Network-based assessment of the selectivity of metabolic drug targets in Plasmodium falciparum with respect to human liver metabolism

BMC Systems Biology

Hermann-Georg Holzhütter¹  Andreas Hoppe¹  Susanna Bazzani¹ 

[1] Institut für Biochemie, Charite-Universitätsmedizin, Reinickendorfer Str. 61, Haus 10, 13347 Berlin

关键词: Flux balance analysis;    Reduced fitness;    Genome-scale networks;    Drug selectivity;    Drug targets;    Human hepatocyte;    Plasmodium falciparum;   

Others  :  1143656
DOI  :  10.1186/1752-0509-6-118

 received in 2012-03-28, accepted in 2012-07-23,  发布年份 2012

【 摘 要 】

Background

The search for new drug targets for antibiotics against Plasmodium falciparum, a major cause of human deaths, is a pressing scientific issue, as multiple resistance strains spread rapidly. Metabolic network-based analyses may help to identify those parasite’s essential enzymes whose homologous counterparts in the human host cells are either absent, non-essential or relatively less essential.

Results

Using the well-curated metabolic networks PlasmoNet of the parasite Plasmodium falciparum and HepatoNet1 of the human hepatocyte, the selectivity of 48 experimental antimalarial drug targets was analyzed. Applying in silico gene deletions, 24 of these drug targets were found to be perfectly selective, in that they were essential for the parasite but non-essential for the human cell. The selectivity of a subset of enzymes, that were essential in both models, was evaluated with the reduced fitness concept. It was, then, possible to quantify the reduction in functional fitness of the two networks under the progressive inhibition of the same enzymatic activity. Overall, this in silico analysis provided a selectivity ranking that was in line with numerous in vivo and in vitro observations.

Conclusions

Genome-scale models can be useful to depict and quantify the effects of enzymatic inhibitions on the impaired production of biomass components. From the perspective of a host-pathogen metabolic interaction, an estimation of the drug targets-induced consequences can be beneficial for the development of a selective anti-parasitic drug.

