Hostname: page-component-cd9895bd7-q99xh Total loading time: 0 Render date: 2024-12-14T11:34:51.509Z Has data issue: false hasContentIssue false

The silicon trypanosome

Published online by Cambridge University Press:  06 May 2010

BARBARA M. BAKKER*
Affiliation:
Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
R. LUISE KRAUTH-SIEGEL
Affiliation:
Biochemie-Zentrum der Universität Heidelberg, 69120 Heidelberg, Germany
CHRISTINE CLAYTON
Affiliation:
Zentrum für Molekulare Biologie der Universität Heidelberg, ZMBH-DKFZ Alliance, D69120 Heidelberg, Germany
KEITH MATTHEWS
Affiliation:
School of Biological Sciences, University of Edinburgh, Ashworth Laboratories, Edinburgh EH9 3JT, United Kingdom
MARK GIROLAMI
Affiliation:
University of Glasgow, Department of Computing Science & Department of Statistics, Glasgow, G12 8QQ, United Kingdom
HANS V. WESTERHOFF
Affiliation:
Department of Molecular Cell Physiology, VU University Amsterdam, 1081 HV Amsterdam, The Netherlands; and Manchester Centre for Integrative Systems Biology, Manchester Interdisciplinary BioCentre, The University of Manchester, Manchester M1 7ND, United Kingdom
PAUL A. M. MICHELS
Affiliation:
Research Unit for Tropical Diseases, de Duve Institute and Laboratory of Biochemistry, Université catholique de Louvain, Brussels, Belgium and Faculty of Biomolecular and Life Sciences, University of Glasgow, Glasgow, G12 8QQ, UK
RAINER BREITLING
Affiliation:
Groningen Bioinformatics Centre, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, 9751 NN Haren, The Netherlands
MICHAEL P. BARRETT
Affiliation:
Faculty of Biomolecular and Life Sciences and Wellcome Centre of Molecular Parasitology, University of Glasgow, Glasgow Biomedical Research Centre, Glasgow G12 8TA, United Kingdom
*
*Corresponding author: B. M. Bakker, Tel: +31 (0) 50 361 1542. E-mail: b.m.bakker@med.umcg.nl

Summary

African trypanosomes have emerged as promising unicellular model organisms for the next generation of systems biology. They offer unique advantages, due to their relative simplicity, the availability of all standard genomics techniques and a long history of quantitative research. Reproducible cultivation methods exist for morphologically and physiologically distinct life-cycle stages. The genome has been sequenced, and microarrays, RNA-interference and high-accuracy metabolomics are available. Furthermore, the availability of extensive kinetic data on all glycolytic enzymes has led to the early development of a complete, experiment-based dynamic model of an important biochemical pathway. Here we describe the achievements of trypanosome systems biology so far and outline the necessary steps towards the ambitious aim of creating a ‘Silicon Trypanosome’, a comprehensive, experiment-based, multi-scale mathematical model of trypanosome physiology. We expect that, in the long run, the quantitative modelling enabled by the Silicon Trypanosome will play a key role in selecting the most suitable targets for developing new anti-parasite drugs.

