Construction and validation of a detailed kinetic model of glycolysis in <i>Plasmodium falciparum</i>

Penkler, G.P.; Toit, François du; Adams, Waldo; Rautenbach, Marina; Palm, Daniel C.; Niekerk, David D. van; Snoep, Jacky L.

doi:10.1111/febs.13237

Cited by 34 publications

(42 citation statements)

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“…Projects of all sizes can be registered; from large, multinational consortia to those undertaken by individual researchers. An example of a published (3) collection of data and models is the ‘Glucose metabolism in Plasmodium falciparum trophozoites’ investigation (https://fairdomhub.org/investigations/56) that has 3 Studies, 24 Assays, 16 Data files, 19 Models, 13 SOPs and 3 Publications. The Investigation describes the construction, analysis and validation of a model of glycolysis in the malaria parasite P. falciparum .…”

Section: Methodsmentioning

confidence: 99%

“…For publication, digital object identifiers (DOI) can be minted for individual assets or for a collection that forms part of an investigation (e.g. DOI: 10.15490/seek.1.investigation.56, which is referenced in (3)). This means that content can be directly cited by researchers.…”

Section: Methodsmentioning

confidence: 99%

“…Assays are displayed in two groups; top right shows experimental assays, and bottom left shows modeling assays (analyses). This is a simpler investigation than that of (3) chosen for clarity on the printed page. In practice the interface is designed to be interactive so that users navigate through the graph.…”

Section: Methodsmentioning

confidence: 99%

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FAIRDOMHub: a repository and collaboration environment for sharing systems biology research

et al. 2016

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The FAIRDOMHub is a repository for publishing FAIR (Findable, Accessible, Interoperable and Reusable) Data, Operating procedures and Models (https://fairdomhub.org/) for the Systems Biology community. It is a web-accessible repository for storing and sharing systems biology research assets. It enables researchers to organize, share and publish data, models and protocols, interlink them in the context of the systems biology investigations that produced them, and to interrogate them via API interfaces. By using the FAIRDOMHub, researchers can achieve more effective exchange with geographically distributed collaborators during projects, ensure results are sustained and preserved and generate reproducible publications that adhere to the FAIR guiding principles of data stewardship.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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FAIRDOMHub: a repository and collaboration environment for sharing systems biology research

et al. 2016

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“…In the study by Snoep and colleagues, the authors first measured the specific activity of every glycolytic enzyme at a single reference physiological pH and temperature in cell-free extracts of P. falciparum trophozoites [4]. They also measured the activities of glucose, pyruvate and lactate transporters under these conditions.…”

Section: Constructing a P Falciparum-specific Mathematical Model Of mentioning

confidence: 99%

Malaria, metabolism and mathematical models

Gemayel¹

2017

The FEBS Journal

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In the malaria parasite Plasmodium, the glycolysis pathway and the pentose phosphate pathway (PPP) represent the main routes of central carbon metabolism. Glycolysis is a series of 10 enzymatic reactions that transform a molecule of glucose into two molecules of pyruvate and two molecules of ATP (Fig. 1). In Plasmodium, the tricarboxylic acid cycle is not directly linked to glycolysis since pyruvate dehydrogenase is located in another subcellular compartment (apicoplast); instead, pyruvate is mostly reduced into lactate in the absence of oxygen [1]. The parasite thus depends entirely on glycolysis for ATP production, making this pathway an attractive target for antimalarial drugs.In the seven-step PPP, three molecules of glucose 6-phosphate are converted into three molecules of CO 2 , two of fructose 6-phosphate, one of glyceraldehyde 3-phosphate and six molecules of NADPH. The products then enter glycolysis for further degradation (Fig. 1). In Plasmodium, the PPP is the main source of NADPH needed for many enzymatic reactions as well as ribose 5-phosphate for ribonucleotide synthesis. PPP activity in infected erythrocytes is 78-fold higher than uninfected erythrocytes [2] and in humans, deficiencies in glucose 6-phopshate dehydrogenase (G6PDH), the first enzyme of the PPP, provide partial protection against malaria infections [3], making the PPP a second potential target for antimalarial drugs.It is still unclear to what extent the malaria parasite's metabolic activity affects the host's metabolism. However, understanding how the host and parasite metabolisms are interconnected will help identify the optimal metabolic step(s) that should be targeted for drug development. For the malaria parasite, an organism with a complex life cycle and multiple hosts, there is the added challenge that the parasite is exposed to different environments at each stage of its life cycle, and therefore has different metabolic requirements and undergoes substantive metabolic rewiring. This requires understanding the dynamic behaviour of the metabolism rather than acquiring a static snapshot of enzyme activities and metabolite concentrations.Enter metabolic flux analysis. Metabolic flux analysis allows the quantification of the flow of metabolites (i.e. rates of production and consumption) within a metabolic pathway. It combines experimental quantification of metabolic intermediates and end-products, kinetic data of enzymes and mathematical modelling. Metabolic flux analysis can be used to understand how a metabolic pathway is regulated and how it responds to genetic or environmental perturbations. The mathematical model can predict the behaviour of a metabolic pathway when certain variables (e.g. substrate concentration, enzyme activity. . .) change and, as a result, be used to identify the best metabolic reaction to target to achieve the desired outcome (pathway inhibition, decreased end-product concentration. . .). Combined with structural data of metabolic enzymes, this information will ultimately point to optimal targets for dru...

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“…Penkler et al [85] nicely showed how a modeling study can be described and published in a reproducible manner, using standard formats and the SEEK platform. Their model code is available, together with raw data, simulation setups and result data.…”

Section: B Depositing Reproducible Modelsmentioning

confidence: 99%

How Modeling Standards, Software, and Initiatives Support Reproducibility in Systems Biology and Systems Medicine

Waltemath

Wolkenhauer

2016

IEEE Trans. Biomed. Eng.

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Construction and validation of a detailed kinetic model of glycolysis in Plasmodium falciparum

Cited by 34 publications

References 120 publications

FAIRDOMHub: a repository and collaboration environment for sharing systems biology research

FAIRDOMHub: a repository and collaboration environment for sharing systems biology research

Malaria, metabolism and mathematical models

How Modeling Standards, Software, and Initiatives Support Reproducibility in Systems Biology and Systems Medicine

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