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dc.contributor.advisorSmith, Terry K.
dc.contributor.advisorMüller, Sylke
dc.contributor.authorWilliams, Chris L.
dc.description.abstractMalaria caused by the protozan parasite Plasmodium is one of the most serious infectious diseases in the developing world. It is estimated that malaria causes an annual mortality rate of ~627,000. New drugs are urgently required, as the incidence of resistance is spreading rapidly. Glycosylphosphatidylinositol (GPI) anchored proteins decorate the merozoite surface and several of which, including merozoite surface proteins - 1 and -2 have previously been shown to be essential for erythrocyte invasion and parasite survival. Plasmodium GPI-anchors contain a glycan core consisting of four mannose residues. Therefore, the enzymes involved in the synthesis of activated mannose, guanidine diphosphomannose pyrophosphorylase (GDP-Man PP) and dolichol phosphate mannose synthase (DPMS), are thought to be crucial for GPI-anchor biosynthesis and as such potential drug targets. Double homologous recombination has been exploited to test whether PfGDP-Man PP and PfDPMS are essential during the erythrocytic portion of the parasite’s life cycle. Additionally, overexpression parasite lines for both enzymes have been generated and have shown that the regulation of the two enzymes are intricately linked. Focused metabolomics by multi-reaction monitoring of the overexpression lines suggests that the fucosylation pathway may have a novel function within the parasite, possibly as a dynamic store for activated fucose/mannose. In order to determine the cellular concentration of key metabolites within the parasite, the volumes of the intra-erythrocytic stages have been determined and show that the concentration of metabolites in the ring stage parasites is substantially higher than previously thought. Furthermore, the sub-cellular localisation of GDP-Man PP and DPMS has been determined by immunofluorescence assay. The recombinant expression of DPMS in E. coli allowed its active site residues to be probed as well as establishing a platform for inhibitors to be screened against the enzyme. Finally, inhibitors of the T. brucei DPMS enzyme have been screened against the P. falciparum parasites in culture.en_US
dc.publisherUniversity of St Andrews
dc.rightsCreative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
dc.subjectPlasmodium falciparumen_US
dc.subject.lcshPlasmodium falciparumen_US
dc.subject.lcshOverexpression (Genetics)en_US
dc.titleAn investigation into mannose activation and its impact on glycosylphosphatidylinositol biosynthesis in Plasmodium falciparumen_US
dc.type.qualificationnamePhD Doctor of Philosophyen_US
dc.publisher.institutionThe University of St Andrewsen_US
dc.publisher.departmentThe University of Glasgowen_US
dc.rights.embargodatePrint and electronic copy restricted until 10th March 2017en_US
dc.rights.embargoreasonThesis restricted in accordance with University regulationsen_US

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Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
Except where otherwise noted within the work, this item's licence for re-use is described as Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International