Type
Research Article
Copyright
Copyright © Cambridge University Press 2010

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

REFERENCES

Albert, M. A., Haanstra, J. R., Hannaert, V., Van Roy, J., Opperdoes, F. R., Bakker, B. M., and Michels, P. A. M. (2005). Experimental and in silico analyses of glycolytic flux control in bloodstream form Trypanosoma brucei. Journal of Biological Chemistry 280, 2830628315.CrossRefGoogle ScholarPubMed
Archer, S. K., Luu, V.- D., de Queiroz, R., Brems, S. and Clayton, C. E. (2009). Trypanosoma brucei PUF9 regulates mRNAs for proteins involved in replicative processes over the cell cycle. PLoS Pathogens 5, e1000565.CrossRefGoogle ScholarPubMed
Bacchi, C. J., Nathan, H. C., Hutner, S. H., McCann, P. P. and Sjoerdsma, A. (1980). Polyamine metabolism: a potential therapeutic target in trypanosomes. Science 210, 332334.CrossRefGoogle ScholarPubMed
Bakker, B. M., Aßmus, H. E., Bruggeman, F., Haanstra, J., Klipp, E. and Westerhoff, H. V. (2002). Network-based selectivity of antiparasitic inhibitors. Molecular Biology Reports 29, 15.CrossRefGoogle ScholarPubMed
Bakker, B. M., Mensonides, F. I. C., Teusink, B., Michels, P. A. M. and Westerhoff, H. V. (2000). Compartmentation protects trypanosomes from the dangerous design of glycolysis. Proceedings of the National Academy of Sciences, USA 97, 20872092.CrossRefGoogle ScholarPubMed
Bakker, B. M., Michels, P. A. M., Opperdoes, F. R. and Westerhoff, H. V. (1997). Glycolysis in bloodstream form Trypanosoma brucei can be understood in terms of the kinetics of the glycolytic enzymes. Journal of Biological Chemistry 272, 32073215.CrossRefGoogle ScholarPubMed
Bakker, B. M., Michels, P. A. M., Opperdoes, F. R. and Westerhoff, H. V. (1999 a). What controls glycolysis in bloodstream form Trypanosoma brucei? Journal of Biological Chemistry 274, 1455114559.CrossRefGoogle ScholarPubMed
Bakker, B. M., Walsh, M. C., ter Kuile, B. H., Mensonides, F. I., Michels, P. A. M., Opperdoes, F. R. and Westerhoff, H. V. (1999 b). Contribution of glucose transport to the control of the glycolytic flux in Trypanosoma brucei. Proceedings of the National Academy of Sciences, USA 96, 1009810103.CrossRefGoogle Scholar
Barrett, M. P. (1997). The pentose phosphate pathway and parasitic protozoa. Parasitology Today 13, 1116.CrossRefGoogle ScholarPubMed
Barrett, M. P., Burchmore, R. J., Stich, A., Lazzari, J. O., Frasch, A. C., Cazzulo, J. J. and Krishna, S. (2003). The trypanosomiases. Lancet 362, 14691480.CrossRefGoogle ScholarPubMed
Berriman, M., Ghedin, E., Hertz-Fowler, C., Blandin, G., Renauld, H. et al. (2005). The genome of the African trypanosome Trypanosoma brucei. Science 309, 416422.CrossRefGoogle ScholarPubMed
Bruggeman, F. J. and Westerhoff, H. V. (2007). The nature of systems biology. Trends in Microbiology 15, 4550.CrossRefGoogle ScholarPubMed
Chukualim, B., Peters, N., Hertz-Fowler, C. and Berriman, M. (2008). TrypanoCyc – a metabolic pathway database for Trypanosoma brucei. BMC Bioinformatics 9 (Suppl 10), P5.CrossRefGoogle Scholar
Clayton, C. and Shapira, M. (2007). Post-transcriptional regulation of gene expression in trypanosomes and leishmanias. Molecular and Biochemical Parasitology 156, 93–101.CrossRefGoogle ScholarPubMed
Daran-Lapujade, P., Rossell, S., van Gulik, W. M., Luttik, M. A. H., de Groot, M. J. L., Slijper, M., Heck, A. J. R., Daran, J. M., de Winde, J. H., Westerhoff, H. V., Pronk, J. T. and Bakker, B. M. (2007). The fluxes through glycolytic enzymes in Saccharomyces cerevisiae are predominantly regulated at posttranscriptional levels. Proceedings of the National Academy of Sciences, USA 104, 1575315758.CrossRefGoogle ScholarPubMed