【 授权许可】

   
2012 Bazzani et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]Lin Z, Will Y: Evaluation of Drugs with Specific Organ Toxicities in Organ Specific Cell Lines. Toxicol Sci 2012, 126(1):114-27. [ http://view.ncbi.nlm.nih.gov/pubmed/22166485 webcite]
• [2]Armstrong PB: Proteases and protease inhibitors: a balance of activities in host-pathogen interaction. Immunobiology 2006, 211(4):263-81. [ http://view.ncbi.nlm.nih.gov/pubmed/16697919 webcite]
• [3]Singh VK, Ghosh I: Kinetic modeling of tricarboxylic acid cycle and glyoxylate bypass in Mycobacterium tuberculosis, and its application to assessment of drug targets. Theor Biol Med Model 2006, 3:27. [ http://view.ncbi.nlm.nih.gov/pubmed/16887020 webcite] BioMed Central Full Text
• [4]Hornberg JJ, Bruggeman FJ, Bakker BM, Westerhoff HV: Metabolic control analysis to identify optimal drug targets. Prog Drug Res 2007, 64(171):173-89. [ http://view.ncbi.nlm.nih.gov/pubmed/17195475 webcite]
• [5]Murabito E, Smallbone K, Swinton J, Westerhoff HV, Steuer R: A probabilistic approach to identify putative drug targets in biochemical networks. J R Soc Interface 2011, 8(59):880-95. [ http://view.ncbi.nlm.nih.gov/pubmed/21123256 webcite]
• [6]Edwards JS, Palsson BO: Metabolic flux balance analysis and the in silico analysis of Escherichia coli K-12 gene deletions. BMC Bioinformatics 2000, 1:1. [ http://view.ncbi.nlm.nih.gov/pubmed/11001586 webcite] BioMed Central Full Text
• [7]Snitkin ES, Dudley AM, Janse DM, Wong K, Church GM, Segrè D: Model-driven analysis of experimentally determined growth phenotypes for 465 yeast gene deletion mutants under 16 different conditions. Genome Biol 2008, 9(9):R140. [ http://view.ncbi.nlm.nih.gov/pubmed/18808699 webcite] BioMed Central Full Text
• [8]Raman K, Rajagopalan P, Chandra N: Flux balance analysis of mycolic acid pathway: targets for anti-tubercular drugs. PLoS Comput Biol 2005, 1(5):e46. [ http://view.ncbi.nlm.nih.gov/pubmed/16261191 webcite]
• [9]Lee DS, Burd H, Liu J, Almaas E, Wiest O, Barabási AL, Oltvai ZN, Kapatral V: Comparative genome-scale metabolic reconstruction and flux balance analysis of multiple Staphylococcus aureus genomes identify novel antimicrobial drug targets. J Bacteriol 2009, 191(12):4015-24. [ http://view.ncbi.nlm.nih.gov/pubmed/19376871 webcite]
• [10]Mazumdar V, Snitkin ES, Amar S, Segrè D: Metabolic network model of a human oral pathogen. J Bacteriol 2009, 191:74-90. [ http://view.ncbi.nlm.nih.gov/pubmed/18931137 webcite]
• [11]Oberhardt MA, Puchałka J Fryer KE: Genome-scale metabolic network analysis of the opportunistic pathogen Pseudomonas aeruginosa PAO1. J Bacteriol 2008, 190(8):2790-803. [ http://view.ncbi.nlm.nih.gov/pubmed/18192387 webcite]
• [12]Fatumo S, Plaimas K, Adebiyi E, König R: Comparing metabolic network models based on genomic and automatically inferred enzyme information from Plasmodium and its human host to define drug targets in silico. Infect Genet Evol 2011, 11(4):708-15. [ http://view.ncbi.nlm.nih.gov/pubmed/21515412 webcite]
• [13]Bordbar A, Lewis NE, Schellenberger J, Palsson BO, Jamshidi N: Insight into human alveolar macrophage and M. tuberculosis interactions via metabolic reconstructions. Mol Syst Biol 2010, 6:422. [ http://view.ncbi.nlm.nih.gov/pubmed/20959820 webcite]
• [14]Huthmacher C, Hoppe A, Bulik S, Holzhütter HG: Antimalarial drug targets in Plasmodium falciparum predicted by stage-specific metabolic network analysis. BMC Syst Biol 2010, 4:120. [ http://view.ncbi.nlm.nih.gov/pubmed/20807400 webcite] BioMed Central Full Text
• [15]Folger O, Jerby L, Frezza C, Gottlieb E, Ruppin E, Shlomi T: Predicting selective drug targets in cancer through metabolic networks. Mol Syst Biol 2011, 7:501. [ http://view.ncbi.nlm.nih.gov/pubmed/21694718 webcite]
• [16]Gille C, Bölling C, Hoppe A, Bulik S, Hoffmann S, Hübner K, Karlstädt A, Ganeshan R, König M, Rother K, Weidlich M, Behre J, Holzhütter HG: HepatoNet1: a comprehensive metabolic reconstruction of the human hepatocyte for the analysis of liver physiology. Mol Syst Biol 2010, 6:411. [ http://view.ncbi.nlm.nih.gov/pubmed/20823849 webcite]
