We present the first computational kinetic model of
polyamine metabolism in bloodstream-form Trypanosoma brucei, the causative agent of human
African trypanosomiasis. We systematically extracted the
polyamine pathway from the complete metabolic network while still maintaining the predictive capability 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 defined. Uncharacterised
enzyme kinetics were approximated and justified with available physiological properties of the system. Optimisation-based dynamic simulations were performed to train the model with experimental data and inconsistent predictions prompted an iterative procedure of model refinement. 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 catalysing 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 production 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.