title: Antimalarial drug targets in Plasmodium falciparum predicted by stage-specific metabolic network analysis.
abstract: BACKGROUND
  Despite enormous efforts to combat malaria the disease still afflicts up to half a billion people each year of which more than one million die. Currently no approved vaccine is available and resistances to antimalarials are widely spread. Hence, new antimalarial drugs are urgently needed.
  
  
  RESULTS
  Here, we present a computational analysis of the metabolism of Plasmodium falciparum, the deadliest malaria pathogen. We assembled a compartmentalized metabolic model and predicted life cycle stage specific metabolism with the help of a flux balance approach that integrates gene expression data. Predicted metabolite exchanges between parasite and host were found to be in good accordance with experimental findings when the parasite's metabolic network was embedded into that of its host (erythrocyte). Knock-out simulations identified 307 indispensable metabolic reactions within the parasite. 35 out of 57 experimentally demonstrated essential enzymes were recovered and another 16 enzymes, if additionally the assumption was made that nutrient uptake from the host cell is limited and all reactions catalyzed by the inhibited enzyme are blocked. This predicted set of putative drug targets, shown to be enriched with true targets by a factor of at least 2.75, was further analyzed with respect to homology to human enzymes, functional similarity to therapeutic targets in other organisms and their predicted potency for prophylaxis and disease treatment.
  
  
  CONCLUSIONS
  The results suggest that the set of essential enzymes predicted by our flux balance approach represents a promising starting point for further drug development.
authors.affiliation: Institute of Biochemistry, Charité, Monbijoustrasse 2, 10117 Berlin, Germany. carola.huthmacher@charite.de
authors.forename: Carola
authors.initials: C
authors.lastname: Huthmacher
authors.forename: Andreas
authors.initials: A
authors.lastname: Hoppe
authors.forename: Sascha
authors.initials: S
authors.lastname: Bulik
authors.forename: Hermann-Georg
authors.initials: HG
authors.lastname: Holzhütter
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000378:metabolism* / Q000494:pharmacology; D019295:Computational Biology / Q000379:methods*; D004912:Erythrocytes / Q000378:metabolism / Q000469:parasitology; D020869:Gene Expression Profiling; D054884:Host-Pathogen Interactions; D006801:Humans; D008018:Life Cycle Stages / Q000235:genetics; D053858:Metabolic Networks and Pathways; D010963:Plasmodium falciparum / Q000187:drug effects / Q000235:genetics / Q000254:growth & development* / Q000378:metabolism*; D015203:Reproducibility of Results
chemical_list: D000962:Antimalarials
references.citation: Biochem J. 2000 Jul 1;349(Pt 1):67-75
references.pmid: 10861212
references.citation: Proc Natl Acad Sci U S A. 2004 Apr 20;101(16):6206-11
references.pmid: 15073329
references.citation: Science. 1999 Sep 3;285(5433):1573-6
references.pmid: 10477522
references.citation: J Med Chem. 1994 May 13;37(10):1486-94
references.pmid: 8182707
references.citation: Mol Biochem Parasitol. 1986 Jan;18(1):3-15
references.pmid: 3515174
references.citation: Proc Natl Acad Sci U S A. 2008 Feb 19;105(7):2463-8
references.pmid: 18263733
