ArticlePLoS computational biology2013
Handling uncertainty in dynamic models: the pentose phosphate pathway in Trypanosoma brucei.
Article in PLoS computational biology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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20 citing papers in PubMed, 51 citations in OpenAlex.
- From Genome to Function: Metabolism-Wide Models of Lifecycle Stages of Parasites.Methods in molecular biology (Clifton, N.J.) · 2026Article
- PEMPS: a phylogenetic software tool to model the evolution of metabolic pathways.BMC bioinformatics · 2024Article
- Structure ofInternational journal of molecular sciences · 2023Article
- Quantitative modeling of pentose phosphate pathway response to oxidative stress reveals a cooperative regulatory strategy.iScience · 2022Article
- Trypanosoma brucei: Metabolomics for analysis of cellular metabolism and drug discovery.Metabolomics : Official journal of the Metabolomic Society · 2022Review
- 6-Phosphogluconate dehydrogenase and its crystal structures.Acta crystallographica. Section F, Structural biology communications · 2022Review
- Biochemical and structural insights into 6-phosphogluconate dehydrogenase from Leishmania donovani.Applied microbiology and biotechnology · 2021Article
- Glucose 6-Phosphate Dehydrogenase from Trypanosomes: Selectivity for Steroids and Chemical Validation in BloodstreamMolecules (Basel, Switzerland) · 2021Article
- Suramin exposure alters cellular metabolism and mitochondrial energy production in African trypanosomes.The Journal of biological chemistry · 2020Article
- A Global Analysis of Enzyme Compartmentalization to Glycosomes.Pathogens (Basel, Switzerland) · 2020Article
- Gluconeogenesis using glycerol as a substrate in bloodstream-form Trypanosoma brucei.PLoS pathogens · 2018Article
- Deletion of transketolase triggers a stringent metabolic response in promastigotes and loss of virulence in amastigotes of Leishmania mexicana.PLoS pathogens · 2018Article
- Article
- Targeting pathogen metabolism without collateral damage to the host.Scientific reports · 2017Article
- The return of metabolism: biochemistry and physiology of the pentose phosphate pathway.Biological reviews of the Cambridge Philosophical Society · 2015Review
- Probing the metabolic network in bloodstream-form Trypanosoma brucei using untargeted metabolomics with stable isotope labelled glucose.PLoS pathogens · 2015Article
- Ribose 5-phosphate isomerase B knockdown compromises Trypanosoma brucei bloodstream form infectivity.PLoS neglected tropical diseases · 2015Article
- Computational strategies for a system-level understanding of metabolism.Metabolites · 2014Review
- Gluconeogenesis in Leishmania mexicana: contribution of glycerol kinase, phosphoenolpyruvate carboxykinase, and pyruvate phosphate dikinase.The Journal of biological chemistry · 2014Article
- LC-MS-based absolute metabolite quantification: application to metabolic flux measurement in trypanosomes.Metabolomics : Official journal of the Metabolomic SocietyArticle
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11 authors at 7 institutions in 3 countries.
Funding
Abstract
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.
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