Duffieux, F., Van Roy, J., Michels, P. A. M., Opperdoes, F. R. (2000). Molecular characterization of the first two enzymes of the pentose-phosphate pathway of Trypanosoma brucei. Glucose-6-phosphate dehydrogenase and 6-phosphogluconolactonase. Journal of Biological Chemistry 275, 2755927565.CrossRefGoogle ScholarPubMed
Estévez, A. (2008). The RNA-binding protein TbDRBD3 regulates the stability of a specific subset of mRNAs in trypanosomes. Nucleic Acids Research 36, 45734586.CrossRefGoogle ScholarPubMed
Fairlamb, A. H. and Cerami, A. (1992). Metabolism and functions of trypanothione in the Kinetoplastida. Annual Review of Microbiology 46, 695729.CrossRefGoogle ScholarPubMed
Fairlamb, A. J., Opperdoes, F. R. and Borst, P. (1977). New approach to screening drugs for activity against African trypanosomes. Nature 265, 270271.CrossRefGoogle ScholarPubMed
Fairlamb, A. H., Henderson, G. B., Bacchi, C. J. and Cerami, A. (1987). In vivo effects of difluoromethylornithine on trypanothione and polyamine levels in bloodstream forms of Trypanosoma brucei. Molecular and Biochemical Parasitology 24, 185191.CrossRefGoogle ScholarPubMed
Fenn, K. and Matthews, K. R. (2007). The cell biology of Trypanosoma brucei differentiation. Current Opinion in Microbiology 10, 539546.CrossRefGoogle ScholarPubMed
Flynn, I. W. and Bowman, I. B. (1973). The metabolism of carbohydrate by pleomorphic African trypanosomes. Comparative Biochemistry and Physiology B 45, 2542.CrossRefGoogle Scholar
Frearson, J. A., Wyatt, P. G., Gilbert, I. H. and Fairlamb, A. H. (2007). Target assessment for antiparasitic drug discovery. Trends in Parasitology 23, 589595.CrossRefGoogle ScholarPubMed
Grigull, J., Mnaimneh, S., Pootoolal, J., Robinson, M. and Hughes, T. (2004). Genome-wide analysis of mRNA stability using transcription inhibitors and microarrays reveals posttranscriptional control of ribosome biogenesis factors. Molecular and Cellular Biology 24, 55345547.CrossRefGoogle ScholarPubMed
Grunau, S., Mindthoff, S., Rottensteiner, H., Sormunen, R. T., Hiltunen, J. K., Erdmann, R. and Antonenkov, V. D. (2009) Channel-forming activities of peroxisomal membrane proteins from the yeast Saccharomyces cerevisiae. FEBS Journal 276, 16981708.CrossRefGoogle ScholarPubMed
Haanstra, J. (2009). The power of network-based drug design and the interplay between metabolism and gene expression in Trypanosoma brucei. PhD thesis Vrije Universiteit Amsterdam, ISBN 978-90-8659-331-6.Google Scholar
Haanstra, J. R., Stewart, M., Luu, V. D., van Tuijl, A., Westerhoff, H. V., Clayton, C. and Bakker, B. M. (2008 b). Control and regulation of gene expression: quantitative analysis of the expression of phosphoglycerate kinase in bloodstream form Trypanosoma brucei. Journal of Biological Chemistry 283, 24952507.CrossRefGoogle ScholarPubMed
Haanstra, J. R., van Tuijl, A., Kessler, P., Reijnders, W., Michels, P. A. M., Westerhoff, H. V., Parsons, M. and Bakker, B. M. (2008 a). Compartmentation prevents a lethal turbo-explosion of glycolysis in trypanosomes. Proceedings of the National Academy of Sciences, USA 105, 1771817723.CrossRefGoogle ScholarPubMed
Hanau, S., Rippa, M., Bertelli, M., Dallocchio, F. and Barrett, M. P. (1996). 6-Phosphogluconate dehydrogenase from Trypanosoma brucei. Kinetic analysis and inhibition by trypanocidal drugs. European Journal of Biochemistry 240, 592599.CrossRefGoogle ScholarPubMed
Heise, N. and Opperdoes, F. R. (1999). Purification, localisation and characterisation of glucose-6-phosphate dehydrogenase of Trypanosoma brucei. Molecular and Biochemical Parasitology 99, 2132.CrossRefGoogle ScholarPubMed
Helfert, S., Bakker, B. M., Michels, P. A. M. and Clayton, C. (2001). An essential role of triosephosphate isomerase and aerobic metabolism in trypanosomes. Biochemical Journal 357, 117125.CrossRefGoogle Scholar