• [17]Nussenzweig RS, Long CA: Malaria vaccines: multiple targets. Science 1994, 265(5177):1381-3. [ http://view.ncbi.nlm.nih.gov/pubmed/8073276 webcite]
• [18]Fatumo S, Plaimas K, Mallm JP, Schramm G, Adebiyi E, Oswald M, Eils R, König R: Estimating novel potential drug targets of Plasmodium falciparum by analysing the metabolic network of knock-out strains in silico. Infect Genet Evol 2009, 9(3):351-8. [ http://view.ncbi.nlm.nih.gov/pubmed/18313365 webcite]
• [19]Yeh I, Hanekamp T, Tsoka S, Karp PD, Altman RB: Computational analysis of Plasmodium falciparum metabolism: organizing genomic information to facilitate drug discovery. Genome Res 2004, 14(5):917-24. [ http://view.ncbi.nlm.nih.gov/pubmed/15078855 webcite]
• [20]Holzhütter HG: The generalized flux-minimization method and its application to metabolic networks affected by enzyme deficiencies. Biosystems 2006, 83(2-3):98-107. [ http://view.ncbi.nlm.nih.gov/pubmed/16229937 webcite]
• [21]Tomoda H, Igarashi K, Cyong JC, Omura S: Evidence for an essential role of long chain acyl-CoA synthetase in animal cell proliferation. Inhibition of long chain acyl-CoA synthetase by triacsins caused inhibition of Raji cell proliferation. J Biol Chem 1991, 266(7):4214-9. [ http://view.ncbi.nlm.nih.gov/pubmed/1999415 webcite]
• [22]Galvani E, Peters GJ, Giovannetti E: Thymidylate synthase inhibitors for non-small cell lung cancer. Expert Opin Investig Drugs 2011, 20(10):1343-56. [ http://view.ncbi.nlm.nih.gov/pubmed/21905922 webcite]
• [23]Wilson PM, Labonte MJ, Lenz HJD, Mack PC, Ladner RD: Inhibition of dUTPase induces synthetic lethality with thymidylate synthase-targeted therapies in non-small cell lung cancer. Mol Cancer Ther 2012, 11(3):616-28. [ http://view.ncbi.nlm.nih.gov/pubmed/22172489 webcite]
• [24]Bello AM, Konforte D, Poduch E, Furlonger C, Wei L, Liu Y, Lewis M, Pai EF, Paige CJ, Kotra LP: Structure-activity relationships of orotidine-5’-monophosphate decarboxylase inhibitors as anticancer agents. J Med Chem 2009, 52(6):1648-58. [ http://view.ncbi.nlm.nih.gov/pubmed/19260677 webcite]
• [25]Ochiai T, Nishimura K, Noguchi H, Kitajima M, Tsukada A, Watanabe E, Nagaoka I, Futagawa S: Prognostic impact of orotate phosphoribosyl transferase among 5-fluorouracil metabolic enzymes in resectable colorectal cancers treated by oral 5-fluorouracil-based adjuvant chemotherapy. Int J Cancer 2006, 118(12):3084-8. [ http://view.ncbi.nlm.nih.gov/pubmed/16425285 webcite]
• [26]Pausch J, Rasenack J, Häussinger D, Gerok W: Hepatic carbamoyl phosphate metabolism. Role of cytosolic and mitochondrial carbamoyl phosphate in de novo pyrimidine synthesis. Eur J Biochem 1985, 150:189-94. [ http://view.ncbi.nlm.nih.gov/pubmed/4018077 webcite]
• [27]Brooke J, Szabados E, Lyons SD, Goodridge RJ, Harsanyi MC, Poiner A, Christopherson RI: Cytotoxic effects of dihydroorotase inhibitors upon human CCRF-CEM leukemia. Cancer Res 1990, 50(24):7793-8. [ http://view.ncbi.nlm.nih.gov/pubmed/1979249 webcite]
• [28]Keil S, Müller M, Zoller G, Haschke G, Schroeter K, Glien M, Ruf S, Focken I, Herling AW, Schmoll D: Identification and synthesis of novel inhibitors of acetyl-CoA carboxylase with in vitro and in vivo efficacy on fat oxidation. J Med Chem 2010, 53(24):8679-87. [ http://view.ncbi.nlm.nih.gov/pubmed/21082864 webcite]
• [29]Chajès V, Cambot M, Moreau K, Lenoir GM, Joulin V: Acetyl-CoA carboxylase alpha is essential to breast cancer cell survival. Cancer Res 2006, 66(10):5287-94. [ http://view.ncbi.nlm.nih.gov/pubmed/16707454 webcite]
• [30]Marrero M, Prough RA, Putnam RS, Bennett M, Milewich L: Inhibition of carbamoyl phosphate synthetase-I by dietary dehydroepiandrosterone. J Steroid Biochem Mol Biol 1991, 38(5):599-609. [ http://view.ncbi.nlm.nih.gov/pubmed/1828177 webcite]
