Please use this identifier to cite or link to this item: http://buratest.brunel.ac.uk/handle/2438/9768
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dc.contributor.authorGu, X-
dc.contributor.authorReid, D-
dc.contributor.authorHigham, DJ-
dc.contributor.authorGilbert, D-
dc.date.accessioned2015-01-16T12:03:22Z-
dc.date.available2015-01-16T12:03:22Z-
dc.date.issued2013-
dc.identifier.citationPLoS One, Accepted for publication, 2013en_US
dc.identifier.urihttp://journals.plos.org/plosone/article?id=10.1371/journal.pone.0053734-
dc.identifier.urihttp://bura.brunel.ac.uk/handle/2438/9768-
dc.description.abstractWe present the first computational kinetic model of polyamine metabolism in bloodstream-form Try- panosoma brucei, the causative agent of human African trypanosomiasis. We systematically extracted the polyamine pathway from the complete metabolic network while still maintaining the predictive ca- pability of the pathway. The kinetic model is constructed on the basis of information gleaned from the experimental biology literature and defined as a set of ordinary differential equations. We applied Michaelis-Menten kinetics featuring regulatory factors to describe enzymatic activities that are well de- fined. Uncharacterized enzyme kinetics were approximated and justified with available physiological properties of the system. Optimization-based dynamic simulations were performed to train the model with experimental data and inconsistent predictions prompted an iterative procedure of model refine- ment. Good agreement between simulation results and measured data reported in various experimental conditions shows that the model has good applicability in spite of there being gaps in the required data. With this kinetic model, the relative importance of the individual pathway enzymes was assessed. We observed that, at low-to-moderate levels of inhibition, enzymes catalyzing reactions of de novo AdoMet (MAT) and ornithine production (OrnPt) have more efficient inhibitory effect on total trypanothione content in comparison to other enzymes in the pathway. In our model, Prozyme and TSHSyn (the pro- duction catalyst of total trypanothione) were also found to exhibit potent control on total trypanothione content but only when they were strongly inhibited. Different chemotherapeutic strategies against T. brucei were investigated using this model and interruption of polyamine synthesis via joint inhibition of MAT or OrnPt together with other polyamine enzymes was identified as an optimal therapeutic strategy.en_US
dc.language.isoenen_US
dc.subjectComputational kinetic modelen_US
dc.subjectPolyamine metabolismen_US
dc.subjectTry- panosoma bruceien_US
dc.subjectHuman African trypanosomiasisen_US
dc.subjectCausative agenten_US
dc.titleMathematical Modelling of Polyamine Metabolism in Bloodstream-form Trypanosoma brucei: An Application to Drug Target Identificationen_US
dc.typeArticleen_US
dc.identifier.doihttp://dx.doi.org/10.1371/journal.pone.0053734-
dc.relation.isPartOfPLoS One-
dc.relation.isPartOfPLoS One-
pubs.editionAccepted for publication-
pubs.editionAccepted for publication-
pubs.organisational-data/Brunel-
pubs.organisational-data/Brunel/Brunel Staff by College/Department/Division-
pubs.organisational-data/Brunel/Brunel Staff by College/Department/Division/College of Engineering, Design and Physical Sciences-
pubs.organisational-data/Brunel/Brunel Staff by College/Department/Division/College of Engineering, Design and Physical Sciences/Dept of Computer Science-
pubs.organisational-data/Brunel/Brunel Staff by College/Department/Division/College of Engineering, Design and Physical Sciences/Dept of Computer Science/Computer Science-
pubs.organisational-data/Brunel/Brunel Staff by Institute/Theme-
pubs.organisational-data/Brunel/Brunel Staff by Institute/Theme/Institute of Environmental, Health and Societies-
pubs.organisational-data/Brunel/Brunel Staff by Institute/Theme/Institute of Environmental, Health and Societies/Synthetic Biology-
pubs.organisational-data/Brunel/Group Publication Pages-
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