title: Isoprenoid precursor biosynthesis offers potential targets for drug discovery against diseases caused by apicomplexan parasites.
abstract: Two, simple, C5 compounds, dimethylally diphosphate and isopentenyl diphosphate, are the universal precursors of isoprenoids, a large family of natural products involved in numerous important biological processes. Two distinct biosynthetic pathways have evolved to supply these precursors. Humans use the mevalonate route whilst many species of bacteria including important pathogens, plant chloroplasts and apicomplexan parasites exploit the non-mevalonate pathway. The absence from humans, combined with genetic and chemical validation suggests that the non-mevalonate pathway holds the potential to support new drug discovery programmes targeting Gram-negative bacteria and the apicomplexan parasites responsible for causing serious human diseases, and also infections of veterinary importance. The non-mevalonate pathway relies on eight enzyme-catalyzed stages exploiting a range of cofactors and metal ions. A wealth of structural and mechanistic data, mainly derived from studies of bacterial enzymes, now exists for most components of the pathway and these will be described. Particular attention will be paid to how these data inform on the apicomplexan orthologues concentrating on the enzymes from Plasmodium spp. these cause malaria, one the most important parasitic diseases in the world today.
authors: Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, UK. w.n.hunter@dundee.ac.uk
authors: William N
authors: WN
authors: Hunter
references: J Biol Chem. 2003 Apr 4;278(14):11903-8
references: 12540835
references: Biochemistry. 2006 Mar 21;45(11):3548-53
references: 16533036
references: Curr Opin Chem Biol. 1997 Dec;1(4):570-8
references: 9667899
references: Philos Trans R Soc Lond B Biol Sci. 2010 Mar 12;365(1541):749-63
references: 20124342
references: Proc Natl Acad Sci U S A. 2002 May 14;99(10):6591-6
references: 11997478
references: J Biol Chem. 2009 May 1;284(18):11749-53
references: 19103598
references: Science. 1999 Sep 3;285(5433):1573-6
references: 10477522
references: J Biol Chem. 2004 Dec 10;279(50):52753-61
references: 15466439
references: Biochemistry. 2004 Sep 28;43(38):12189-97
references: 15379557
references: Annu Rev Pharmacol Toxicol. 2005;45:89-118
references: 15822172
references: J Mol Biol. 2005 Jan 7;345(1):115-27
references: 15567415
references: Biochemistry. 1997 Oct 7;36(40):12101-19
references: 9315848
references: Mol Biochem Parasitol. 2010 Apr;170(2):108-11
references: 20018214
references: Nature. 2008 Feb 21;451(7181):990-3
references: 18288193
references: Nat Rev Microbiol. 2010 Apr;8(4):272-80
references: 20208550
references: J Infect. 2007 Feb;54(2):111-21
references: 17215045
references: Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9173-8
references: 12878729
references: Anal Biochem. 2005 May 15;340(2):245-51
references: 15840497
references: Nat Struct Biol. 2001 Jul;8(7):641-8
references: 11427897
references: Eur J Biochem. 2004 Jul;271(14):3028-35
references: 15233799
references: Acta Crystallogr D Biol Crystallogr. 2006 Jul;62(Pt 7):807-13
references: 16790937
references: J Org Chem. 2006 Nov 10;71(23):8824-34
references: 17081012
references: Org Biomol Chem. 2008 Aug 7;6(15):2719-30
references: 18633530
references: J Biol Chem. 2003 May 16;278(20):18401-7
references: 12621040
references: J Med Chem. 2009 Apr 23;52(8):2531-42
references: 19320487
