Login Register Cart 0
Generic placeholder image

Current Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe Translate in Chinese
Review Article

Drug Target Selection for Trypanosoma cruzi Metabolism by Metabolic Control Analysis and Kinetic Modeling

Author(s): Emma Saavedra*, Zabdi González-Chávez, Rafael Moreno-Sánchez and Paul A.M. Michels*

Volume 26, Issue 36, 2019

Page: [6652 - 6671] Pages: 20

DOI: 10.2174/0929867325666180917104242

Price: $65

Abstract

In the search for therapeutic targets in the intermediary metabolism of trypanosomatids the gene essentiality criterion as determined by using knock-out and knock-down genetic strategies is commonly applied. As most of the evaluated enzymes/transporters have turned out to be essential for parasite survival, additional criteria and approaches are clearly required for suitable drug target prioritization. The fundamentals of Metabolic Control Analysis (MCA; an approach in the study of control and regulation of metabolism) and kinetic modeling of metabolic pathways (a bottom-up systems biology approach) allow quantification of the degree of control that each enzyme exerts on the pathway flux (flux control coefficient) and metabolic intermediate concentrations (concentration control coefficient). MCA studies have demonstrated that metabolic pathways usually have two or three enzymes with the highest control of flux; their inhibition has more negative effects on the pathway function than inhibition of enzymes exerting low flux control. Therefore, the enzymes with the highest pathway control are the most convenient targets for therapeutic intervention. In this review, the fundamentals of MCA as well as experimental strategies to determine the flux control coefficients and metabolic modeling are analyzed. MCA and kinetic modeling have been applied to trypanothione metabolism in Trypanosoma cruzi and the model predictions subsequently validated in vivo. The results showed that three out of ten enzyme reactions analyzed in the T. cruzi anti-oxidant metabolism were the most controlling enzymes. Hence, MCA and metabolic modeling allow a further step in target prioritization for drug development against trypanosomatids and other parasites.

Keywords: Metabolic control analysis, drug target, flux-control coefficient, systems biology, metabolic modeling, kinetic modeling, trypanothione, glycolysis.

« Previous Next »
[1]
World Health Organization. Chagas disease in Latin America: an epidemiological update based on 2010 estimates. Wkly. Epidemiol. Rec., 2015, 90(6), 33-43.
[PMID: 25671846]
[2]
Drugs for Neglected Diseases initiative. Available at. https://www.dndi.org/diseases-projects/chagas/ (Accessed June 2018)
[3]
Coura, J.R. The main sceneries of Chagas disease transmission. The vectors, blood and oral transmissions--a comprehensive review. Mem. Inst. Oswaldo Cruz, 2015, 110(3), 277-282.
[http://dx.doi.org/10.1590/0074-0276140362] [PMID: 25466622]
[4]
Coura, J.R.; Viñas, P.A.; Junqueira, A.C. Ecoepidemiology, short history and control of Chagas disease in the endemic countries and the new challenge for non-endemic countries. Mem. Inst. Oswaldo Cruz, 2014, 109(7), 856-862.
[http://dx.doi.org/10.1590/0074-0276140236] [PMID: 25410988]
[5]
Rassi, A., Jr; Rassi, A.; Marin-Neto, J.A. Chagas disease. Lancet, 2010, 375(9723), 1388-1402.
[http://dx.doi.org/10.1016/S0140-6736(10)60061-X] [PMID: 20399979]
[6]
Pérez-Molina, J.A.; Molina, I. Chagas disease. Lancet, 2018, 391(10115), 82-94.
[http://dx.doi.org/10.1016/S0140-6736(17)31612-4] [PMID: 28673423]
[7]
Drugs for Neglected Diseases initiative. Available at. www.dndi.org/wp-content/uploads/2017/08/Factsheet_2016_Chagas.pdf (Last accessed January 2018)
[8]
Marin-Neto, J.A.; Rassi, A., Jr; Morillo, C.A.; Avezum, A.; Connolly, S.J.; Sosa-Estani, S.; Rosas, F.; Yusuf, S. BENEFIT Investigators. Rationale and design of a randomized placebo-controlled trial assessing the effects of etiologic treatment in Chagas’ cardiomyopathy: the BENznidazole evaluation for interrupting trypanosomiasis (BENEFIT). Am. Heart J., 2008, 156(1), 37-43.
