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Jurgen Haanstra

About Jurgen Haanstra:
No description specified

SEEK ID: https://fairdomhub.org/people/387

Location:  Netherlands

Expertise: regulation of gene expression, quantative biology, Cell physiology, Trypanosoma brucei, Mathematical modelling of biological systems, Glycolysis, carbon metabolism

Tools: PySCeS

ORCID: Not specified

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Project positions

SilicoTryp (University of Groningen)

IMOMESIC (VU University Amsterdam)

Related items

IMOMESIC

IMOMESIC - Integrating Modelling of Metabolism and Signalling towards an Application in Liver Cancer

One of the most challenging questions in cancer research is currently the interconnection of metabolism and signalling. An understanding of mechanisms that facilitate the physiological shift towards a proliferative metabolism in cancer cells is considered a major upcoming topic in oncology and is a key activity for future drug development. Due to the complexity of interrelations, a systems biology
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Programme: ERASysAPP

Public web page: Not specified

SilicoTryp

The SilicoTryp project aims at the creation of a “Silicon Trypanosome”, a comprehensive, experiment-based, multi-scale mathematical model of trypanosome physiology.
Trypanosomes are blood-stream parasites transmitted by tsetse flies; they cause African sleeping sickness in humans and livestock. Currently available drugs have severe side effects, and the parasites are rapidly developing resistance.
In this project, we collect a wide range of new experimental data on the parasite in its various
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Programme: SysMO

Public web page: http://silicotryp.ibls.gla.ac.uk/wiki/Main_Page

Dynamic modelling of redox metabolism and gene expression
SilicoTryp

Aim. Constructing a predictive, dynamic model of the redox metabolism of trypanosomes. Aided by
this model we will quantify the impact of gene-expression and metabolic regulation on redox
metabolism. The model will be constructed in an iterative cycle of experimentation – modelling –
analysis – experimentation, such that it can be extended and refined based on new experimental
insights.

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Kinetic modelling of Trypanothione Synthetase to elucidate the enzyme mechanism and an overall rate equation
SilicoTryp

The enzyme Trypanothione Synthetase (TryS) is a complex enzyme that catalyses the two step reaction that forms trypanothione from 2 molecules of GSH and 1 molecule of Spd and the use of ATP

Person responsible: Jurgen Haanstra

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Iterative cycles of model improvement and extension.
SilicoTryp

The output of the initial model of redox metabolism will be compared to experimental flux and metabolite data. Deviations between model and experiment will be prioritized together with WP2. We will apply Metabolic Control
Analysis (Fell 1992 PMID: 1530563) to diagnose which enzymes control the deviating metabolite
concentrations and/or rates. When the agreement between model and experiment is sufficient
we will first link it to the existing model of trypanosome glycolysis and repeat the same
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Person responsible: Jurgen Haanstra

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Modelling of gene expression and Regulation Analysis.
SilicoTryp

Our current gene-expression model (Haanstra et al. 2008 PMID: 19008351) will be parameterized for the different genes of interest.
The framework of this gene expression model has been used to include mRNA half life data into the model of glycolysis
For the enzymes of redox metabolism we will use newly measured rates of transcription, RNA precursor degradation, mRNA degradation, concentrations of mature mRNAs and proteins, enzyme turnover, Vmax values and metabolic fluxes (WP3&5).
Regulation
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Person responsible: Jurgen Haanstra

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Modelling of redox metabolism.
SilicoTryp

We are in the process of construct an ODE model of the trypanothione pathway. As input we will use
newly determined and existing kinetic data and measured metabolite concentrations at the boundaries
(from WP3&6).
Recently the glycolysis model was extended with the pentose phosphate pathway. This pathway will yield the NAPDH that maintains trypanothione in a reduced state.
For some complex enzymes (i.e trypanothione synthase) we are intensively discussing the kinetic data obtained on the
...

Person responsible: Jurgen Haanstra

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Modelling the gene expression cascade with length-dependent processes
SilicoTryp

The RNAseq data on mRNA processing and mRNA decay were used to update a previously published model and to interrogate which process should be dependent on mRNA length

Contributor: Jurgen Haanstra

Biological problem addressed: Model Analysis Type

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Creating kinetic model of Trypanothione Synthetase
SilicoTryp

We here create a kinetic model for a single enzyme within the T. brucei trypanothione synthesis pathway, the enzyme trypanothione synthetase based on the insights from the laboratory experiments

Contributor: Jurgen Haanstra

Biological problem addressed: Enzymology

Snapshots: No snapshots

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TryS: entire dataset with simulations
SilicoTryp

All datapoints that were measured are displayed together with the accompanying simulations by the computational model

Creators: Jurgen Haanstra, Alejandro Leroux

Contributor: Jurgen Haanstra

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TryS: extended model description
SilicoTryp

An extended model description of the TryS model

Creators: Jurgen Haanstra, Alejandro Leroux

Contributor: Jurgen Haanstra

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Final model of TryS
SilicoTryp