references.citation: Curr Drug Targets. 2007 Jan;8(1):75-88
references.pmid: 17266532
references.citation: Mini Rev Med Chem. 2008 Mar;8(3):239-47
references.pmid: 18336344
references.citation: Mol Biochem Parasitol. 1999 Jul 30;102(1):91-101
references.pmid: 10477179
references.citation: Mol Biochem Parasitol. 2005 Aug;142(2):224-36
references.pmid: 15913804
references.citation: J Biol Chem. 1995 Nov 3;270(44):26538-42
references.pmid: 7592873
references.citation: Biochemistry. 1998 Jun 2;37(22):8011-9
references.pmid: 9609694
references.citation: Nat Med. 2000 Aug;6(8):898-903
references.pmid: 10932227
references.citation: Mol Biochem Parasitol. 1999 Jan 25;98(2):215-23
references.pmid: 10080390
references.citation: Nat Rev Microbiol. 2004 Nov;2(11):886-97
references.pmid: 15494745
references.citation: Blood. 1994 Aug 1;84(3):910-5
references.pmid: 8043872
references.citation: PLoS Pathog. 2008 Feb 29;4(2):e1000008
references.pmid: 18389080
references.citation: J Biol Chem. 2002 Feb 1;277(5):3226-31
references.pmid: 11706018
references.citation: J Biol Chem. 2004 Oct 8;279(41):43000-7
references.pmid: 15304495
references.citation: BMC Syst Biol. 2009 Mar 25;3:37
references.pmid: 19321003
references.citation: J Biol Chem. 2008 Oct 10;283(41):27636-27643
references.pmid: 18694927
references.citation: Mol Biochem Parasitol. 2002 Feb;119(2):273-8
references.pmid: 11814579
references.citation: PLoS Comput Biol. 2008 Oct;4(10):e1000210
references.pmid: 18974823
references.citation: Proc Natl Acad Sci U S A. 2007 Feb 6;104(6):1777-82
references.pmid: 17267599
references.citation: Fundam Clin Pharmacol. 2003 Apr;17(2):147-53
references.pmid: 12667224
references.citation: J Enzyme Inhib Med Chem. 2004 Jun;19(3):249-56
references.pmid: 15499996
references.citation: Nat Struct Biol. 1999 Jun;6(6):582-7
references.pmid: 10360365
references.citation: Biochem Biophys Res Commun. 1992 Sep 16;187(2):744-50
references.pmid: 1356337
references.citation: Metab Eng. 2010 Mar;12(2):150-60
references.pmid: 19646545
references.citation: Antimicrob Agents Chemother. 2003 Jan;47(1):297-301
references.pmid: 12499205
references.citation: Mol Biochem Parasitol. 2002 Feb;119(2):249-56
references.pmid: 11814576
references.citation: Biochemistry. 2002 Oct 15;41(41):12395-406
references.pmid: 12369829
references.citation: Biochem Biophys Res Commun. 2004 Jul 23;320(2):311-7
references.pmid: 15219828
references.citation: Biochem Pharmacol. 1992 Mar 17;43(6):1295-301
references.pmid: 1348618
references.citation: J Biol Chem. 2005 Jan 7;280(1):571-7
references.pmid: 15507440
references.citation: J Biol Chem. 2003 Nov 14;278(46):45661-71
references.pmid: 12930838
references.citation: Acta Physiol Pol. 1980 Mar-Apr;31(2):209-15
references.pmid: 7395544
references.citation: Biochim Biophys Acta. 1980 Oct 1;632(2):159-63
references.pmid: 7417521
references.citation: Biochem J. 1984 Sep 15;222(3):815-9
references.pmid: 6435607
references.citation: Mol Microbiol. 2004 Sep;53(5):1291-305
references.pmid: 15387810
references.citation: Mol Biochem Parasitol. 1993 Jul;60(1):153-6
references.pmid: 8366890
references.citation: FEMS Microbiol Rev. 2006 Jul;30(4):596-630
references.pmid: 16774588
references.citation: Mol Biochem Parasitol. 1984 Sep;13(1):53-65
references.pmid: 6392884