[http://dx.doi.org/10.1016/j.ahj.2008.04.001] [PMID: 18585495]
[9]
Rassi, A., Jr; Marin, J.A.; Rassi, A. Chronic Chagas cardiomyopathy: a review of the main pathogenic mechanisms and the efficacy of aetiological treatment following the BENznidazole evaluation for interrupting trypanosomiasis (BENEFIT) trial. Mem. Inst. Oswaldo Cruz, 2017, 112(3), 224-235.
[http://dx.doi.org/10.1590/0074-02760160334] [PMID: 28225900]
[10]
Pecoul, B.; Batista, C.; Stobbaerts, E.; Ribeiro, I.; Vilasanjuan, R.; Gascon, J.; Pinazo, M.J.; Moriana, S.; Gold, S.; Pereiro, A.; Navarro, M.; Torrico, F.; Bottazzi, M.E.; Hotez, P.J. The BENEFIT trial: Where do we go from here? PLoS Negl. Trop. Dis., 2016, 10(2)e0004343
[http://dx.doi.org/10.1371/journal.pntd.0004343] [PMID: 26913759]
[11]
Castro, J.A.; de Mecca, M.M.; Bartel, L.C. Toxic side effects of drugs used to treat Chagas’ disease (American trypanosomiasis). Hum. Exp. Toxicol., 2006, 25(8), 471-479.
[http://dx.doi.org/10.1191/0960327106het653oa] [PMID: 16937919]
[12]
Rodriques Coura, J.; de Castro, S.L. A critical review on Chagas disease chemotherapy. Mem. Inst. Oswaldo Cruz, 2002, 97(1), 3-24.
[http://dx.doi.org/10.1590/S0074-02762002000100001] [PMID: 11992141]
[13]
Chatelain, E. Chagas disease drug discovery: toward a new era. J. Biomol. Screen., 2015, 20(1), 22-35.
[http://dx.doi.org/10.1177/1087057114550585] [PMID: 25245987]
[14]
Duschak, V.G. Targets and patented drugs for chemotherapy of Chagas disease in the last 15 years-period. Recent Pat Antiinfect Drug Discov, 2016, 11(2), 74-173.
[http://dx.doi.org/10.2174/1574891X11666161024165304] [PMID: 27784230]
[15]
Paucar, R.; Moreno-Viguri, E.; Pérez-Silanes, S. Challenges in chagas disease drug discovery: a review. Curr. Med. Chem., 2016, 23(28), 3154-3170.
[http://dx.doi.org/10.2174/0929867323999160625124424] [PMID: 27356544]
[16]
Field, M.C.; Horn, D.; Fairlamb, A.H.; Ferguson, M.A.J.; Gray, D.W.; Read, K.D.; De Rycker, M.; Torrie, L.S.; Wyatt, P.G.; Wyllie, S.; Gilbert, I.H. Anti-trypanosomatid drug discovery: an ongoing challenge and a continuing need. Nat. Rev. Microbiol., 2017, 15(4), 217-231.
[http://dx.doi.org/10.1038/nrmicro.2016.193] [PMID: 28239154]
[17]
Jones, N.G.; Catta-Preta, C.M.C.; Lima, A.P.C.A.; Mottram, J.C. Genetically validated drug targets in Leishmania; Current knowledge and future prospects. ACS Infect. Dis., 2018, 4(4), 467-477.
[http://dx.doi.org/10.1021/acsinfecdis.7b00244] [PMID: 29384366]
[18]
Glover, L.; Alsford, S.; Baker, N.; Turner, D.J.; Sanchez-Flores, A.; Hutchinson, S.; Hertz-Fowler, C.; Berriman, M.; Horn, D. Genome-scale RNAi screens for high-throughput phenotyping in bloodstream-form African trypanosomes. Nat. Protoc., 2015, 10(1), 106-133.
[http://dx.doi.org/10.1038/nprot.2015.005] [PMID: 25502887]
[19]
Peng, D.; Kurup, S.P.; Yao, P.Y.; Minning, T.A.; Tarleton, R.L. CRISPR-Cas9-mediated single-gene and gene family disruption in Trypanosoma cruzi. MBio, 2014, 6(1), e02097-e14.
