title: Enzyme Mechanism and Slow-Onset Inhibition of Plasmodium falciparum Enoyl-Acyl Carrier Protein Reductase by an Inorganic Complex.
abstract: Malaria continues to be a major cause of children's morbidity and mortality worldwide, causing nearly one million deaths annually. The human malaria parasite, Plasmodium falciparum, synthesizes fatty acids employing the Type II fatty acid biosynthesis system (FAS II), unlike humans that rely on the Type I (FAS I) pathway. The FAS II system elongates acyl fatty acid precursors of the cell membrane in Plasmodium. Enoyl reductase (ENR) enzyme is a member of the FAS II system. Here we present steady-state kinetics, pre-steady-state kinetics, and equilibrium fluorescence spectroscopy data that allowed proposal of P. falciparum ENR (PfENR) enzyme mechanism. Moreover, building on previous results, the present study also evaluates the PfENR inhibition by the pentacyano(isoniazid)ferrateII compound. This inorganic complex represents a new class of lead compounds for the development of antimalarial agents focused on the inhibition of PfENR.
authors: Instituto de Pesquisas em Patologias Tropicais (IPEPATRO), Rua da Beira 7671, Rodovia BR364 km 3.5, 76812-245 Porto Velho, RO, Brazil.
authors: Patrícia Soares de Maria
authors: PS
authors: de Medeiros
authors: Rodrigo Gay
authors: RG
authors: Ducati
authors: Luiz Augusto
authors: LA
authors: Basso
authors: Diógenes Santiago
authors: DS
authors: Santos
authors: Luiz Hildebrando Pereira
authors: LH
authors: da Silva
references: Biochem J. 2004 Aug 1;381(Pt 3):735-41
references: 15139852
references: Adv Protein Chem. 1975;29:1-83
references: 1136898
references: Science. 1994 Jan 14;263(5144):227-30
references: 8284673
references: Nat Rev Microbiol. 2005 Jan;3(1):81-90
references: 15608702
references: Chem Commun (Camb). 2004 Feb 7;(3):312-3
references: 14740053
references: Mol Microbiol. 1995 Jan;15(2):235-45
references: 7746145
references: Trends Microbiol. 1997 Feb;5(2):52-8
references: 9108930
references: Biochem J. 2004 Aug 1;381(Pt 3):725-33
references: 15125687
references: Adv Enzymol Relat Areas Mol Biol. 1988;61:201-301
references: 3281418
references: Curr Pharm Des. 2006;12(19):2409-24
references: 16842188
references: Nat Med. 2001 Feb;7(2):167-73
references: 11175846
references: Biochim Biophys Acta. 1998 Sep 8;1387(1-2):395-405
references: 9748656
references: Lancet Infect Dis. 2002 Apr;2(4):209-18
references: 11937421
references: Biochemistry. 2002 Oct 15;41(41):12320-8
references: 12369820
references: J Biol Chem. 2002 Nov 8;277(45):42633-8
references: 12205099
references: Biochem J. 1979 Jul 1;181(1):153-7
references: 226079
references: J Biol Chem. 2000 Jan 28;275(4):2520-6
references: 10644708
references: Biochemistry. 2008 Apr 8;47(14):4228-36
references: 18335995
references: Biochem J. 1913 Oct;7(5):471-80
references: 16742267
references: J Biol Chem. 2002 Apr 12;277(15):13106-14
references: 11792710
references: Biochemistry. 2008 May 20;47(20):5481-92
references: 18412369
references: Trends Microbiol. 1999 Aug;7(8):328-33
references: 10431206
references: Antimicrob Agents Chemother. 2003 Apr;47(4):1241-50
references: 12654653
references: Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):13881-6
references: 14623976
references: J Med Chem. 1998 Apr 23;41(9):1367-70
references: 9554869
references: Biochemistry. 1989 Feb 7;28(3):1222-6
references: 2540819
references: Lancet. 2005 Apr 23-29;365(9469):1467-73
references: 15850630
references: Drugs. 1987 Jan;33(1):50-65
references: 3545765
references: J Biol Chem. 1968 Mar 25;243(6):1180-9
references: 4384650
references: J Biol Chem. 1973 Dec 25;248(24):8348-52
references: 4357736
references: Prog Lipid Res. 2008 Jan;47(1):50-61
references: 18023422
references: Mol Biochem Parasitol. 2003 Feb;126(2):143-54
references: 12615313
references: Nat Rev Microbiol. 2004 Mar;2(3):203-16
references: 15083156
references: Proc Natl Acad Sci U S A. 1998 Oct 13;95(21):12352-7
references: 9770490
references: J Biol Chem. 1997 Apr 4;272(14):8867-70
references: 9083004
references: Eur J Biochem. 1995 Dec 1;234(2):603-15
references: 8536710
references: Angew Chem Int Ed Engl. 1999 Sep;38(17):2588-2590
references: 10508348
references: Science. 1998 Jan 2;279(5347):98-102
references: 9417034
references: Biochem Biophys Res Commun. 2001 Dec 14;289(4):832-7
references: 11735121
references: Biochim Biophys Acta. 1996 Jul 12;1302(1):1-16
references: 8695652
references: Biochemistry. 2010 Feb 16;49(6):1281-9
references: 20055482
references: Trans R Soc Trop Med Hyg. 1986;80(2):201-3
references: 3538522