references.citation: Biochem J. 2000 Mar 1;346 Pt 2:545-52
references.pmid: 10677377
references.citation: Eur J Biochem. 2004 Jul;271(14):2905-22
references.pmid: 15233787
references.citation: J Am Chem Soc. 2007 May 30;129(21):6872-9
references.pmid: 17488013
references.citation: Angew Chem Int Ed Engl. 2006 Feb 6;45(7):1069-74
references.pmid: 16392111
references.citation: Biotechnol Bioeng. 1998 Apr 20-May 5;58(2-3):162-9
references.pmid: 10191386
references.citation: Science. 2003 Sep 12;301(5639):1503-8
references.pmid: 12893887
references.citation: Nucleic Acids Res. 2009 Jan;37(Database issue):D588-92
references.pmid: 18984617
references.citation: Cell Host Microbe. 2008 Dec 11;4(6):509-11
references.pmid: 19064250
references.citation: Proc Natl Acad Sci U S A. 2000 May 9;97(10):5528-33
references.pmid: 10805808
references.citation: J Nutr. 1981 Apr;111(4):618-23
references.pmid: 7218034
references.citation: Mol Pharmacol. 1974 Jan;10(1):140-5
references.pmid: 4602912
references.citation: Mol Syst Biol. 2007;3:121
references.pmid: 17593909
references.citation: Nephrol Dial Transplant. 1997 Sep;12(9):1921-7
references.pmid: 9306344
references.citation: Biochem Biophys Res Commun. 2003 Mar 21;302(4):659-64
references.pmid: 12646219
references.citation: Mol Pharmacol. 1998 Dec;54(6):1140-7
references.pmid: 9855645
references.citation: Nature. 2006 Oct 5;443(7111):582-5
references.pmid: 17006451
references.citation: J Bacteriol. 2009 Jun;191(12):4015-24
references.pmid: 19376871
references.citation: Genome Res. 2004 Nov;14(11):2308-18
references.pmid: 15520293
references.citation: Cell Host Microbe. 2009 Feb 19;5(2):191-9
references.pmid: 19218089
references.citation: J Biol Chem. 2002 Jul 19;277(29):25970-5
references.pmid: 12004069
references.citation: J Inherit Metab Dis. 1994;17(6):667-77
references.pmid: 7707690
references.citation: Bioorg Med Chem Lett. 2004 Jun 7;14(11):2931-4
references.pmid: 15125962
references.citation: Theor Biol Med Model. 2005 May 09;2:18
references.pmid: 15882454
references.citation: Mol Syst Biol. 2007;3:135
references.pmid: 17882155
references.citation: J Biol Chem. 1997 Jul 4;272(27):16940-5
references.pmid: 9202005
references.citation: Bioorg Med Chem. 2003 Nov 17;11(23):4941-4
references.pmid: 14604655
references.citation: Curr Pharm Des. 2008;14(9):855-71
references.pmid: 18473835
references.citation: Antimicrob Agents Chemother. 2000 Apr;44(4):1047-50
references.pmid: 10722510
references.citation: J Clin Invest. 1982 Aug;70(2):461-9
references.pmid: 7047569
references.citation: Nature. 2002 Feb 7;415(6872):680-5
references.pmid: 11832956
references.citation: J Biol Chem. 2005 Jun 10;280(23):21847-53
references.pmid: 15795226
references.citation: Biochem J. 1989 Jun 1;260(2):401-11
references.pmid: 2548476
references.citation: Biochemistry. 2005 Feb 8;44(5):1643-52
references.pmid: 15683248
references.citation: Biochem Pharmacol. 1986 Jul 15;35(14):2435-42
references.pmid: 3524576
references.citation: Blood Cells Mol Dis. 2006 Mar-Apr;36(2):239-47
references.pmid: 16533612
references.citation: Nature. 1998 Jun 25;393(6687):801-5
references.pmid: 9655396
references.citation: BMC Syst Biol. 2009 Sep 15;3:92
references.pmid: 19754970
references.citation: Methods Mol Biol. 2009;500:61-80
references.pmid: 19399432