[http://dx.doi.org/10.1128/mBio.02097-14] [PMID: 25550322]
[20]
Romagnoli, B.A.A.; Picchi, G.F.A.; Hiraiwa, P.M.; Borges, B.S.; Alves, L.R.; Goldenberg, S. Improvements in the CRISPR/Cas9 system for high efficiency gene disruption in Trypanosoma cruzi. Acta Trop., 2018, 178, 190-195.
[http://dx.doi.org/10.1016/j.actatropica.2017.11.013] [PMID: 29174293]
[21]
Krauth-Siegel, R.L.; Comini, M.A. Redox control in trypanosomatids, parasitic protozoa with trypanothione-based thiol metabolism. Biochim. Biophys. Acta, 2008, 1780(11), 1236-1248.
[http://dx.doi.org/10.1016/j.bbagen.2008.03.006] [PMID: 18395526]
[22]
Irigoín, F.; Cibils, L.; Comini, M.A.; Wilkinson, S.R.; Flohé, L.; Radi, R. Insights into the redox biology of Trypanosoma cruzi: Trypanothione metabolism and oxidant detoxification. Free Radic. Biol. Med., 2008, 45(6), 733-742.
[http://dx.doi.org/10.1016/j.freeradbiomed.2008.05.028] [PMID: 18588970]
[23]
Olin-Sandoval, V.; Moreno-Sánchez, R.; Saavedra, E. Targeting trypanothione metabolism in trypanosomatid human parasites. Curr. Drug Targets, 2010, 11(12), 1614-1630.
[http://dx.doi.org/10.2174/1389450111009011614] [PMID: 20735352]
[24]
Gilbert, I.H. Target-based drug discovery for human African trypanosomiasis: selection of molecular target and chemical matter. Parasitology, 2014, 141(1), 28-36.
[http://dx.doi.org/10.1017/S0031182013001017] [PMID: 23931634]
[25]
Bakker, B.M.; Westerhoff, H.V.; Opperdoes, F.R.; Michels, P.A. Metabolic control analysis of glycolysis in trypanosomes as an approach to improve selectivity and effectiveness of drugs. Mol. Biochem. Parasitol., 2000, 106(1), 1-10.
[http://dx.doi.org/10.1016/S0166-6851(99)00197-8] [PMID: 10743606]
[26]
Hornberg, J.J.; Bruggeman, F.J.; Bakker, B.M.; Westerhoff, H.V. Metabolic control analysis to identify optimal drug targets. Prog. Drug Res., 2007, 64, 171-, 173-189.
[http://dx.doi.org/10.1007/978-3-7643-7567-6_7] [PMID: 17195475]
[27]
Moreno-Sánchez, R.; Saavedra, E.; Rodríguez-Enríquez, S.; Olín-Sandoval, V. Metabolic control analysis: a tool for designing strategies to manipulate metabolic pathways. J. Biomed. Biotechnol., 2008, 2008597913
[http://dx.doi.org/10.1155/2008/597913] [PMID: 18629230]
[28]
Saavedra, E.; Rodríguez-Enríquez, S.; Quezada, H.; Jasso-Chávez, R.; Moreno-Sánchez, R. Rational design of strategies based on Metabolic Control Analysis for successful manipulation of pathways and cellular processes.In: Comprehensive Biotechnology; Moo-Young, M., Ed.; Elsevier: Amsterdam, 2011, Vol. 1, pp. 511-524.
[http://dx.doi.org/10.1016/B978-0-08-088504-9.00061-1]
[29]
Saavedra, E.; Moreno-Sánchez, R. Metabolic Control Analysis, drug target identification.In: Encyclopedia of Systems Biology; Dubitzky, W.; Wolkenhauer, O.; Cho, K.; Yokota, H.Y., Eds.; Springer-Verlag: New York, 2013, pp. 1234-1239.
[http://dx.doi.org/10.1007/978-1-4419-9863-7_1162]
[30]
Fell, D. Understanding the control of metabolism; Portland Press: London, 1997.