Mechanistical model of the catalytic cycle of Trypanothione Synthetase

Creators: Jurgen Haanstra, Alejandro Leroux

Contributor: Jurgen Haanstra

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Evolution, dynamics and specialized functions of glycosomes in metabolism and development of trypanosomatids
SilicoTryp

Abstract (Expand)

Kinetoplastea such as trypanosomatid parasites contain specialized peroxisomes that uniquely contain enzymes of the glycolytic pathway and other parts of intermediary metabolism and hence are called … glycosomes. Their specific enzyme content can vary strongly, quantitatively and qualitatively, between different species and during the parasites’ life cycle. The correct sequestering of enzymes has great importance for the regulation of the trypanosomatids’ metabolism and can, dependent on environmental conditions, even be essential. Glycosomes also play a pivotal role in life-cycle regulation of Trypanosoma brucei, as the translocation of a protein phosphatase from the cytosol forms part of a crucial developmental control switch. Many glycosomal proteins are differentially phosphorylated in different life-cycle stages, possibly indicative for unique forms of activity regulation, whereas many kinetic activity regulation mechanisms common for glycolytic enzymes are absent in these organisms. Glycosome turnover occurs by autophagic degradation of redundant organelles and assembly of new ones. This may provide the trypanosomatids with a manner to rapidly and efficiently adapt their metabolism to the sudden, major nutritional changes often encountered during the life cycle. This could also have helped facilitating successful adaptation of kinetoplastids, at multiple occasions during evolution, to their parasitic life style.

Authors: Balázs Szöör, Jurgen Haanstra, Melisa Gualdrón-López, Paul AM Michels

Date Published: 1st Dec 2014

Journal: Current Opinion in Microbiology

Transcriptome-wide analysis of trypanosome mRNA decay reveals complex degradation kinetics and suggests a role for co-transcriptional degradation in determining mRNA levels
SilicoTryp

Abstract (Expand)

African trypanosomes are an excellent system for quantitative modelling of post-transcriptional mRNA control. Transcription is constitutive and polycistronic; individual mRNAs are excised by trans … splicing and polyadenylation. We here measure mRNA decay kinetics in two life cycle stages, bloodstream and procyclic forms, by transcription inhibition and RNASeq. Messenger RNAs with short half-lives tend to show initial fast degradation, followed by a slower phase; they are often stabilized by depletion of the 5'-3' exoribonuclease XRNA. Many longer-lived mRNAs show initial slow degradation followed by rapid destruction: we suggest that the slow phase reflects gradual deadenylation. Developmentally regulated mRNAs often show regulated decay, and switch their decay pattern. Rates of mRNA decay are good predictors of steady state levels for short mRNAs, but mRNAs longer than 3 kb show unexpectedly low abundances. Modelling shows that variations in splicing and polyadenylation rates can contribute to steady-state mRNA levels, but this is completely dependent on competition between processing and co-transcriptional mRNA precursor destruction.

Authors: Abeer Fadda, M. Ryten, D. Droll, Federico Rojas, V. Farber, Jurgen Haanstra, C. Merce, Barbara Bakker, Keith Matthews, Christine Clayton

Date Published: 26th Aug 2014

Journal: Mol Microbiol

The silicon trypanosome: a test case of iterative model extension in systems biology
SilicoTryp

Abstract (Expand)

The African trypanosome, Trypanosoma 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.

Authors: Fiona Achcar, Abeer Fadda, Jurgen Haanstra, Eduard Kerkhoven, Dong-Hyun Kim, Alejandro Leroux, T. Papamarkou, Federico Rojas, Barbara Bakker, Mike Barrett, Christine Clayton, Mark Girolami, Luise Krauth-Siegel, Keith Matthews, Rainer Breitling

Date Published: 7th May 2014

Journal: Adv Microb Physiol

Handling uncertainty in dynamic models: the pentose phosphate pathway in Trypanosoma brucei
SilicoTryp

Abstract (Expand)

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.

Authors: Eduard Kerkhoven, Fiona Achcar, V. P. Alibu, R. J. Burchmore, I. H. Gilbert, M. Trybilo, N. N. Driessen, D. Gilbert, Rainer Breitling, Barbara Bakker, Mike Barrett

Date Published: 5th Dec 2013

Journal: PLoS Comput Biol

Dissecting the Catalytic Mechanism of Trypanosoma brucei Trypanothione Synthetase by Kinetic Analysis and Computational Modelling
SilicoTryp

Abstract (Expand)

