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Abstract
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.
Highlights
The development of drugs to combat human African trypanosomiasis (HAT) has become a major public concern due to toxicity, inefficacy and availability problems with current drug treatments [1,2]
We develop the first kinetic model of polyamine metabolism in blood-stream form T. brucei, derived from published information related to system components and their interactions
Since mathematical models are manipulable, the mechanisms underlying the metabolic regulation of polyamine biosynthesis can be evaluated in silico. This kinetic model aims at understanding the effectiveness of the anti-trypanosomal drug DFMO in detail and examining other polyamine enzymes as potential targets for antitrypanosomal chemotherapy. As this is the first model of polyamine metabolism in T. brucei, we shall summarise the main points from the the model design procedure before presenting the simulation results of the kinetic model
Summary
The development of drugs to combat human African trypanosomiasis (HAT) has become a major public concern due to toxicity, inefficacy and availability problems with current drug treatments [1,2]. Identification of potential drug targets within the T. brucei parasite is an invaluable tool for designing chemotherapeutic agents against the disease. A challenge in drug design arises from the similarity of metabolic pathways in parasitic protozoa and their mammalian hosts, resulting in toxicity to the host as well as the parasite. Polyamine metabolism in mammalian cells has previously been studied using mathematical modelling [3]. The major differences lie in the specificity of metabolites and enzymes as well as the associated regulation patterns. Spermidine (Spd), in addition to its plethora of other cellular roles (e.g. serving as an important inducer for the compact form of DNA), in trypanosomatids, is linked to two molecules of glutathione to yield the redox active metabolite trypanothione, T(SH), which is a compound critical for trypanosome viability and virulence
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