[31]
Sauro, H.M. Control and regulation of pathways via negative feedback. J. R. Soc. Interface, 2017, 14(127)pii 20160848
[http://dx.doi.org/10.1098/rsif.2016.0848] [PMID: 28202588]
[32]
Cazzulo, J.J.; Franke de Cazzulo, B.M.; Engel, J.C.; Cannata, J.J. End products and enzyme levels of aerobic glucose fermentation in trypanosomatids. Mol. Biochem. Parasitol., 1985, 16(3), 329-343.
[http://dx.doi.org/10.1016/0166-6851(85)90074-X] [PMID: 3903497]
[33]
Marín-Hernández, A.; Gallardo-Pérez, J.C.; Rodríguez-Enríquez, S.; Encalada, R.; Moreno-Sánchez, R.; Saavedra, E. Modeling cancer glycolysis. Biochim. Biophys. Acta, 2011, 1807(6), 755-767.
[http://dx.doi.org/10.1016/j.bbabio.2010.11.006] [PMID: 21110941]
[34]
Teusink, B.; Passarge, J.; Reijenga, C.A.; Esgalhado, E.; van der Weijden, C.C.; Schepper, M.; Walsh, M.C.; Bakker, B.M.; van Dam, K.; Westerhoff, H.V.; Snoep, J.L. Can yeast glycolysis be understood in terms of in vitro kinetics of the constituent enzymes? Testing biochemistry. Eur. J. Biochem., 2000, 267(17), 5313-5329.
[http://dx.doi.org/10.1046/j.1432-1327.2000.01527.x] [PMID: 10951190]
[35]
Nelson, D.L.; Cox, M.M. Lehninger Principles of Biochemistry, 6th ed; W.H. Freeman: New York, 2008.
[36]
Saavedra, E. Moreno-Sánchez, R. Metabolic Control Theory.In: Encyclopedia of Systems Biology; Dubitzky, W.; Wolkenhauer, O.; Cho, K.; Yokota, H.Y., Eds.; Springer-Verlag: New York, 2013, pp. 1239-1243.
[http://dx.doi.org/10.1007/978-1-4419-9863-7_1161]
[37]
Kacser, H.; Burns, J.A. The control of flux. Symp. Soc. Exp. Biol., 1973, 27, 65-104.
[PMID: 4148886]
[38]
Kacser, H.; Burns, J.A. The control of flux. Biochem. Soc. Trans., 1995, 23(2), 341-366.
[http://dx.doi.org/10.1042/bst0230341] [PMID: 7672373]
[39]
Heinrich, R.; Rapoport, T.A. A linear steady-state treatment of enzymatic chains. General properties, control and effector strength. Eur. J. Biochem., 1974, 42(1), 89-95.
[http://dx.doi.org/10.1111/j.1432-1033.1974.tb03318.x] [PMID: 4830198]
[40]
Moreno-Sánchez, R.; Saavedra, E.; Gallardo-Pérez, J.C.; Rumjanek, F.D.; Rodríguez-Enríquez, S. Understanding the cancer cell phenotype beyond the limitations of current omics analyses. FEBS J., 2016, 283(1), 54-73.
[http://dx.doi.org/10.1111/febs.13535] [PMID: 26417966]
[41]
Krauth-Siegel, R.L.; Leroux, A.E. Low-molecular-mass antioxidants in parasites. Antioxid. Redox Signal., 2012, 17(4), 583-607.
[http://dx.doi.org/10.1089/ars.2011.4392] [PMID: 22053812]
[42]
Manta, B.; Comini, M.; Medeiros, A.; Hugo, M.; Trujillo, M.; Radi, R. Trypanothione: a unique bis-glutathionyl derivative in trypanosomatids. Biochim. Biophys. Acta, 2013, 1830(5), 3199-3216.
[http://dx.doi.org/10.1016/j.bbagen.2013.01.013] [PMID: 23396001]
[43]
Flohé, L. The trypanothione system and the opportunities it offers to create drugs for the neglected kinetoplast diseases. Biotechnol. Adv., 2012, 30(1), 294-301.
[http://dx.doi.org/10.1016/j.biotechadv.2011.05.012] [PMID: 21620942]
[44]
Leroux, A.E.; Krauth-Siegel, R.L. Thiol redox biology of trypanosomatids and potential targets for chemotherapy. Mol. Biochem. Parasitol., 2016, 206(1-2), 67-74.
