the monB genes in the cyclisation of the final monensin intermediate is proposed. Acid-catalysed cyclisation of surmised cyclisation intermediates from this mutant served to confirm this proposal. An approach to trapping a triepoxide intermediate analogue that is unable to spontaneously cyclise was then explored. The preliminary results suggest that such an approach might lead to the isolation and characterisation of such a triepoxide. The closest marine relatives of the terrestrial polyethers are the ladder polyethers, such as brevetoxin and ciguatoxin. By extrapolating the polyepoxide model to all known marine ladder polyethers, a simple biosynthetic model is proposed, based on the development and justification of the “stereochemical uniformity rule”. Interestingly, application of this model and rule to the largest known ladder polyether, maitotoxin, reveals a stereochemical discrepancy at one of the ring junctions. It is thus suggested that this new rule may have uncovered an error in the established structure of this molecule, as well as being a potentially useful rule in the assignment of new ladder polyether ladder structures.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available