Mathematical modelling of polyamine metabolism in bloodstream-form Trypanosoma brucei: an application to drug target identification.
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.
Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom. Xu.Gu@igmm.ed.ac.uk
Xu
X
Gu
David
D
Reid
Desmond J
DJ
Higham
David
D
Gilbert
D012437:Adenosylmethionine Decarboxylase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D003198:Computer Simulation; D000518:Eflornithine / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D008956:Models, Chemical; D009952:Ornithine / Q000378:metabolism; D009955:Ornithine Decarboxylase / Q000378:metabolism; D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012436:S-Adenosylmethionine / Q000378:metabolism; D014344:Trypanocidal Agents / Q000737:chemistry / Q000494:pharmacology*; D014346:Trypanosoma brucei brucei / Q000187:drug effects / Q000378:metabolism*; D014353:Trypanosomiasis, African / Q000188:drug therapy / Q000469:parasitology
D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines; D014344:Trypanocidal Agents; D012436:S-Adenosylmethionine; D009952:Ornithine; D009955:Ornithine Decarboxylase; D012437:Adenosylmethionine Decarboxylase; D000518:Eflornithine