| 1. |
- Shameer, S., et al.
(författare)
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TrypanoCyc: a community-led biochemical pathways database for Trypanosoma brucei
- 2015
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Ingår i: Nucleic Acids Research. - : Oxford University Press (OUP). - 0305-1048 .- 1362-4962. ; 43:D1, s. D637-D644
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Tidskriftsartikel (refereegranskat)abstract
- The metabolic network of a cell represents thecatabolic and anabolic reactions that interconvertsmall molecules (metabolites) through the activity ofenzymes, transporters and non-catalyzed chemicalreactions. Our understanding of individual metabolicnetworks is increasing as we learn more aboutthe enzymes that are active in particular cells underparticular conditions and as technologies advanceto allow detailed measurements of the cellularmetabolome. Metabolic network databases areof increasing importance in allowing us to contextualisedata sets emerging from transcriptomic,proteomic and metabolomic experiments. Here wepresent a dynamic database, TrypanoCyc (http://www.metexplore.fr/trypanocyc/), which describesthe generic and condition-specific metabolic networkof Trypanosoma brucei, a parasitic protozoan responsiblefor human and animal African trypanosomiasis.In addition to enabling navigation through the BioCyc-based TrypanoCyc interface, we have alsoimplemented a network-based representation of theinformation through MetExplore, yielding a novel environmentin which to visualise the metabolism ofthis important parasite.
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| 2. |
- Achcar, F., et al.
(författare)
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The Silicon Trypanosome: A Test Case of Iterative Model Extension in Systems Biology
- 2014
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Ingår i: Advances in Microbial Physiology. - : Elsevier. - 0065-2911. - 9780128001431 ; 64, s. 115-143
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- The African trypanosome, Ttypanosoma brucei, is a unicellular parasite causing African Trypanosomiasis (sleeping sickness in humans and nagana in animals). Due to some of its unique properties, it has emerged as a popular model organism in systems biology. A predictive quantitative model of glycolysis in the bloodstream form of the parasite has been constructed and updated several times. The Silicon Trypanosome is a project that brings together modellers and experimentalists to improve and extend this core model with new pathways and additional levels of regulation. These new extensions and analyses use computational methods that explicitly take different levels of uncertainty into account. During this project, numerous tools and techniques have been developed for this purpose, which can now be used for a wide range of different studies in systems biology.
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| 3. |
- Creek, D. J., et al.
(författare)
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Probing the Metabolic Network in Bloodstream-Form Trypanosoma brucei Using Untargeted Metabolomics with Stable Isotope Labelled Glucose
- 2015
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Ingår i: PLoS Pathogens. - : Public Library of Science (PLoS). - 1553-7366 .- 1553-7374. ; 11:3, s. 1-25
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Tidskriftsartikel (refereegranskat)abstract
- Metabolomics coupled with heavy-atom isotope-labelled glucose has been used to probe the metabolic pathways active in cultured bloodstream form trypomastigotes of Trypanosoma brucei, a parasite responsible for human African trypanosomiasis. Glucose enters many branches of metabolism beyond glycolysis, which has been widely held to be the sole route of glucose metabolism. Whilst pyruvate is the major end-product of glucose catabolism, its transamination product, alanine, is also produced in significant quantities. The oxidative branch of the pentose phosphate pathway is operative, although the non-oxidative branch is not. Ribose 5-phosphate generated through this pathway distributes widely into nucleotide synthesis and other branches of metabolism. Acetate, derived from glucose, is found associated with a range of acetylated amino acids and, to a lesser extent, fatty acids; while labelled glycerol is found in many glycerophospholipids. Glucose also enters inositol and several sugar nucleotides that serve as precursors to macromolecule biosynthesis. Although a Krebs cycle is not operative, malate, fumarate and succinate, primarily labelled in three carbons, were present, indicating an origin from phosphoenolpyruvate via oxaloacetate. Interestingly, the enzyme responsible for conversion of phosphoenolpyruvate to oxaloacetate, phosphoenolpyruvate carboxykinase, was shown to be essential to the bloodstream form trypanosomes, as demonstrated by the lethal phenotype induced by RNAi-mediated downregulation of its expression. In addition, glucose derivatives enter pyrimidine biosynthesis via oxaloacetate as a precursor to aspartate and orotate.
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| 4. |
- Achcar, F., et al.
(författare)
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Trypanosoma brucei: meet the system
- 2014
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Ingår i: Current Opinion in Microbiology. - : Elsevier BV. - 1369-5274 .- 1879-0364. ; 20, s. 162-169
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Forskningsöversikt (refereegranskat)abstract
- African trypanosomes cause devastating diseases in humans and domestic animals. The parasites evolved early in the eukaryotic lineage and have numerous biochemical peculiarities that distinguish them from other systems. These include unconventional mechanisms for expressing nuclear and mitochondrial genes as well as unusual subcellular localizations for a variety of enzymes. Systems biology has arisen partly to allow contextualization of the massive datasets that describe individual chemical parts of biological systems. Here we describe recent efforts to collect and analyse data pertaining to all aspects of the trypanosome's biochemical physiology that go some way to describing the parasite as an integrated system.
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| 5. |
- Johnston, Katharina, et al.
(författare)
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Mapping the metabolism of five amino acids in bloodstream form Trypanosoma brucei using U- 13C-labelled substrates and LC–MS
- 2019
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Ingår i: Bioscience Reports. - 0144-8463 .- 1573-4935. ; 39:5
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Tidskriftsartikel (refereegranskat)abstract
- The metabolism of the parasite Trypanosoma brucei has been the focus of numerous studies since the 1940s. Recently it was shown, using metabolomics coupled with heavy-atom isotope labelled glucose, that the metabolism of the bloodstream form parasite is more complex than previously thought. The present study also raised a number of questions regarding the origin of several metabolites, for example succinate, only a proportion of which derives from glucose. In order to answer some of these questions and explore the metabolism of bloodstream form T. brucei in more depth we followed the fate of five heavy labelled amino acids – glutamine, proline, methionine, cysteine and arginine – using an LC–MS based metabolomics approach. We found that some of these amino acids have roles beyond those previously thought and we have tentatively identified some unexpected metabolites which need to be confirmed and their function determined.
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| 6. |
- Kerkhoven, Eduard, 1985, et al.
(författare)
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Handling Uncertainty in Dynamic Models: The Pentose Phosphate Pathway in Trypanosoma brucei
- 2013
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Ingår i: PLoS Computational Biology. - : Public Library of Science (PLoS). - 1553-734X .- 1553-7358. ; 9:12, s. Art. no. e1003371-
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Tidskriftsartikel (refereegranskat)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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