In pathogenic trypanosomes, trypanothione synthetase (TryS) catalyzes the synthesis of both glutathionylspermidine (Gsp) and trypanothione [bis(glutathionyl)spermidine, T(SH)2]. Here we present a … thorough kinetic analysis of Trypanosoma brucei TryS in a newly developed phosphate buffer system at pH 7.0 and 37 °C, mimicking the physiological environment of the enzyme in the cytosol of bloodstream parasites. Under these conditions, TryS displays Km-values for GSH, ATP, spermidine and Gsp of 34, 18, 687, and 32 μM, respectively, as well as Ki-values for GSH and T(SH)2 of 1 mM and 360 μM, respectively. As Gsp hydrolysis has a Km-value of 5.6 mM, the in vivo amidase activity is probably negligible. To obtain a deeper insight in the molecular mechanism of TryS, we have formulated alternative kinetic models, with elementary reaction steps represented by linear kinetic equations. The model parameters were fitted to the extensive matrix of steady-state data obtained for different substrate/product combinations under the in vivo-like conditions. The best model describes the full kinetic profile and is able to predict time course data that were not used for fitting. This systems biology approach to enzyme kinetics led us to conclude that (i) TryS follows a ter-reactant mechanism, (ii) the intermediate Gsp dissociates from the enzyme between the two catalytic steps and (iii) T(SH)2 inhibits the enzyme by remaining bound at its product site and, as does the inhibitory GSH, by binding to the activated enzyme complex. The newly detected concerted substrate and product inhibition suggests that TryS activity is tightly regulated.

Authors: None

Date Published: 3rd Jul 2013

Journal: J. Biol. Chem.

Naphthoquinone derivatives exert their antitrypanosomal activity via a multi-target mechanism
SilicoTryp

Abstract (Expand)

BACKGROUND AND METHODOLOGY: Recently, we reported on a new class of naphthoquinone derivatives showing a promising anti-trypanosomatid profile in cell-based experiments. The lead of this series (B6, … 2-phenoxy-1,4-naphthoquinone) showed an ED(50) of 80 nM against Trypanosoma brucei rhodesiense, and a selectivity index of 74 with respect to mammalian cells. A multitarget profile for this compound is easily conceivable, because quinones, as natural products, serve plants as potent defense chemicals with an intrinsic multifunctional mechanism of action. To disclose such a multitarget profile of B6, we exploited a chemical proteomics approach. PRINCIPAL FINDINGS: A functionalized congener of B6 was immobilized on a solid matrix and used to isolate target proteins from Trypanosoma brucei lysates. Mass analysis delivered two enzymes, i.e. glycosomal glycerol kinase and glycosomal glyceraldehyde-3-phosphate dehydrogenase, as potential molecular targets for B6. Both enzymes were recombinantly expressed and purified, and used for chemical validation. Indeed, B6 was able to inhibit both enzymes with IC(50) values in the micromolar range. The multifunctional profile was further characterized in experiments using permeabilized Trypanosoma brucei cells and mitochondrial cell fractions. It turned out that B6 was also able to generate oxygen radicals, a mechanism that may additionally contribute to its observed potent trypanocidal activity. CONCLUSIONS AND SIGNIFICANCE: Overall, B6 showed a multitarget mechanism of action, which provides a molecular explanation of its promising anti-trypanosomatid activity. Furthermore, the forward chemical genetics approach here applied may be viable in the molecular characterization of novel multitarget ligands.

Authors: S. Pieretti, Jurgen Haanstra, M. Mazet, R. Perozzo, C. Bergamini, F. Prati, R. Fato, G. Lenaz, G. Capranico, R. Brun, Barbara Bakker, P. A. Michels, L. Scapozza, M. L. Bolognesi, A. Cavalli

Date Published: 17th Jan 2013

Journal: PLoS Negl Trop Dis

Proliferating bloodstream-form Trypanosoma brucei use a negligible part of consumed glucose for anabolic processes
SilicoTryp

Abstract (Expand)

Our quantitative knowledge of carbon fluxes in the long slender bloodstream form (BSF) Trypanosoma brucei is mainly based on non-proliferating parasites, isolated from laboratory animals and kept in … buffers. In this paper we present a carbon balance for exponentially growing bloodstream form trypanosomes. The cells grew with a doubling time of 5.3h, contained 46 mu mol of carbon (10(8) cells)(-1) and had a glucose consumption flux of 160 nmol min(-1) (10(8) cells)(-1). The molar ratio of pyruvate excreted versus glucose consumed was 2.1. Furthermore, analysis of the (13)C label distribution in pyruvate in (13)C-glucose incubations of exponentially growing trypanosomes showed that glucose was the sole substrate for pyruvate production. We conclude that the glucose metabolised in glycolysis was hardly, if at all, used for biosynthetic processes. Carbon flux through glycolysis in exponentially growing trypanosomes was 10 times higher than the incorporation of carbon into biomass. This biosynthetic carbon is derived from other precursors present in the nutrient rich growth medium. Furthermore, we found that the glycolytic flux was unaltered when the culture went into stationary phase, suggesting that most of the ATP produced in glycolysis is used for processes other than growth.

Authors: Jurgen Haanstra, A. van Tuijl, J. van Dam, W. van Winden, A. G. Tielens, J. J. van Hellemond, Barbara Bakker

Date Published: 8th May 2012

Journal: Int J Parasitol

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