references.citation: Proc Natl Acad Sci U S A. 1993 Dec 15;90(24):12020-4
references.pmid: 8265664
references.citation: Nature. 2004 Jun 10;429(6992):661-4
references.pmid: 15190353
references.citation: Biochem Pharmacol. 1988 Mar 1;37(5):855-60
references.pmid: 3278712
references.citation: Biochem J. 2002 Jul 15;365(Pt 2):343-7
references.pmid: 12033986
references.citation: Biochem J. 2002 Oct 15;367(Pt 2):321-7
references.pmid: 12119044
references.citation: Ann Trop Med Parasitol. 1997 Sep;91(6):603-9
references.pmid: 9425362
references.citation: J Med Chem. 2002 Jan 31;45(3):748-51
references.pmid: 11806727
references.citation: Nat Genet. 2000 May;25(1):25-9
references.pmid: 10802651
references.citation: Bioinformatics. 2004 Jan 22;20(2):226-34
references.pmid: 14734314
references.citation: Proc Natl Acad Sci U S A. 1989 Jan;86(2):651-5
references.pmid: 2463635
references.citation: Blood. 2003 May 15;101(10):4189-94
references.pmid: 12531811
references.citation: Nucleic Acids Res. 2010 Jan;38(Database issue):D355-60
references.pmid: 19880382
references.citation: J Chromatogr B Analyt Technol Biomed Life Sci. 2002 Dec 5;781(1-2):57-71
references.pmid: 12450653
references.citation: Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13134-9
references.pmid: 14578455
references.citation: Exp Parasitol. 2002 Jan;100(1):54-61
references.pmid: 11971654
references.citation: Exp Parasitol. 2000 Jan;94(1):23-32
references.pmid: 10631077
references.citation: J Cell Biol. 1989 Jun;108(6):2183-92
references.pmid: 2661561
references.citation: Nucleic Acids Res. 2009 Jan;37(Database issue):D539-43
references.pmid: 18957442
references.citation: Mol Cell Biol. 1999 Mar;19(3):1720-30
references.pmid: 10022859
references.citation: Mol Syst Biol. 2006;2:2006.0004
references.pmid: 16738551
references.citation: J Biol Chem. 2008 Jun 13;283(24):16342-54
references.pmid: 18430732
references.citation: Mol Microbiol. 2009 Nov;74(3):519-28
references.pmid: 19796339
references.citation: Parasitol Res. 1998 Jul;84(7):552-8
references.pmid: 9694371
references.citation: Mol Biochem Parasitol. 2001 Jan 15;112(1):29-37
references.pmid: 11166384
references.citation: Biochem J. 2002 Dec 15;368(Pt 3):761-8
references.pmid: 12225291
references.citation: Biochemistry. 2003 Feb 4;42(4):1160-9
references.pmid: 12549938
references.citation: Genome Biol. 2003;4(9):117
references.pmid: 12952525
references.citation: Nat Biotechnol. 2008 Jun;26(6):659-67
references.pmid: 18536691
references.citation: Nucleic Acids Res. 2005 Oct 24;33(19):6083-9
references.pmid: 16246909
references.citation: Mol Syst Biol. 2008;4:177
references.pmid: 18364711
references.citation: FEBS Lett. 2001 Jul 6;500(3):169-71
references.pmid: 11445079
references.citation: Biochem Pharmacol. 1998 Nov 15;56(10):1305-13
references.pmid: 9825729
references.citation: Nat Med. 2001 Feb;7(2):167-73
references.pmid: 11175846
references.citation: Mol Biochem Parasitol. 2002 Sep-Oct;124(1-2):85-90
references.pmid: 12387854
references.citation: Genome Res. 2004 May;14(5):917-24
references.pmid: 15078855
references.citation: Methods Mol Biol. 2008;416:433-57
references.pmid: 18392986
references.citation: NMR Biomed. 2009 Apr;22(3):292-302
references.pmid: 19021153
references.citation: Nature. 2007 Dec 13;450(7172):1091-5
references.pmid: 18046333
references.citation: Biotechnol Bioeng. 1993 Jun 5;42(1):59-73
