title: Targeting glycolysis in the malaria parasite Plasmodium falciparum.
abstract: Glycolysis is the main pathway for ATP production in the malaria parasite Plasmodium falciparum and essential for its survival. Following a sensitivity analysis of a detailed kinetic model for glycolysis in the parasite, the glucose transport reaction was identified as the step whose activity needed to be inhibited to the least extent to result in a 50% reduction in glycolytic flux. In a subsequent inhibitor titration with cytochalasin B, we confirmed the model analysis experimentally and measured a flux control coefficient of 0.3 for the glucose transporter. In addition to the glucose transporter, the glucokinase and phosphofructokinase had high flux control coefficients, while for the ATPase a small negative flux control coefficient was predicted. In a broader comparative analysis of glycolytic models, we identified a weakness in the P. falciparum pathway design with respect to stability towards perturbations in the ATP demand.
  
  
  METHODS
  The mathematical model described here has been submitted to the JWS Online Cellular Systems Modelling Database and can be accessed at http://jjj.bio.vu.nl/database/vanniekerk1. The SEEK-study including the experimental data set is available at DOI 10.15490/seek.1.
  
  
  METHODS
  56 (http://dx.doi.org/10.15490/seek.1.
  
  
  METHODS
  56).
authors.affiliation: Department of Biochemistry, Stellenbosch University, Matieland, South Africa.
authors.forename: David D
authors.initials: DD
authors.lastname: van Niekerk
authors.affiliation: Department of Biochemistry, Stellenbosch University, Matieland, South Africa.|Molecular Cell Physiology, Vrije Universiteit Amsterdam, The Netherlands.
authors.forename: Gerald P
authors.initials: GP
authors.lastname: Penkler
authors.affiliation: Department of Biochemistry, Stellenbosch University, Matieland, South Africa.
authors.forename: Francois
authors.initials: F
authors.lastname: du Toit
authors.affiliation: Department of Biochemistry, Stellenbosch University, Matieland, South Africa.|Molecular Cell Physiology, Vrije Universiteit Amsterdam, The Netherlands.|MIB, University of Manchester, UK.
authors.forename: Jacky L
authors.initials: JL
authors.lastname: Snoep
mesh_terms: D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000096:biosynthesis; D003571:Cytochalasin B / Q000494:pharmacology; D005947:Glucose / Q000037:antagonists & inhibitors / Q000378:metabolism; D051246:Glucose Transport Proteins, Facilitative / Q000037:antagonists & inhibitors / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects*; D008958:Models, Molecular; D009010:Monte Carlo Method; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*
chemical_list: D051246:Glucose Transport Proteins, Facilitative; D003571:Cytochalasin B; D000255:Adenosine Triphosphate; D000251:Adenosine Triphosphatases; D005947:Glucose
keywords: drug target identification; glycolysis; mathematical model; metabolic control analysis; systems biology