• [31]Wydysh EA, Medghalchi SM, Vadlamudi A, Townsend CA: Design and synthesis of small molecule glycerol 3-phosphate acyltransferase inhibitors. J Med Chem 2009, 52(10):3317-27. [ http://view.ncbi.nlm.nih.gov/pubmed/19388675 webcite]
• [32]Mashima T, Oh-hara T, Sato S, Mochizuki M, Sugimoto Y, Yamazaki K, Hamada Ji, Tada M, Moriuchi T, Ishikawa Y, Kato Y, Tomoda H, Yamori T, Tsuruo T: p53-defective tumors with a functional apoptosome-mediated pathway: a new therapeutic target. J Natl Cancer Inst 2005, 97(10):765-77. [ http://view.ncbi.nlm.nih.gov/pubmed/15900046 webcite]
• [33]Mitamura T, Palacpac NMQ: Lipid metabolism in Plasmodium falciparum-infected erythrocytes: possible new targets for malaria chemotherapy. Microbes Infect 2003, 5(6):545-52. [ http://view.ncbi.nlm.nih.gov/pubmed/12758284 webcite]
• [34]Labaied M, Dagan A, Dellinger M, Gèze M, Egée S, Thomas SL, Wang C, Gatt S, Grellier P: Anti-Plasmodium activity of ceramide analogs. Malar J 2004, 3:49. [ http://view.ncbi.nlm.nih.gov/pubmed/15588325 webcite] BioMed Central Full Text
• [35]Keppler DO, Schulz-Holstege C, Fauler J, Reiffen KA, Schneider F: Uridylate trapping, induction of UTP deficiency, and stimulation of pyrimidine synthesis de novo by D-galactosone. Biochem J 1982, 206:139-46. [ http://view.ncbi.nlm.nih.gov/pubmed/7126188 webcite]
• [36]Kuhajda FP, Aja S, Tu Y, Han WF, Medghalchi SM, El Meskini R, Landree LE, Peterson JM, Daniels K, Wong K, Wydysh EA, Townsend CA, Ronnett GV: Pharmacological glycerol-3-phosphate acyltransferase inhibition decreases food intake and adiposity and increases insulin sensitivity in diet-induced obesity. Am J Physiol Regul Integr Comp Physiol 2011, 301:R116-30. [ http://view.ncbi.nlm.nih.gov/pubmed/21490364 webcite]
• [37]Santiago TC, Zufferey R, Mehra RS, Coleman RA, Mamoun CB: The Plasmodium falciparum PfGatp is an endoplasmic reticulum membrane protein important for the initial step of malarial glycerolipid synthesis. J Biol Chem 2004, 279(10):9222-32. [ http://view.ncbi.nlm.nih.gov/pubmed/14668349 webcite]
• [38]Palacpac NMQ, Hiramine Y, Mi-ichi F, Torii M, Kita K, Hiramatsu R, Horii T, Mitamura T: Developmental-stage-specific triacylglycerol biosynthesis, degradation and trafficking as lipid bodies in Plasmodium falciparum-infected erythrocytes. J Cell Sci 2004, 117(Pt 8):1469-80. [ http://view.ncbi.nlm.nih.gov/pubmed/15020675 webcite]
• [39]Velanker SS, Ray SS, Gokhale RS, Suma S, Balaram H, Balaram P, Murthy MR: Triosephosphate isomerase from Plasmodium falciparum: the crystal structure provides insights into antimalarial drug design. Structure 1997, 5(6):751-61. [ http://view.ncbi.nlm.nih.gov/pubmed/9261072 webcite]
• [40]Hübscher G, Mayer RJ, Hansen HJ: Glycolytic enzymes as a multi-enzyme system. J Bioenerg 1971, 2(2):115-8. [ http://view.ncbi.nlm.nih.gov/pubmed/4257578 webcite]
• [41]Srinivasan P, Beatty WL, Diouf A, Herrera R, Ambroggio X, Moch JK, Tyler JS, Narum DL, Pierce SK, Boothroyd JC, Haynes JD, Miller LH: Binding of Plasmodium merozoite proteins RON2 and AMA1 triggers commitment to invasion. Proc Natl Acad Sci U S A 2011, 108(32):13275-80. [ http://view.ncbi.nlm.nih.gov/pubmed/21788485 webcite]
• [42]van Schalkwyk D A, Priebe W, Saliba KJ: The inhibitory effect of 2-halo derivatives of D-glucose on glycolysis and on the proliferation of the human malaria parasite Plasmodium falciparum. J Pharmacol Exp Ther 2008, 327(2):511-7. [ http://view.ncbi.nlm.nih.gov/pubmed/18713952 webcite]
• [43]Santos de Macedo C, Gerold P, Jung N, Azzouz N, Kimmel J, Schwarz RT: Inhibition of glycosyl-phosphatidylinositol biosynthesis in Plasmodium falciparum by C-2 substituted mannose analogues. Eur J Biochem 2001, 268(23):6221-8. [ http://view.ncbi.nlm.nih.gov/pubmed/11733018 webcite]
• [44]van Brummelen A C, Olszewski KL, Wilinski D, Llinás M, Louw AI, Birkholtz LM: Co-inhibition of Plasmodium falciparum S-adenosylmethionine decarboxylase/ornithine decarboxylase reveals perturbation-specific compensatory mechanisms by transcriptome, proteome, and metabolome analyses. J Biol Chem 2009, 284(7):4635-46. [ http://view.ncbi.nlm.nih.gov/pubmed/19073607 webcite]
