Quantitative analysis of drug effects at the whole-body level: a case study for glucose metabolism in malaria patients.

We propose a hierarchical modelling approach to construct models for disease states at the whole-body level. Such models can simulate effects of drug-induced inhibition of reaction steps on the whole-body physiology. We illustrate the approach for glucose metabolism in malaria patients, by merging two detailed kinetic models for glucose metabolism in the parasite Plasmodium falciparum and the human red blood cell with a coarse-grained model for whole-body glucose metabolism.

Construction and validation of a detailed kinetic model of glycolysis in Plasmodium falciparum.

Unlabelled: The enzymes in the Embden-Meyerhof-Parnas pathway of Plasmodium falciparum trophozoites were kinetically characterized and their integrated activities analyzed in a mathematical model. For validation of the model, we compared model predictions for steady-state fluxes and metabolite concentrations of the hexose phosphates with experimental values for intact parasites. The model, which is completely based on kinetic parameters that were measured for the individual enzymes, gives an accurate prediction of the steady-state fluxes and intermediate concentrations.

Incorporating covalent and allosteric effects into rate equations: the case of muscle glycogen synthase.

Several enzymes have been described that undergo both allosteric and covalent regulation, but, to date, there exists no succinct kinetic description that is able to account for both of these mechanisms of regulation. Muscle glycogen synthase, an enzyme implicated in the pathogenesis of several metabolic diseases, is activated by glucose 6-phosphate and inhibited by ATP and phosphorylation at multiple sites. A kinetic description of glycogen synthase could provide insight into the relative importance of these modifiers.

Regulation of glycogen synthase from mammalian skeletal muscle--a unifying view of allosteric and covalent regulation.

It is widely accepted that insufficient insulin-stimulated activation of muscle glycogen synthesis is one of the major components of non-insulin-dependent (type 2) diabetes mellitus. Glycogen synthase, a key enzyme in muscle glycogen synthesis, is extensively regulated, both allosterically (by glucose-6-phosphate, ATP, and others) and covalently (by phosphorylation). Although glycogen synthase has been a topic of intense study for more than 50 years, its kinetic characterization has been confounded by its large number of phosphorylation states.