references.pmid: 18609648
references.citation: Cell Host Microbe. 2008 Sep 11;4(3):209-18
references.pmid: 18779047
references.citation: Biochem Pharmacol. 1998 Mar 1;55(5):709-11
references.pmid: 9515582
references.citation: J Biol Chem. 2007 Sep 28;282(39):28791-28799
references.pmid: 17573341
references.citation: Brief Bioinform. 2009 Jul;10(4):435-49
references.pmid: 19287049
references.citation: Mol Cell. 2003 Apr;11(4):885-94
references.pmid: 12718875
references.citation: J Biol Chem. 2003 Apr 25;278(17):14788-97
references.pmid: 12588865
references.citation: J Bacteriol. 2008 Apr;190(8):2790-803
references.pmid: 18192387
references.citation: J Med Chem. 2003 Feb 27;46(5):734-46
references.pmid: 12593654
references.citation: Mini Rev Med Chem. 2006 Nov;6(11):1231-41
references.pmid: 17100634
references.citation: Proc Natl Acad Sci U S A. 1997 Dec 9;94(25):13944-9
references.pmid: 9391132
references.citation: Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):13821-6
references.pmid: 14623980
references.citation: Nat Rev Microbiol. 2004 Mar;2(3):203-16
references.pmid: 15083156
references.citation: Appl Environ Microbiol. 1994 Oct;60(10):3724-31
references.pmid: 7986045
references.citation: Nat Biotechnol. 2008 Sep;26(9):1003-10
references.pmid: 18711341
references.citation: FEMS Microbiol Rev. 2008 Jan;32(1):56-106
references.pmid: 18173393
references.citation: Mol Syst Biol. 2007;3:149
references.pmid: 18059444
references.citation: J Biol Chem. 2004 Jan 9;279(2):1336-42
references.pmid: 12972411
references.citation: J Mol Biol. 2004 Jan 30;335(5):1251-64
references.pmid: 14729341
references.citation: Adv Exp Med Biol. 1984;165 Pt A:367-71
references.pmid: 6720405
references.citation: Curr Pharm Des. 2003;9(11):867-77
references.pmid: 12678871
references.citation: Parasitol Int. 2000 Feb;48(4):275-80
references.pmid: 10725690
references.citation: Biochem Pharmacol. 1994 Jan 20;47(2):418-20
references.pmid: 8304987
references.citation: Genome Inform. 2006;17(1):195-207
references.pmid: 17503369
references.citation: J Biol Chem. 2004 Dec 10;279(50):51749-59
references.pmid: 15452112
references.citation: Proc Natl Acad Sci U S A. 2005 Mar 22;102(12):4336-41
references.pmid: 15784746
references.citation: Nucleic Acids Res. 2008 Jan;36(Database issue):D919-22
references.pmid: 17942422
references.citation: Trends Parasitol. 2009 Jan;25(1):37-43
references.pmid: 18986839
references.citation: J Biol Chem. 1989 Feb 25;264(6):3194-9
references.pmid: 2536737
references.citation: J Gen Physiol. 1988 Oct;92(4):449-74
references.pmid: 3204363
references.citation: J Med Chem. 2004 Nov 18;47(24):5972-83
references.pmid: 15537352
references.citation: J Vector Borne Dis. 2006 Sep;43(3):95-103
references.pmid: 17024857
references.citation: Antimicrob Agents Chemother. 2006 Sep;50(9):3132-41
references.pmid: 16940112
references.citation: Nature. 2007 Mar 1;446(7131):88-91
references.pmid: 17330044
references.citation: Bioorg Med Chem. 2005 Mar 15;13(6):1945-67
references.pmid: 15727850
references.citation: Blood. 2006 Aug 1;108(3):791-801
references.pmid: 16861337
references.citation: Postgrad Med J. 1998 Jul;74(873):425-7
references.pmid: 9799920
references.citation: Proteins. 2003 Sep 1;52(4):624-32
references.pmid: 12910461
