title: The Sphingolipid Biosynthetic Pathway Is a Potential Target for Chemotherapy against Chagas Disease.
abstract: The protozoan parasite Trypanosoma cruzi is the causative agent of human Chagas disease, for which there currently is no cure. The life cycle of T. cruzi is complex, including an extracellular phase in the triatomine insect vector and an obligatory intracellular stage inside the vertebrate host. These phases depend on a variety of surface glycosylphosphatidylinositol-(GPI-) anchored glycoconjugates that are synthesized by the parasite. Therefore, the surface expression of GPI-anchored components and the biosynthetic pathways of GPI anchors are attractive targets for new therapies for Chagas disease. We identified new drug targets for chemotherapy by taking the available genome sequence information and searching for differences in the sphingolipid biosynthetic pathways (SBPs) of mammals and T. cruzi. In this paper, we discuss the major steps of the SBP in mammals, yeast and T. cruzi, focusing on the IPC synthase and ceramide remodeling of T. cruzi as potential therapeutic targets for Chagas disease.
authors: Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Centro de Ciências da Saúde, Bloco G-019, Cidade Universitária-Ilha do Fundão, 21941-902 Rio de Janeiro RJ, Brazil.
authors: Carolina Macedo
authors: CM
authors: Koeller
authors: Norton
authors: N
authors: Heise
references: Biochim Biophys Acta. 1998 Dec 8;1436(1-2):233-43
references: 9838138
references: Adv Lipid Res. 1993;26:253-74
references: 8379454
references: J Cell Sci. 2008 Feb 15;121(Pt 4):522-35
references: 18230649
references: Eukaryot Cell. 2007 Mar;6(3):454-64
references: 17220466
references: Eur J Biochem. 1990 Sep 11;192(2):337-45
references: 2145155
references: Mol Biochem Parasitol. 2012 Mar-Apr;182(1-2):62-74
references: 22226824
references: J Biol Chem. 2006 Sep 22;281(38):28200-9
references: 16861742
references: Biochim Biophys Acta. 2008 Mar;1780(3):410-20
references: 17913366
references: EMBO J. 2003 Nov 17;22(22):6016-26
references: 14609948
references: Exp Parasitol. 2004 Mar-Apr;106(3-4):135-49
references: 15172221
references: J Bacteriol. 1992 Apr;174(8):2575-81
references: 1556076
references: J Biol Chem. 2000 Oct 6;275(40):31369-78
references: 10900202
references: Mol Biol Cell. 2006 Dec;17(12):5253-64
references: 17021251
references: Chemotherapy. 2006;52(4):205-9
references: 16675903
references: Proc Natl Acad Sci U S A. 2000 Sep 12;97(19):10336-41
references: 10954751
references: Mol Microbiol. 2004 Aug;53(3):725-33
references: 15255887
references: J Biol Chem. 1998 Nov 13;273(46):30688-94
references: 9804843
references: Mol Microbiol. 2009 May;72(4):1068-79
references: 19400804
references: Science. 2005 Jul 15;309(5733):409-15
references: 16020725
references: Biochim Biophys Acta. 2003 Jun 10;1632(1-3):16-30
references: 12782147
references: Nat Rev Mol Cell Biol. 2008 Feb;9(2):112-24
references: 18216768
references: J Biol Chem. 1970 Jan 25;245(2):342-50
references: 5412064
references: J Biol Chem. 1995 Jun 2;270(22):13171-8
references: 7768913
references: Eur J Biochem. 1993 Oct 15;217(2):597-602
references: 8223603
references: Lab Invest. 1999 Mar;79(3):293-9
references: 10092065
references: J Infect Dis. 2007 Feb 1;195(3):311-3
references: 17205466
references: Eukaryot Cell. 2003 Aug;2(4):756-68
references: 12912895
