Jurgen Haanstra

Aim. Constructing a predictive, dynamic model of the redox metabolism of trypanosomes. Aided by
this model we will quantify the impact of gene-expression and metabolic regulation on redox
metabolism. The model will be constructed in an iterative cycle of experimentation – modelling –
analysis – experimentation, such that it can be extended and refined based on new experimental
insights.

The enzyme Trypanothione Synthetase (TryS) is a complex enzyme that catalyses the two step reaction that forms trypanothione from 2 molecules of GSH and 1 molecule of Spd and the use of ATP

The output of the initial model of redox metabolism will be compared to experimental flux and metabolite data. Deviations between model and experiment will be prioritized together with WP2. We will apply Metabolic Control
Analysis (Fell 1992 PMID: 1530563) to diagnose which enzymes control the deviating metabolite
concentrations and/or rates. When the agreement between model and experiment is sufficient
we will first link it to the existing model of trypanosome glycolysis and repeat the same
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Our current gene-expression model (Haanstra et al. 2008 PMID: 19008351) will be parameterized for the different genes of interest.
The framework of this gene expression model has been used to include mRNA half life data into the model of glycolysis
For the enzymes of redox metabolism we will use newly measured rates of transcription, RNA precursor degradation, mRNA degradation, concentrations of mature mRNAs and proteins, enzyme turnover, Vmax values and metabolic fluxes (WP3&5).
Regulation
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We are in the process of construct an ODE model of the trypanothione pathway. As input we will use
newly determined and existing kinetic data and measured metabolite concentrations at the boundaries
(from WP3&6).
Recently the glycolysis model was extended with the pentose phosphate pathway. This pathway will yield the NAPDH that maintains trypanothione in a reduced state.
For some complex enzymes (i.e trypanothione synthase) we are intensively discussing the kinetic data obtained on the
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We here create a kinetic model for a single enzyme within the T. brucei trypanothione synthesis pathway, the enzyme trypanothione synthetase based on the insights from the laboratory experiments

The RNAseq data on mRNA processing and mRNA decay were used to update a previously published model and to interrogate which process should be dependent on mRNA length

All datapoints that were measured are displayed together with the accompanying simulations by the computational model

An extended model description of the TryS model

Mechanistical model of the catalytic cycle of Trypanothione Synthetase

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