[http://dx.doi.org/10.1016/j.molbiopara.2015.11.003] [PMID: 26592324]
[45]
Torres, N.V.; Souto, R.; Meléndez-Hevia, E. Study of the flux and transition time control coefficient profiles in a metabolic system in vitro and the effect of an external stimulator. Biochem. J., 1989, 260(3), 763-769.
[http://dx.doi.org/10.1042/bj2600763] [PMID: 2764903]
[46]
Giersch, C. Determining elasticities from multiple measurements of flux rates and metabolite concentrations. Application of the multiple modulation method to a reconstituted pathway. Eur. J. Biochem., 1995, 227(1-2), 194-201.
[http://dx.doi.org/10.1111/j.1432-1033.1995.tb20376.x] [PMID: 7851386]
[47]
Moreno-Sánchez, R.; Encalada, R.; Marín-Hernández, A.; Saavedra, E. Experimental validation of metabolic pathway modeling. FEBS J., 2008, 275(13), 3454-3469.
[http://dx.doi.org/10.1111/j.1742-4658.2008.06492.x] [PMID: 18510554]
[48]
González-Chávez, Z.; Olin-Sandoval, V.; Rodíguez-Zavala, J.S.; Moreno-Sánchez, R.; Saavedra, E. Metabolic control analysis of the Trypanosoma cruzi peroxide detoxification pathway identifies tryparedoxin as a suitable drug target. Biochim. Biophys. Acta, 2015, 1850(2), 263-273.
[http://dx.doi.org/10.1016/j.bbagen.2014.10.029] [PMID: 25450181]
[49]
van Dam, K.; van der Vlag, J.; Kholodenko, B.N.; Westerhoff, H.V. The sum of the control coefficients of all enzymes on the flux through a group-transfer pathway can be as high as two. Eur. J. Biochem., 1993, 212(3), 791-799.
[http://dx.doi.org/10.1111/j.1432-1033.1993.tb17720.x] [PMID: 8462550]
[50]
Vázquez, K.; Paulino, M.; Salas, C.O.; Zarate-Ramos, J.J.; Vera, B.; Rivera, G. Trypanothione reductase: A target for the development of anti-Trypanosoma cruzi drugs. Mini Rev. Med. Chem., 2017, 17(11), 939-946.
[http://dx.doi.org/10.2174/1389557517666170315145410] [PMID: 28302040]
[51]
Colotti, G.; Baiocco, P.; Fiorillo, A.; Boffi, A.; Poser, E.; Chiaro, F.D.; Ilari, A. Structural insights into the enzymes of the trypanothione pathway: targets for antileishmaniasis drugs. Future Med. Chem., 2013, 5(15), 1861-1875.
[http://dx.doi.org/10.4155/fmc.13.146] [PMID: 24144416]
[52]
Bernardes, L.S.; Zani, C.L.; Carvalho, I. Trypanosomatidae diseases: from the current therapy to the efficacious role of trypanothione reductase in drug discovery. Curr. Med. Chem., 2013, 20(21), 2673-2696.
[http://dx.doi.org/10.2174/0929867311320210005] [PMID: 23410156]
[53]
Westerhoff, H.V. Systems biology left and right. Methods Enzymol., 2011, 500, 3-11.
[http://dx.doi.org/10.1016/B978-0-12-385118-5.00001-3] [PMID: 21943889]
[54]
Honigmann, A.; Nadler, A. The next frontier: Quantitative biochemistry in living cells. Biochemistry, 2018, 57(1), 47-55.
[http://dx.doi.org/10.1021/acs.biochem.7b01060] [PMID: 29200271]
[55]
Westerhoff, H.V.; Nakayama, S.; Mondeel, T.D.; Barberis, M. Systems Pharmacology: An opinion on how to turn the impossible into grand challenges. Drug Discov. Today. Technol., 2015, 15, 23-31.
[http://dx.doi.org/10.1016/j.ddtec.2015.06.006] [PMID: 26464087]
[56]
Haanstra, J.R.; Bakker, B.M. Drug target identification through systems biology. Drug Discov. Today. Technol., 2015, 15, 17-22.
[http://dx.doi.org/10.1016/j.ddtec.2015.06.002] [PMID: 26464086]
[57]
Bruggeman, F.J.; Westerhoff, H.V. The nature of systems biology. Trends Microbiol., 2007, 15(1), 45-50.