Hirumi, H. and Hirumi, K. (1989). Continuous cultivation of Trypanosoma brucei blood stream forms in a medium containing a low concentration of serum protein without feeder cell layers. Journal of Parasitology 75, 985989.CrossRefGoogle Scholar
Hornberg, J. J., Bruggeman, F. J., Bakker, B. M. and Westerhoff, H. V. (2007). Metabolic control analysis to identify optimal drug targets. Progress in Drug Research 64, 173189.Google ScholarPubMed
Hynne, F., Danø, S. and Sørensen, P. G. (2001). Full-scale model of glycolysis in Saccharomyces cerevisiae. Biophysical Chemistry 94, 121163.CrossRefGoogle ScholarPubMed
Kabani, S., Fenn, K., Ross, A., Ivens, A., Smith, T. K., Ghazal, P. and Matthews, K. (2009). Genome-wide expression profiling of in vivo-derived bloodstream parasite stages and dynamic analysis of mRNA alterations during synchronous differentiation in Trypanosoma brucei. BMC Genomics 10, 427.CrossRefGoogle ScholarPubMed
Kessler, P. S. and Parsons, M. (2005). Probing the role of compartmentation of glycolysis in procyclic form Trypanosoma brucei: RNA interference studies of PEX14, hexokinase and phosphofructokinase. Journal of Biological Chemistry 280, 90309036.CrossRefGoogle ScholarPubMed
Krauth-Siegel, R. L. and Comini, M. A. (2008). Redox control in trypanosomatids, parasitic protozoa with trypanothione-based thiol metabolism. Biochimica et Biophysica Acta 1780, 12361248CrossRefGoogle ScholarPubMed
Lee, J. H., Jung, H. S. and Gunzl, A. (2009). Transcriptionally active TFIIH of the early-diverged eukaryote Trypanosoma brucei harbors two novel core subunits but not a cyclin-activating kinase complex. Nucleic Acids Research 37, 38113820.CrossRefGoogle Scholar
Liang, X., Haritan, A., Uliel, S. and Michaeli, S. (2003). Trans and cis splicing in trypanosomatids: mechanism, factors, and regulation. Eukaryotic Cell 2, 830840.CrossRefGoogle ScholarPubMed
Lustig, Y., Sheiner, L., Vagima, Y., Goldshmidt, H., Das, A., Bellofatto, V. and Michaeli, S. (2007). Spliced-leader RNA silencing: a novel stress-induced mechanism in Trypanosoma brucei. EMBO Reports 8, 408413.CrossRefGoogle ScholarPubMed
Michels, P. A. M., Bringaud, F., Herman, M. and Hannaert, V. (2006). Metabolic functions of glycosomes in trypanosomatids. Biochimica et Biophysica Acta 1763, 14631477.CrossRefGoogle ScholarPubMed
Nikerel, I. E., van Winden, W. A., van Gulik, W. M. and Heijnen, J. J. (2006). A method for estimation of elasticities in metabolic networks using steady state and dynamic metabolomics data and linlog kinetics. BMC Bioinformatics 7, 540.CrossRefGoogle ScholarPubMed
Nikerel, I. E., van Winden, W. A., Verheijen, J. and Heijnen, J. J. (2009). Model reduction and a priori kinetic parameter identifiability analysis using metabolome time series for metabolic reaction networks with linlog kinetics. Metabolic Engineering 11, 2030.CrossRefGoogle Scholar
Opperdoes, F. R. and Borst, P. (1977). Localization of nine glycolytic enzymes in a microbody-like organelle in Trypanosoma brucei: the glycosome. FEBS Letters 80, 360364.CrossRefGoogle Scholar
Parsons, M. (2004). Glycosomes: parasites and the divergence of peroxisomal purpose. Molecular Microbiology 53, 717724.CrossRefGoogle ScholarPubMed
Palenchar, J. B. and Bellofatto, V. (2006). Gene transcription in trypanosomes. Molecular and Biochemical Parasitology 146, 135141.CrossRefGoogle ScholarPubMed
Paterou, A., Walrad, P., Craddy, P., Fenn, K. and Matthews, K. (2006). Identification and stage-specific association with the translational apparatus of TbZFP3, a ccch protein that promotes trypanosome life cycle development. Journal of Biological Chemistry 281, 3900239013.CrossRefGoogle ScholarPubMed
