Explicit consideration of topological and parameter uncertainty gives new insights into a well-established model of glycolysis

Authors

  • Fiona Achcar,

    1. Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, UK
    Search for more papers by this author
  • Michael P.  Barrett,

    1. Wellcome Trust Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, UK
    Search for more papers by this author
  • Rainer Breitling

    Corresponding author
    1. Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, UK
    2. Groningen Bioinformatics Centre, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, The Netherlands
    3. Faculty of Life Sciences, Manchester Institute of Biotechnology, University of Manchester, UK
    • Correspondence

      R. Breitling, Faculty of Life Sciences, Manchester Institute of Biotechnology, University of Manchester, 131 Princess Street, Manchester M17DN, UK

      Tel: +44 (0)141 306 5117

      E-mail: rainer.breitling@manchester.ac.uk

    Search for more papers by this author

Abstract

Previous models of glycolysis in the sleeping sickness parasite Trypanosoma brucei assumed that the core part of glycolysis in this unicellular parasite is tightly compartimentalized within an organelle, the glycosome, which had previously been shown to contain most of the glycolytic enzymes. The glycosomes were assumed to be largely impermeable, and exchange of metabolites between the cytosol and the glycosome was assumed to be regulated by specific transporters in the glycosomal membrane. This tight compartmentalization was considered to be essential for parasite viability. Recently, size-specific metabolite pores were discovered in the membrane of glycosomes. These channels are proposed to allow smaller metabolites to diffuse across the membrane but not larger ones. In light of this new finding, we re-analyzed the model taking into account uncertainty about the topology of the metabolic system in T. brucei, as well as uncertainty about the values of all parameters of individual enzymatic reactions. Our analysis shows that these newly-discovered nonspecific pores are not necessarily incompatible with our current knowledge of the glycosomal metabolic system, provided that the known cytosolic activities of the glycosomal enzymes play an important role in the regulation of glycolytic fluxes and the concentration of metabolic intermediates of the pathway.

Database

The mathematical models described here have been submitted to the JWS Online Cellular Systems Modelling Database and can be accessed at http://jjj.mib.ac.uk/database/achcar/index.html.

[Database section added 24 June 2014 after original online publication]

Ancillary