Mathematical modelling of metabolic pathways affected by an enzyme deficiency. A mathematical model of glycolysis in normal and pyruvate-kinase-deficient red blood cells

Abstract

A mathematical model of glycolysis in human erythrocytes is proposed to study the influence of a pyruvate kinase deficiency on the energy metabolism. The model takes into account the main regulatory properties of the non-equilibrium enzymes and the magnesium-complex formation by the adenine nucleotides and by 2,3-bisphosphoglycerate. In the normal case (no enzyme defect) the calculated flux rates and metabolite concentrations are in a good agreement with experimental data. It is shown that a severe pyruvate kinase deficiency manifested in a tenfold diminished activity of that enzyme leads to a remarkable decrease of the glycolytic flux and the ATP concentration of about 50% of the normal values. On the other hand a lowering of the pyruvate kinase activity to half of the normal value, characteristic for the heterozygotes, gives no significant alterations of the metabolite concentrations and the flux rates compared with the normal case which is in accordance with the lack of clinical symptoms for a metabolic disease of these probands. For three patients with known alterations of their pyruvate kinase mutants the calculated metabolite concentrations and the control characteristics permit estimation of the degree of disorder of the glycolytic pathway. The resulting classification corresponds well to other independent experimental and clinical findings. In particular, the calculation demonstrates that there is no simple correlation between the lowered enzyme activity and the reduced flux rate through the affected pathway.