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Title: Biochemical characterization of metabolic enzymes from the liver fluke, Fasciola hepatica
Author: Zinsser, Veronika Lucille Anne
ISNI:       0000 0004 5371 2159
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2014
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The common liver fluke, Fasciola hepatica, infects both human and animals causing fasciolosis. The World Health Organization estimates that ~2 .4 million people are infected with fasciolosis and another 180 million are at risk of being infected. It is thought to be the most economically damaging livestock disease compared to any other helminth parasite diseases. An important influence on the biochemistry of the parasite is its changing environment throughout its life cycle, requiring its metabolism to move from aerobic to anaerobic as it matures. The fluke's metabolic adaptations permit energy extraction to occur even in an anaerobic environment using a variation on the CA cycle. is thesis explores five enzymes from Fasciola hepatica concerned witl~ energy production - citrate synthase (FhCS), triose-phosphate isomerase (FhTPI), glyceraldehyde-3-phosphate dehydrogenase (FhG3PDH), and galactokinase (FhGALK), and UDP-galactose 4-epimerase (FhGALE). FhCS was cloned and sequenced; however, expression and purification proved difficult. Nevertheless, extracts from bacterial cells expressing the protein showed additional CS activity. FhTPI, FhG3PDH, FhGALK and FhGALE have been successfully cloned, sequenced, expressed, purified and characterized. TPI from the related helminth, Schistosoma mansoni, (SmTPI) was also characterised in a comparative study. FhTPI and SmTPI show remarkable thermal and proteolytic stability. FhG3PDH shows increased stability in the presences of substrate; furthermore the addition of ligands results in the change of the enzymes conformation and oligomierc state. FhGALK shows similarity to both galactokinase and N-acetylgalactoasmine from other organisms; however no activity was displayed with either of heir substrates. FhGALE has been characterized kinetically; early inhibition studies have identified two compounds (found through an in silico screen) which show selectivity for the fluke enzyme over the human one. these biochemical studies, combined with molecular modelling, were used to assess whether these metabolic enzymes from F. hepatica may make plausible targets for the development of novel anthelmintics.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available