Kinetic modeling can describe in vivo glycolysis in Entamoeba histolytica

Glycolysis in the human parasite Entamoeba histolytica is characterized by the absence of cooperative modulation and the prevalence of pyrophosphate-dependent (over ATP-dependent) enzymes. To determine the flux-control distribution of glycolysis and understand its underlying control mechanisms, a ki...

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Published in:The FEBS journal 2007-09, Vol.274 (18), p.4922-4940
Main Authors: Saavedra, Emma, Marín-Hernández, Alvaro, Encalada, Rusely, Olivos, Alfonso, Mendoza-Hernández, Guillermo, Moreno-Sánchez, Rafael
Format: Article
Language:English
Subjects:
Animals
ATPases
drug targeting
Entamoeba histolytica
Entamoeba histolytica - drug effects
Entamoeba histolytica - enzymology
Entamoeba histolytica - metabolism
Entamoebiasis - drug therapy
Enzymes
Ethanol - metabolism
Glycolysis - drug effects
hexokinase
Hexokinase - metabolism
Kinetics
Metabolism
Models, Biological
Parasitology
Pharmacology
phosphoglycerate mutase
Signal transduction
Time Factors
Titrimetry
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Summary:Glycolysis in the human parasite Entamoeba histolytica is characterized by the absence of cooperative modulation and the prevalence of pyrophosphate-dependent (over ATP-dependent) enzymes. To determine the flux-control distribution of glycolysis and understand its underlying control mechanisms, a kinetic model of the pathway was constructed by using the software gepasi. The model was based on the kinetic parameters determined in the purified recombinant enzymes, and the enzyme activities, and steady-state fluxes and metabolite concentrations determined in amoebal trophozoites. The model predicted, with a high degree of accuracy, the flux and metabolite concentrations found in trophozoites, but only when the pyrophosphate concentration was held constant; at variable pyrophosphate, the model was not able to completely account for the ATP production/consumption balance, indicating the importance of the pyrophosphate homeostasis for amoebal glycolysis. Control analysis by the model revealed that hexokinase exerted the highest flux control (73%), as a result of its low cellular activity and strong AMP inhibition. 3-Phosphoglycerate mutase also exhibited significant flux control (65%) whereas the other pathway enzymes showed little or no control. The control of the ATP concentration was also mainly exerted by ATP consuming processes and 3-phosphoglycerate mutase and hexokinase (in the producing block). The model also indicated that, in order to diminish the amoebal glycolytic flux by 50%, it was required to decrease hexokinase or 3-phosphoglycerate mutase by 24% and 55%, respectively, or by 18% for both enzymes. By contrast, to attain the same reduction in flux by inhibiting the pyrophosphate-dependent enzymes pyrophosphate-phosphofructokinase and pyruvate phosphate dikinase, they should be decreased > 70%. On the basis of metabolic control analysis, steps whose inhibition would have stronger negative effects on the energy metabolism of this parasite were identified, thus becoming alternative targets for drug design.
ISSN:1742-464X
1742-4658
DOI:10.1111/j.1742-4658.2007.06012.x