Comparative cross-species analysis of detailed kinetic models of glycolysis

[摘要] ENGLISH ABSTRACT:With the recent advances in the field of molecular biology, there is an increased need tointegrate data on the various constituents of the cell in kinetic models that can predict anddescribe cellular behavior. When working towards a description of the entire cell usingsuch kinetic models, the question arises: How do we compare different models for a givenbiological network? This is the central question addressed in my thesis and I developedand applied mathematical and computational methods for comparing dozens of existingmodels of erythrocyte and yeast glycolysis.To compare the steady-state behavior in models of erythrocyte glycolysis, I focussedon the function of the pathway, which is to supply the cell with Gibbs-free energy (γ-phosphate of ATP). I used supply-demand analysis in the framework of metabolic controlanalysis to make this comparison, which revealed that the ATP concentrations werehomeostatically buffered at varying supply rates. I also applied this approach to comparesteady-state behavior in models of yeast glycolysis, finding that they were not necessarilyoptimized for homeostatic maintenance of the ATP concentration and that in models forthis organism the rate of ATP production is often determined by the supply reactions ofglycolysis.In addition, I tested whether a kinetic model can describe novel behavior if it is adjustedto conditions different from those for which the model was originally constructed.More specifically, using a model of steady-state yeast glycolysis, I showed that smalladjustments to the original enzyme concentrations are enough to obtain an oscillatingmodel, which shows a remarkable resemblance to the experimentally observed oscillations.Importantly, some of these enzyme concentrations changes are known to occurduring the pre-treatment of the cells which is necessary to obtain oscillatory behavior.To the best of my knowledge, the resulting model is the first detailed kinetic model that describes the experimentally observed strong synchronization of glycolytic oscillationsin yeast populations.To analyze the dynamic behavior of yeast glycolytic models and to compare differentmodels in terms of dynamics, I introduced a framework used in physics and engineeringto create a vector based, two dimensional graphical representation of the oscillatingmetabolites and reactions of glycolysis. Not only was it possible to make a concise comparisonof the set of models, but with the method I could also quantify the contributionof the interactions in the network to the transduction of the oscillations. Furthermore Icould distinguish between different mechanisms of oscillation for each of the models, anddemonstrated how the framework can be used to create such representations for experimentaldata sets.

[发布机构] Stellenbosch University