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Metabolic systems biology of the malaria parasite

Forth, Thomas (2012) Metabolic systems biology of the malaria parasite. PhD thesis, University of Leeds.

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Abstract

Quantitative one-dimensional proton NMR metabolomics is performed on growth medium samples gathered at up to ten time-points during the in vitro culture of P. falciparum in human red blood cells. From this study, exchange fluxes between the parasite-host complex and the growth medium are calculated for glucose, lactate, glycerol, glutamine, hypoxanthine, valine, leucine, isoleucine, alanine, tyrosine and phenylanaine. Carbon-source exchange fluxes are added as constraints to a new model of malaria metabolism — built using my published MetNetMaker software — consisting of 249 reactions, 143 genes and a novel experimentally derived biomass function. Analysis of this network including by flux-balance analysis and flux-variability analysis are projected onto a live map of the network providing the most accessible view of malaria metabolism to date. This model reproduces key phenotypes of the malaria parasite such as the unusual branched TCA cycle, and accurately predicts internal fluxes through the pentose-phosphate cycle and the low oxygen-dependence of the parasite’s metabolism during its erythrocytic life stages. The model is carbon balanced and accurately predicts the parasite’s growth-rate at measured glucose uptake rates. Furthermore, it accurately reproduces measured amino acid and purine-source exchange fluxes at the optimal solution and implies that the parasite digests 30% of its red blood cell host’s haemoglobin but incorporates just 40% of the resulting freed amino acids into its proteome. Lethal single and double gene deletions are predicted and suggest potential drug and vaccine targets. The metabolic model is available in MetNetMaker format for easy editing, SBML format including constraints for metabolic modelling and the independent reproduction of the reported results, and cytoscape format with metadata for visualisation of both the network and the results of simulations performed on it.

Item Type: Thesis (PhD)
ISBN: 978-0-85731-297-6
Academic Units: The University of Leeds > Faculty of Maths and Physical Sciences (Leeds) > School of Physics and Astronomy (Leeds)
Identification Number/EthosID: uk.bl.ethos.568128
Depositing User: Ethos Import
Date Deposited: 12 Mar 2013 10:41
Last Modified: 07 Mar 2014 11:24
URI: http://etheses.whiterose.ac.uk/id/eprint/3739

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