| 1. |
- 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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| 2. |
- 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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| 3. |
- 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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| 4. |
- Ledesma-Amaro, R., et al.
(författare)
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Genome Scale Metabolic Modeling of the Riboflavin Overproducer Ashbya gossypii
- 2014
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Ingår i: Biotechnology and Bioengineering. - : Wiley. - 0006-3592 .- 1097-0290. ; 111:6, s. 1191-1199
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Tidskriftsartikel (refereegranskat)abstract
- Ashbya gossypii is a filamentous fungus that naturally overproduces riboflavin, or vitamin B2. Advances in genetic and metabolic engineering of A. gossypii have permitted the switch from industrial chemical synthesis to the current biotechnological production of this vitamin. Additionally, A. gossypii is a model organism with one of the smallest eukaryote genomes being phylogenetically close to Saccharomyces cerevisiae. It has therefore been used to study evolutionary aspects of bakers' yeast. We here reconstructed the first genome scale metabolic model of A. gossypii, iRL766. The model was validated by biomass growth, riboflavin production and substrate utilization predictions. Gene essentiality analysis of the A. gossypii model in comparison with the S. cerevisiae model demonstrated how the whole-genome duplication event that separates the two species has led to an even spread of paralogs among all metabolic pathways. Additionally, iRL766 was used to integrate transcriptomics data from two different growth stages of A. gossypii, comparing exponential growth to riboflavin production stages. Both reporter metabolite analysis and in silico identification of transcriptionally regulated enzymes demonstrated the important involvement of beta-oxidation and the glyoxylate cycle in riboflavin production. Biotechnol. Bioeng. 2014;111: 1191-1199.
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