Targeting glycolysis in the malaria parasite Plasmodium falciparum
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BiBTeXGlycolysis 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.
SEEK ID: https://fairdomhub.org/publications/268
DOI: 10.1111/febs.13615
Projects: Whole body modelling of glucose metabolism in malaria patients
Publication type: Not specified
Journal: FEBS J
Citation: FEBS J 283(4) : 634
Date Published: 1st Feb 2016
Registered Mode: Not specified
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Created: 30th Aug 2016 at 13:04
Last updated: 8th Dec 2022 at 17:26
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Projects: PSYSMO, MOSES, SysMO DB, SysMO-LAB, SulfoSys, SulfoSys - Biotec, Whole body modelling of glucose metabolism in malaria patients, FAIRDOM, Molecular Systems Biology, COMBINE Multicellular Modelling, HOTSOLUTE, Steroid biosynthesis, Yeast glycolytic oscillations, Computational pathway design for biotechnological applications, SCyCode The Autotrophy-Heterotrophy Switch in Cyanobacteria: Coherent Decision-Making at Multiple Regulatory Layers, Project Coordination, WP 3: Drug release kinetics study, Glucose metabolism in cancer cell lines
Institutions: Manchester Centre for Integrative Systems Biology, University of Manchester, University of Stellenbosch, University of Manchester - Department of Computer Science, Stellenbosch University
https://orcid.org/0000-0003-2633-0537
The Snoep Lab’s core research efforts are in Computational Systems Biology; a combined experimental, modeling and theoretical approach to quantitatively understand the functional behavior of Biological Systems resulting from the characteristics of their components. Our main focus is on metabolism, of human pathogens such as Plasmodium falciparum, Mycobacterium tuberculosis, but also of breast cancer cell lines, and on modelling disease states such as glucose homeostatis in type 2 diabetes, and ...
Projects: Whole body modelling of glucose metabolism in malaria patients, Steroid biosynthesis, Yeast glycolytic oscillations, Computational pathway design for biotechnological applications, Glucose metabolism in cancer cell lines
Web page: http://www.sun.ac.za/english/faculty/science/biochemistry/research/snoep-group
Hypoglycaemia and lactic acidosis are key diagnostics for poor chances of survival in malaria patients. In this project we aim to test to what extent the metabolic activity of Plasmodium falciparum contributes to a changed glucose metabolism in malaria patients. The approach is to start with detailed bottom up models for the parasite and then merge these with more coarse grained models at the whole body level.
Programme: SARCHI: Mechanistic modelling of health and epidemiology
Public web page: Not specified
The investigation entails the construction and validation of a detailed mathematical model for glycolysis of the malaria parasite Plasmodium falciparum in the blood stage trophozoite form.
Submitter: Dawie van Niekerk
Studies: Model analysis, Model construction, Model validation
Assays: ALD, ATPASE, Culturing and synchronisation of P. falciparum, ENO, G3PDH, GAPDH, GLC incubation, GLCtr, GLYtr, HK, Inhibition of glucose transport, Inhibition of lactate flux, LACtr, LDH, PFK, PGI, PGK, PGM, PK, PYRtr, Steady state, Supply-demand analysis, TPI, Trophozoite Isolation and Lysate Preparation
Submitter: Dawie van Niekerk
Investigation: Glucose metabolism in Plasmodium falciparum tro...
Assays: Inhibition of glucose transport, Inhibition of lactate flux, Supply-demand analysis