[http://dx.doi.org/10.1016/j.tim.2006.11.003] [PMID: 17113776]
[58]
Saa, P.A.; Nielsen, L.K. Formulation, construction and analysis of kinetic models of metabolism: A review of modelling frameworks. Biotechnol. Adv., 2017, 35(8), 981-1003.
[http://dx.doi.org/10.1016/j.biotechadv.2017.09.005] [PMID: 28916392]
[59]
Segel, I.H. Enzyme Kinetics; Wiley: New York, 1975.
[60]
Tummler, K.; Lubitz, T.; Schelker, M.; Klipp, E. New types of experimental data shape the use of enzyme kinetics for dynamic network modeling. FEBS J., 2014, 281(2), 549-571.
[http://dx.doi.org/10.1111/febs.12525] [PMID: 24034816]
[61]
Hoops, S.; Sahle, S.; Gauges, R.; Lee, C.; Pahle, J.; Simus, N.; Singhal, M.; Xu, L.; Mendes, P.; Kummer, U. COPASI--a COmplex PAthway SImulator. Bioinformatics, 2006, 22(24), 3067-3074.
[http://dx.doi.org/10.1093/bioinformatics/btl485] [PMID: 17032683]
[62]
Olivier, B.G.; Rohwer, J.M.; Hofmeyr, J.H. Modelling cellular systems with PySCeS. Bioinformatics, 2005, 21(4), 560-561.
[http://dx.doi.org/10.1093/bioinformatics/bti046] [PMID: 15454409]
[63]
Christensen, C.D.; Hofmeyr, J.S.; Rohwer, J.M. PySCeSToolbox: a collection of metabolic pathway analysis tools. Bioinformatics, 2018, 34(1), 124-125.
[http://dx.doi.org/10.1093/bioinformatics/btx567] [PMID: 28968872]
[64]
Adamczyk, M.; van Eunen, K.; Bakker, B.M.; Westerhoff, H.V. Enzyme kinetics for systems biology when, why and how. Methods Enzymol., 2011, 500, 233-257.
[http://dx.doi.org/10.1016/B978-0-12-385118-5.00013-X] [PMID: 21943901]
[65]
van Eunen, K.; Kiewiet, J.A.; Westerhoff, H.V.; Bakker, B.M. Testing biochemistry revisited: how in vivo metabolism can be understood from in vitro enzyme kinetics. PLOS Comput. Biol., 2012, 8(4)e1002483
[http://dx.doi.org/10.1371/journal.pcbi.1002483] [PMID: 22570597]
[66]
Rapoport, T.A.; Heinrich, R.; Jacobasch, G.; Rapoport, S. A linear steady-state treatment of enzymatic chains. A mathematical model of glycolysis of human erythrocytes. Eur. J. Biochem., 1974, 42(1), 107-120.
[http://dx.doi.org/10.1111/j.1432-1033.1974.tb03320.x] [PMID: 4364392]
[67]
du Preez, F.B.; Conradie, R.; Penkler, G.P.; Holm, K.; van Dooren, F.L.; Snoep, J.L. A comparative analysis of kinetic models of erythrocyte glycolysis. J. Theor. Biol., 2008, 252(3), 488-496.
[http://dx.doi.org/10.1016/j.jtbi.2007.10.006] [PMID: 18031761]
[68]
Smallbone, K.; Messiha, H.L.; Carroll, K.M.; Winder, C.L.; Malys, N.; Dunn, W.B.; Murabito, E.; Swainston, N.; Dada, J.O.; Khan, F.; Pir, P.; Simeonidis, E.; Spasić, I.; Wishart, J.; Weichart, D.; Hayes, N.W.; Jameson, D.; Broomhead, D.S.; Oliver, S.G.; Gaskell, S.J.; McCarthy, J.E.; Paton, N.W.; Westerhoff, H.V.; Kell, D.B.; Mendes, P. A model of yeast glycolysis based on a consistent kinetic characterisation of all its enzymes. FEBS Lett., 2013, 587(17), 2832-2841.
[http://dx.doi.org/10.1016/j.febslet.2013.06.043] [PMID: 23831062]
[69]
Bakker, B.M.; Michels, P.A.; Opperdoes, F.R.; Westerhoff, H.V. What controls glycolysis in bloodstream form Trypanosoma brucei? J. Biol. Chem., 1999, 274(21), 14551-14559.