Queiroz, R., Benz, C., Fellenberg, K., Hoheisel, J. and Clayton, C. (2009). Transcriptome analysis of differentiating trypanosomes reveals the existence of multiple post-transcriptional regulons. BMC Genomics 10, 495.CrossRefGoogle ScholarPubMed
Resendis-Antonio, O. (2009). Filling kinetic gaps: dynamic modeling of metabolism where detailed kinetic information is lacking. PLoS One 4, e4967.CrossRefGoogle ScholarPubMed
Richard, P., Teusink, B., Hemker, M. B., van Dam, K. and Westerhoff, H. V. (1996). Sustained oscillations in free-energy state and hexose phosphates in yeast. Yeast 12, 731740.3.0.CO;2-Z>CrossRefGoogle ScholarPubMed
Rokka, A., Antonenkov, V. D., Soininen, R., Immonen, H. L., Pirilä, P. L., Bergmann, U., Sormunen, R. T., Weckström, M., Benz, R. and Hiltunen, J. K. (2009). Pxmp2 is a channel-forming protein in Mammalian peroxisomal membrane. PLoS One 4, e5090.CrossRefGoogle ScholarPubMed
Schmitz, J. P., Van Riel, N. A., Nicolay, K., Hilbers, P. A. and Jeneson, J. A. (2009). Silencing of glycolysis in muscle: experimental observation and numerical analysis. Experimental Physiology 95, 380397.CrossRefGoogle ScholarPubMed
Schuster, R. and Holzhütter, H. G. (1995). Use of mathematical models for predicting the metabolic effect of large-scale enzyme activity alterations. Application to enzyme deficiencies of red blood cells. European Journal of Biochemistry 229, 403418.Google ScholarPubMed
Siegel, T., Hekstra, D., Kemp, L., Figueiredo, L., Lowell, J., Fenyo, D., Wang, X., Dewell, S. and Cross, G. (2009). Four histone variants mark the boundaries of polycistronic transcription units in Trypanosoma brucei. Genes & Development 23, 10631076.CrossRefGoogle ScholarPubMed
Smallbone, K., Simeonidis, E., Broomhead, D. S. and Kell, D. B. (2007). Something from nothing: bridging the gap between constraint-based and kinetic modelling. FEBS Journal 274, 55765585.CrossRefGoogle Scholar
Snoep, J. L., Bruggeman, F., Olivier, B. G. and Westerhoff, H. V. (2006). Towards building the silicon cell: a modular approach. Biosystems 83, 207216.CrossRefGoogle ScholarPubMed
Stern, M., Gupta, S., Salmon-Divon, M., Haham, T., Barda, O., Levi, S., Wachtel, C., Nilsen, T. and Michaeli, S. (2009). Multiple roles for polypyrimidine tract binding (PTB) proteins in trypanosome RNA metabolism. RNA 15, 648665.CrossRefGoogle ScholarPubMed
Teusink, B., Walsh, M. C., Van Dam, K. and Westerhoff, H. V. (1998). The danger of metabolic pathways with turbo design. Trends in Biochemical Sciences 23, 162169.CrossRefGoogle ScholarPubMed
Walrad, P., Paterou, A., Acosta-Serrano, A. and Matthews, K. R. (2009). Differential trypanosome surface coat regulation by a CCCH protein that co-associates with procyclin mRNA cis-elements. PLoS Pathogens 5, e1000317.CrossRefGoogle ScholarPubMed
Westerhoff, H. V., Kolodkin, A., Conradie, R., Wilkinson, S. J., Bruggeman, F. J., Krab, K., Van Schuppen, J. H., Hardin, H., Bakker, B. M., Moné, M. J., Rybakova, K. N., Eijken, M., Van Leeuwen, H. J. and Snoep, J. L. (2009). Sytems biology towards life in silico: mathematics of the control of living cells. Journal of Mathematical Biology 58, 7–34.CrossRefGoogle Scholar
Westerhoff, H. V., Koster, J. G., Van Workum, M. and Rudd, K. E. (1990). On the control of gene expression. In Control of Metabolic Processes (ed. Cornish-Bowden, A. and Cardenas, M.-L.), pp. 399412. Plenum Press, New York.CrossRefGoogle Scholar
Xiao, Y., McCloskey, D. E. and Phillips, M. A. (2009). RNA interference-mediated silencing of ornithine decarboxylase and spermidine synthase genes in Trypanosoma brucei provides insight into regulation of polyamine biosynthesis. Eukaryotic Cell 8, 747755.CrossRefGoogle ScholarPubMed