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
Created: 29th Feb 2012 at 08:47
The SilicoTryp project aims at the creation of a “Silicon Trypanosome”, a comprehensive, experiment-based, multi-scale mathematical model of trypanosome physiology.
Trypanosomes are blood-stream parasites transmitted by tsetse flies; they cause African sleeping sickness in humans and livestock. Currently available drugs have severe side effects, and the parasites are rapidly developing resistance.
In this project, we collect a wide range of new experimental data on the parasite in its various
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
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).
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
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