[http://dx.doi.org/10.1074/jbc.274.21.14551] [PMID: 10329645]
[70]
Haanstra, J.R.; Gerding, A.; Dolga, A.M.; Sorgdrager, F.J.H.; Buist-Homan, M.; du Toit, F.; Faber, K.N.; Holzhütter, H.G.; Szöör, B.; Matthews, K.R.; Snoep, J.L.; Westerhoff, H.V.; Bakker, B.M. Targeting pathogen metabolism without collateral damage to the host. Sci. Rep., 2017, 7, 40406.
[http://dx.doi.org/10.1038/srep40406] [PMID: 28084422]
[71]
Saavedra, E.; Marín-Hernández, A.; Encalada, R.; Olivos, A.; Mendoza-Hernández, G.; Moreno-Sánchez, R. Kinetic modeling can describe in vivo glycolysis in Entamoeba histolytica. FEBS J., 2007, 274(18), 4922-4940.
[http://dx.doi.org/10.1111/j.1742-4658.2007.06012.x] [PMID: 17824961]
[72]
Penkler, G.; du Toit, F.; Adams, W.; Rautenbach, M.; Palm, D.C.; van Niekerk, D.D.; Snoep, J.L. Construction and validation of a detailed kinetic model of glycolysis in Plasmodium falciparum. FEBS J., 2015, 282(8), 1481-1511.
[http://dx.doi.org/10.1111/febs.13237] [PMID: 25693925]
[73]
van Niekerk, D.D.; Penkler, G.P.; du Toit, F.; Snoep, J.L. Targeting glycolysis in the malaria parasite Plasmodium falciparum. FEBS J., 2016, 283(4), 634-646.
[http://dx.doi.org/10.1111/febs.13615] [PMID: 26648082]
[74]
Marín-Hernández, A.; López-Ramírez, S.Y.; Del Mazo-Monsalvo, I.; Gallardo-Pérez, J.C.; Rodríguez-Enríquez, S.; Moreno-Sánchez, R.; Saavedra, E. Modeling cancer glycolysis under hypoglycemia, and the role played by the differential expression of glycolytic isoforms. FEBS J., 2014, 281(15), 3325-3345.
[http://dx.doi.org/10.1111/febs.12864] [PMID: 24912776]
[75]
Olin-Sandoval, V.; González-Chávez, Z.; Berzunza-Cruz, M.; Martínez, I.; Jasso-Chávez, R.; Becker, I.; Espinoza, B.; Moreno-Sánchez, R.; Saavedra, E. Drug target validation of the trypanothione pathway enzymes through metabolic modelling. FEBS J., 2012, 279(10), 1811-1833.
[http://dx.doi.org/10.1111/j.1742-4658.2012.08557.x] [PMID: 22394478]
[76]
Marín-Hernández, Á.; Rodríguez-Zavala, J.S.; Del Mazo-Monsalvo, I.; Rodríguez-Enríquez, S.; Moreno-Sánchez, R.; Saavedra, E. Inhibition of non-flux-controlling enzymes deters cancer glycolysis by accumulation of regulatory metabolites of controlling steps. Front. Physiol., 2016, 7, 412.
[http://dx.doi.org/10.3389/fphys.2016.00412] [PMID: 27721794]
[77]
Flint, H.J.; Tateson, R.W.; Barthelmess, I.B.; Porteous, D.J.; Donachie, W.D.; Kacser, H. Control of the flux in the arginine pathway of Neurospora crassa. Modulations of enzyme activity and concentration. Biochem. J., 1981, 200(2), 231-246.
[http://dx.doi.org/10.1042/bj2000231] [PMID: 6462136]
[78]
Albert, M.A.; Haanstra, J.R.; Hannaert, V.; Van Roy, J.; Opperdoes, F.R.; Bakker, B.M.; Michels, P.A. Experimental and in silico analyses of glycolytic flux control in bloodstream form Trypanosoma brucei. J. Biol. Chem., 2005, 280(31), 28306-28315.