references.citation: Mol Biochem Parasitol. 2005 Aug;142(2):177-83
references.pmid: 15876462
references.citation: Trends Parasitol. 2006 Jun;22(6):238-40
references.pmid: 16707276
references.citation: PLoS Med. 2009 Apr 14;6(4):e1000054
references.pmid: 19365538
references.citation: Biol Chem. 2002 May;383(5):821-30
references.pmid: 12108547
references.citation: Antimicrob Agents Chemother. 2007 Feb;51(2):696-706
references.pmid: 17145794
references.citation: Proc Natl Acad Sci U S A. 1996 Jan 9;93(1):514-8
references.pmid: 8552672
references.citation: PLoS Biol. 2003 Oct;1(1):E5
references.pmid: 12929205
references.citation: FEBS J. 2007 Sep;274(18):4670-9
references.pmid: 17824953
references.citation: Proc Natl Acad Sci U S A. 2006 Jun 6;103(23):8840-5
references.pmid: 16731623
references.citation: Biochem Pharmacol. 1991 Jun 1;41(11):1713-8
references.pmid: 2043160
references.citation: Proc Natl Acad Sci U S A. 2008 Jan 8;105(1):305-10
references.pmid: 18172196
references.citation: Antimicrob Agents Chemother. 2005 Sep;49(9):3652-7
references.pmid: 16127035
references.citation: J Am Chem Soc. 1948 Oct;70(10):3151-5
references.pmid: 18891812
references.citation: Nucleic Acids Res. 2009 Jan;37(Database issue):D274-8
references.pmid: 19022853
references.citation: Nucleic Acids Symp Ser. 1999;(42):25-6
references.pmid: 10780361
references.citation: Jpn J Infect Dis. 2008 May;61(3):210-1
references.pmid: 18503171
references.citation: Mol Syst Biol. 2008;4:178
references.pmid: 18364712
references.citation: Mol Biochem Parasitol. 1992 Jun;52(2):185-94
references.pmid: 1620158
references.citation: Trends Parasitol. 2009 Jun;25(6):246-9
references.pmid: 19423394
references.citation: J Biol Chem. 2002 Nov 1;277(44):42066-73
references.pmid: 12194969
references.citation: BMC Syst Biol. 2007 Jun 08;1:26
references.pmid: 17555602
references.citation: Bioinformatics. 2003 Jan 22;19(2):185-93
references.pmid: 12538238
references.citation: J Med Chem. 2008 Feb 14;51(3):439-48
references.pmid: 18189347
references.citation: Nucleic Acids Res. 2009 Jan;37(Database issue):D619-22
references.pmid: 18981052
references.citation: Biochemistry. 1994 May 3;33(17):5268-74
references.pmid: 7909690
references.citation: Trop Med Parasitol. 1990 Sep;41(3):273-8
references.pmid: 2255844
references.citation: Metab Eng. 2006 Jan;8(1):1-13
references.pmid: 16199194
references.citation: Brief Bioinform. 2006 Jun;7(2):140-50
references.pmid: 16772264
references.citation: Biochemistry. 2007 Jan 16;46(2):554-60
references.pmid: 17209565
references.citation: Arch Biochem Biophys. 1990 Nov 15;283(1):40-5
references.pmid: 2146924
references.citation: Biochem J. 1999 Apr 15;339 ( Pt 2):363-70
references.pmid: 10191268
references.citation: Mol Biochem Parasitol. 2000 Feb 5;105(2):215-22
references.pmid: 10693744
references.citation: J Gen Physiol. 1996 Jan;107(1):145-59
references.pmid: 8741736
references.citation: Antimicrob Agents Chemother. 2000 Sep;44(9):2540-2
references.pmid: 10952611
references.citation: Infect Genet Evol. 2009 May;9(3):351-8
references.pmid: 18313365
references.citation: BMC Syst Biol. 2007 Jun 01;1:23
references.pmid: 17543097
references.citation: Mol Biol Cell. 2003 Dec;14(12):4947-57
references.pmid: 14595113
references.citation: Bioorg Med Chem Lett. 2006 Jan 1;16(1):88-92
references.pmid: 16236496