• [45]Zini M, Passariello CL, Gottardi D, Cetrullo S, Flamigni F, Pignatti C, Minarini A, Tumiatti V, Milelli A, Melchiorre C, Stefanelli C: Cytotoxicity of methoctramine and methoctramine-related polyamines. Chem Biol Interact 2009, 181(3):409-16. [ http://view.ncbi.nlm.nih.gov/pubmed/19576191 webcite]
• [46]Déchamps S, Wengelnik K, Cerdan R, Vial HJ Gannoun-Zaki, Berry-Sterkers L: The Kennedy phospholipid biosynthesis pathways are refractory to genetic disruption in Plasmodium berghei and therefore appear essential in blood stages. Mol Biochem Parasitol 2010, 173(2):69-80. [ http://view.ncbi.nlm.nih.gov/pubmed/20478340 webcite]
• [47]Saleh A, Friesen J, Baumeister S, Gross U, Bohne W: Growth inhibition of Toxoplasma gondii and Plasmodium falciparum by nanomolar concentrations of 1-hydroxy-2-dodecyl-4(1H)quinolone, a high-affinity inhibitor of alternative (type II) NADH dehydrogenases. Antimicrob Agents Chemother 2007, 51(4):1217-22. [ http://view.ncbi.nlm.nih.gov/pubmed/17242151 webcite]
• [48]Mita T, Tanabe K, Kita K: Spread and evolution of Plasmodium falciparum drug resistance. Parasitol Int 2009, 58(3):201-9. [ http://view.ncbi.nlm.nih.gov/pubmed/19393762 webcite]
• [49]Tang W: Drug metabolite profiling and elucidation of drug-induced hepatotoxicity. Expert Opin Drug Metab Toxicol 2007, 3(3):407-20. [ http://view.ncbi.nlm.nih.gov/pubmed/17539747 webcite]
• [50]Feist AM, Palsson BO: The biomass objective function. Curr Opin Microbiol 2010, 13(3):344-9. [ http://view.ncbi.nlm.nih.gov/pubmed/20430689 webcite]
• [51]Kolev NG, Tschudi C, Ullu E: RNA interference in protozoan parasites: achievements and challenges. Eukaryot Cell 2011, 10(9):1156-63. [ http://view.ncbi.nlm.nih.gov/pubmed/21764910 webcite]
• [52]Bello AM, Poduch E, Liu Y, Wei L, Crandall I, Wang X, Dyanand C, Kain KC, Pai EF, Kotra LP: Structure-activity relationships of C6-uridine derivatives targeting plasmodia orotidine monophosphate decarboxylase. J Med Chem 2008, 51(3):439-48. [ http://view.ncbi.nlm.nih.gov/pubmed/18189347 webcite]
• [53]Bello AM, Poduch E, Fujihashi M, Amani M, Li Y, Crandall I, Hui R, Lee PI, Kain KC, Pai EF, Kotra LP: A potent, covalent inhibitor of orotidine 5’-monophosphate decarboxylase with antimalarial activity. J Med Chem 2007, 50(5):915-21. [ http://view.ncbi.nlm.nih.gov/pubmed/17290979 webcite]
• [54]Chait R, Craney A, Kishony R: Antibiotic interactions that select against resistance. Nature 2007, 446(7136):668-71. [ http://view.ncbi.nlm.nih.gov/pubmed/17410176 webcite]
• [55]Olszewski KL, Morrisey JM, Wilinski D, Burns JM, Vaidya AB, Rabinowitz JD, Llins M: Host-parasite interactions revealed by Plasmodium falciparum metabolomics. Cell Host Microbe 2009, 5(2):191-9. [ http://view.ncbi.nlm.nih.gov/pubmed/19218089 webcite]
• [56]Azzarello J, Fung KM, Lin HK: Tissue distribution of human AKR1C3 and rat homolog in the adult genitourinary system. J Histochem Cytochem 2008, 56(9):853-61. [ http://view.ncbi.nlm.nih.gov/pubmed/18574251 webcite]
• [57]Kanehisa M, Goto S: KEGG: kyoto encyclopedia of genes and genomes. Nucleic Acids Res 2000, 28:27-30. [ http://view.ncbi.nlm.nih.gov/pubmed/10592173 webcite]
• [58]Scheer M, Grote A, Chang A, Schomburg I, Munaretto C, Rother M, Söhngen C, Stelzer M, Thiele J, Schomburg D: BRENDA, the enzyme information system in 2011. Nucleic Acids Res 2011, 39(Database issue):D670—6. [ http://view.ncbi.nlm.nih.gov/pubmed/21062828 webcite]
• [59]Castro J, Cortés JP, Guzmán M: Properties of the mitochondrial membrane and carnitine palmitoyltransferase in the periportal and the perivenous zone of the liver. Effects of chronic ethanol feeding. Biochem Pharmacol 1991, 41(12):1987-95. [ http://view.ncbi.nlm.nih.gov/pubmed/2039548 webcite]
• [60]Holzhütter HG: The principle of flux minimization and its application to estimate stationary fluxes in metabolic networks. Eur J Biochem 2004, 271(14):2905-22. [ http://view.ncbi.nlm.nih.gov/pubmed/15233787 webcite]