[http://dx.doi.org/10.1074/jbc.M502403200] [PMID: 15955817]
[79]
Vázquez, C.; Mejia-Tlachi, M.; González-Chávez, Z.; Silva, A.; Rodríguez-Zavala, J.S.; Moreno-Sánchez, R.; Saavedra, E. Buthionine sulfoximine is a multitarget inhibitor of trypanothione synthesis in Trypanosoma cruzi. FEBS Lett., 2017, 591(23), 3881-3894.
[http://dx.doi.org/10.1002/1873-3468.12904] [PMID: 29127710]
[80]
Ma, Y.F.; Weiss, L.M.; Huang, H. A method for rapid regulation of protein expression in Trypanosoma cruzi. Int. J. Parasitol., 2012, 42(1), 33-37.
[http://dx.doi.org/10.1016/j.ijpara.2011.11.002] [PMID: 22138018]
[81]
Lisvane Silva, P.; Mantilla, B.S.; Barisón, M.J.; Wrenger, C.; Silber, A.M. The uniqueness of the Trypanosoma cruzi mitochondrion: opportunities to identify new drug target for the treatment of Chagas disease. Curr. Pharm. Des., 2011, 17(20), 2074-2099.
[http://dx.doi.org/10.2174/138161211796904786] [PMID: 21718252]
[82]
Menna-Barreto, R.F.; de Castro, S.L. The double-edged sword in pathogenic trypanosomatids: the pivotal role of mitochondria in oxidative stress and bioenergetics. BioMed Res. Int., 2014.2014614014
[http://dx.doi.org/10.1155/2014/614014] [PMID: 24800243]
[83]
Brown, G.C.; Hafner, R.P.; Brand, M.D.A.A. ‘top-down’ approach to the determination of control coefficients in metabolic control theory. Eur. J. Biochem., 1990, 188(2), 321-325.
[http://dx.doi.org/10.1111/j.1432-1033.1990.tb15406.x] [PMID: 2156699]
[84]
Brand, M.D. Top-down elasticity analysis and its application to energy metabolism in isolated mitochondria and intact cells. Mol. Cell. Biochem., 1998, 184(1-2), 13-20.
[http://dx.doi.org/10.1023/A:1006893619101] [PMID: 9746309]
[85]
Groen, A.K.; van Roermund, C.W.; Vervoorn, R.C.; Tager, J.M. Control of gluconeogenesis in rat liver cells. Flux control coefficients of the enzymes in the gluconeogenic pathway in the absence and presence of glucagon. Biochem. J., 1986, 237(2), 379-389.
[http://dx.doi.org/10.1042/bj2370379] [PMID: 3800895]
[86]
Marín-Hernández, A.; Rodríguez-Enríquez, S.; Vital-González, P.A.; Flores-Rodríguez, F.L.; Macías-Silva, M.; Sosa-Garrocho, M.; Moreno-Sánchez, R. Determining and understanding the control of glycolysis in fast-growth tumor cells. Flux control by an over-expressed but strongly product-inhibited hexokinase. FEBS J., 2006, 273(9), 1975-1988.
[http://dx.doi.org/10.1111/j.1742-4658.2006.05214.x] [PMID: 16640561]
[87]
Pineda, E.; Encalada, R.; Vázquez, C.; Néquiz, M.; Olivos-García, A.; Moreno-Sánchez, R.; Saavedra, E. In vivo identification of the steps that control energy metabolism and survival of Entamoeba histolytica. FEBS J., 2015, 282(2), 318-331.
[http://dx.doi.org/10.1111/febs.13131] [PMID: 25350227]
[88]
Moreno-Sánchez, R.; Saavedra, E.; Rodríguez-Enríquez, S.; Gallardo-Pérez, J.C.; Quezada, H.; Westerhoff, H.V. Metabolic control analysis indicates a change of strategy in the treatment of cancer. Mitochondrion, 2010, 10(6), 626-639.
[http://dx.doi.org/10.1016/j.mito.2010.06.002] [PMID: 20599628]
[89]
Wyatt, P.G.; Gilbert, I.H.; Read, K.D.; Fairlamb, A.H. Target validation: linking target and chemical properties to desired product profile. Curr. Top. Med. Chem., 2011, 11(10), 1275-1283.
[http://dx.doi.org/10.2174/156802611795429185] [PMID: 21401506]

Rights & Permissions Print Cite
Article Metrics
29
3
© 2024 Bentham Science Publishers | Privacy Policy