references: J Lipid Res. 2006 Feb;47(2):233-40
references: 16339110
references: J Protozool. 1988 Nov;35(4):518-20
references: 3143826
references: Acta Crystallogr Sect F Struct Biol Cryst Commun. 2010 Mar 1;66(Pt 3):237-41
references: 20208151
references: J Mol Biol. 2002 Feb 8;316(1):79-88
references: 11829504
references: Acta Crystallogr D Biol Crystallogr. 2004 Nov;60(Pt 11):1949-57
references: 15502301
references: J Am Chem Soc. 2004 Sep 8;126(35):10824-5
references: 15339150
references: Nucleic Acids Res. 2007 Jan;35(Database issue):D427-30
references: 17098930
references: Curr Pharm Des. 2008;14(9):855-71
references: 18473835
references: J Biol Chem. 2002 Mar 8;277(10):8667-72
references: 11786530
references: Biochim Biophys Acta. 2004 Apr 8;1698(1):37-44
references: 15063313
references: Proc Natl Acad Sci U S A. 2010 Mar 9;107(10):4522-7
references: 20173096
references: J Biol Chem. 2003 Aug 8;278(32):30022-7
references: 12771135
references: Lipids. 2008 Dec;43(12):1095-107
references: 19011917
references: ChemMedChem. 2008 Jan;3(1):91-101
references: 18033714
references: Philos Trans R Soc Lond B Biol Sci. 2002 Jan 29;357(1417):35-46
references: 11839180
references: Clin Pharmacol Ther. 2009 Jun;85(6):584-95
references: 19404247
references: Int Rev Cytol. 2003;224:57-110
references: 12722949
references: Fundam Clin Pharmacol. 2009 Aug;23(4):387-409
references: 19709319
references: Acta Crystallogr D Biol Crystallogr. 2005 Jan;61(Pt 1):45-52
references: 15608374
references: Cell Mol Life Sci. 2004 Jun;61(12):1401-26
references: 15197467
references: Bioorg Chem. 2004 Oct;32(5):292-308
references: 15381396
references: Expert Opin Ther Targets. 2008 Mar;12(3):253-63
references: 18269336
references: Nature. 2005 Mar 10;434(7030):214-7
references: 15759000
references: Genome Res. 2004 May;14(5):917-24
references: 15078855
references: J Mol Biol. 2007 Aug 10;371(2):540-53
references: 17583736
references: J Biol Chem. 2007 Jul 6;282(27):19905-16
references: 17491006
references: J Pharmacol Toxicol Methods. 2000 Jul-Aug;44(1):235-49
references: 11274893
references: J Biol Chem. 2002 Feb 15;277(7):5378-84
references: 11741911
references: Acta Crystallogr D Biol Crystallogr. 2003 Jan;59(Pt 1):23-31
references: 12499535
references: Proc Natl Acad Sci U S A. 2010 Jan 19;107(3):1077-81
references: 20080550
references: J Biol Chem. 2004 Dec 10;279(50):51749-59
references: 15452112
references: Eukaryot Cell. 2007 Sep;6(9):1511-20
references: 17644655
references: Acta Crystallogr Sect F Struct Biol Cryst Commun. 2010 Mar 1;66(Pt 3):330-2
references: 20208174
references: Nature. 1990 Feb 1;343(6257):425-30
references: 1967820
references: Acta Crystallogr D Biol Crystallogr. 2003 Mar;59(Pt 3):607-10
references: 12595740
references: J Biochem. 2002 Mar;131(3):313-7
references: 11872159
references: FEBS J. 2006 Mar;273(5):1065-73
references: 16478479
references: Eur J Biochem. 2001 Jun;268(11):3190-7
references: 11389720
references: Antimicrob Agents Chemother. 2002 Aug;46(8):2315-20
references: 12121898
references: Science. 1997 Sep 19;277(5333):1788-9
references: 9324768
references: J Org Chem. 2005 Nov 11;70(23):9168-74
references: 16268586
references: FEBS J. 2008 Jun;275(11):2779-94
references: 18422643
references: J Biol Chem. 2007 Jan 26;282(4):2676-82
references: 17135236
references: Biochemistry. 2009 Nov 10;48(44):10483-5
references: 19821611
references: J Biol Chem. 2007 Jul 27;282(30):21573-7
references: 17442674