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Title: Biosynthetic studies on the non mevalonate pathway to terpenes
Author: Fowler, D. J.
Awarding Body: Durham University
Current Institution: Durham University
Date of Award: 2001
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Isoprenoids are a class of secondary metabolites that are widely distributed in Nature. This thesis describes the synthesis and feeding of isotopically labelled enriched substrates to elucidate features of a new mevalonate independent pathway to isoprenoids. Chapter 2 describes studies with a whole plant system, Mentha citrata, which produces the monoterpene linalyl acetate, and a bacterium Escherichia coli which produces ubiquinone-8. Feeding experiments with stable isotopically enriched compounds demonstrate that the terpene unit of linalyl acetate is biosynthesised via the mevalonate independent pathway, hicorporation of deuterium from [6,6-(^2)H(_2)]-glucose, [(^2)H(_3)]-alanine and [(^13)C(^2)H(_3)]-alanine into luialyl acetate show that the conversion to isopentenyl pyrophosphate does not proceed via a series of dehydrations. Feeding experiments with putative intermediates bearing deuterium into E. coli show that none of the intermediates are incorporated. This suggests that E. coli lacks a kinase to activate exogenously administered substrates fed as the free alcohols. Chapter 3 outlines biosynthesis studies on a meroterpene rosnecatone produced by the fungus R. necatrix. Intact incorporation of (^13)C from the feeding of [l,2-(^13)C(_2)]-acetate shows that the terpenoid moiety is produced via the mevalonic acid pathway and the non-terpenoid unit is polyketide derived. Incorporation of deuterium from [6,6-(^2)H(_2)]-glucose fully describes the pentaketide that delivers the non-terpenoid fragment. The effect on the metabolite production of changing the growth conditions of R. necatrix is investigated. Changing from a static culture to a submerged cultures causes an increased rate of growth, an upregulation of the production of cytochalasan E and a cessation of rosnecatone production. Screening of rosnecatone against two Human cancer cell lines shows IC(_50) values of 4.48µM and 5.78µM.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Isoprenoids; Cancer