Handling Uncertainty in Dynamic Models: The Pentose Phosphate Pathway in Trypanosoma brucei
Artikel i vetenskaplig tidskrift, 2013

Dynamic models of metabolism can be useful in identifying potential drug targets, especially in unicellular organisms. A model of glycolysis in the causative agent of human African trypanosomiasis, Trypanosoma brucei, has already shown the utility of this approach. Here we add the pentose phosphate pathway (PPP) of T. brucei to the glycolytic model. The PPP is localized to both the cytosol and the glycosome and adding it to the glycolytic model without further adjustments leads to a draining of the essential bound-phosphate moiety within the glycosome. This phosphate “leak” must be resolved for the model to be a reasonable representation of parasite physiology. Two main types of theoretical solution to the problem could be identified: (i) including additional enzymatic reactions in the glycosome, or (ii) adding a mechanism to transfer bound phosphates between cytosol and glycosome. One example of the first type of solution would be the presence of a glycosomal ribokinase to regenerate ATP from ribose 5-phosphate and ADP. Experimental characterization of ribokinase in T. brucei showed that very low enzyme levels are sufficient for parasite survival, indicating that other mechanisms are required in controlling the phosphate leak. Examples of the second type would involve the presence of an ATP:ADP exchanger or recently described permeability pores in the glycosomal membrane, although the current absence of identified genes encoding such molecules impedes experimental testing by genetic manipulation. Confronted with this uncertainty, we present a modeling strategy that identifies robust predictions in the context of incomplete system characterization. We illustrate this strategy by exploring the mechanism underlying the essential function of one of the PPP enzymes, and validate it by confirming the model predictions experimentally.

Trypanosoma brucei gambiense

Fructoses

Ribose

Glycolysis

Glucose

Phosphates

Simulation and modeling

Oxidative stress

Författare

Eduard Kerkhoven

Chalmers, Kemi- och bioteknik, Livsvetenskaper, Systembiologi

F. Achcar

Rijksuniversiteit Groningen

University of Glasgow

V. P. Alibu

Wellcome Trust Centre for Molecular Parasitology

R. J. Burchmore

Wellcome Trust Centre for Molecular Parasitology

I. H. Gilbert

University of Dundee

M. Trybilo

Brunel University London

N. N. Driessen

Leiden University Medical Center - LUMC

VU University Amsterdam

D. Gilbert

Brunel University London

R. Breitling

University of Manchester

B.M. Bakker

Rijksuniversiteit Groningen

VU University Amsterdam

M. P. Barrett

Wellcome Trust Centre for Molecular Parasitology

PLoS Computational Biology

1553-734X (ISSN) 1553-7358 (eISSN)

Vol. 9 Art. no. e1003371- e1003371

Ämneskategorier

Biologiska vetenskaper

DOI

10.1371/journal.pcbi.1003371