references: J Biochem. 2008 Sep;144(3):287-94
references: 18635593
references: Biochim Biophys Acta. 1996 May 20;1300(3):233-9
references: 8679689
references: EMBO J. 2001 Jun 1;20(11):2655-65
references: 11387200
references: Mol Microbiol. 2004 Apr;52(2):313-27
references: 15066023
references: Annu Rev Biochem. 1998;67:27-48
references: 9759481
references: J Biol Chem. 1994 Apr 8;269(14):10193-6
references: 8144596
references: J Biol Chem. 1998 Jun 12;273(24):14942-9
references: 9614099
references: Cell. 2006 Aug 25;126(4):691-9
references: 16923389
references: J Biol Chem. 2000 Mar 10;275(10):6876-84
references: 10702247
references: Eukaryot Cell. 2009 Mar;8(3):306-14
references: 19074599
references: J Biol Chem. 1992 Nov 25;267(33):23527-33
references: 1429697
references: Eur J Biochem. 1993 Dec 15;218(3):929-36
references: 8281945
references: Nat Rev Mol Cell Biol. 2008 Feb;9(2):139-50
references: 18216770
references: Mol Biochem Parasitol. 2004 Jan;133(1):71-80
references: 14668014
references: EMBO J. 2004 Jan 14;23(1):33-44
references: 14685263
references: Mol Biol Cell. 2006 Jun;17(6):2636-45
references: 16597698
references: J Biol Chem. 1995 Nov 10;270(45):27244-53
references: 7592983
references: Int J Biochem Cell Biol. 2010 Sep;42(9):1553-61
references: 20561598
references: Mol Biol Cell. 2006 Mar;17(3):1410-20
references: 16407401
references: J Biol Chem. 1979 Feb 25;254(4):1050-60
references: 762114
references: J Biol Chem. 1998 Nov 13;273(46):30550-9
references: 9804825
references: Trends Cell Biol. 2000 Feb;10(2):73-80
references: 10652518
references: Mol Microbiol. 2008 Oct;70(2):281-96
references: 18699867
references: Biochim Biophys Acta. 2002 Dec 30;1585(2-3):163-71
references: 12531550
references: J Antibiot (Tokyo). 1993 Sep;46(9):1414-20
references: 8226319
references: Biochim Biophys Acta. 2007 Mar;1771(3):405-20
references: 16859984
references: Mol Biochem Parasitol. 1995 Mar;70(1-2):71-84
references: 7637716
references: Mol Biochem Parasitol. 1996 Aug;79(2):143-51
references: 8855551
references: FEBS Lett. 2001 Feb 23;491(1-2):148-53
references: 11226438
references: J Biol Chem. 2002 Jul 19;277(29):25847-50
references: 12011103
references: Mol Biol Cell. 2000 Jul;11(7):2267-81
references: 10888667
references: J Biol Chem. 1993 Dec 15;268(35):26365-74
references: 8253761
references: Glycobiology. 1997 Sep;7(6):731-5
references: 9376675
references: J Biol Chem. 2004 Nov 19;279(47):49243-50
references: 15328338
references: EMBO J. 1997 Jun 16;16(12):3494-505
references: 9218792
references: EMBO J. 2005 Feb 23;24(4):730-41
references: 15692566
references: Ann Trop Med Parasitol. 2006 Dec;100(8):663-77
references: 17227647
references: Parasitology. 2010 Aug;137(9):1357-92
references: 20602846
references: EMBO J. 2007 Feb 21;26(4):1094-104
references: 17290222
references: Adv Parasitol. 2004;56:1-41
references: 14710995
references: Biochem J. 1993 Sep 1;294 ( Pt 2):305-24
references: 8373346
references: Mol Biol Cell. 2006 Dec;17(12):5265-74
references: 17035628
references: J Biol Chem. 1990 Feb 15;265(5):2518-26
references: 2406236
references: Biochem J. 2005 Aug 15;390(Pt 1):263-71
references: 15823095
references: Mol Biol Cell. 2007 Nov;18(11):4304-16
references: 17761529
references: J Biol Chem. 2010 Jul 2;285(27):20580-7
references: 20457606
references: Mol Biol Cell. 2009 Oct;20(20):4444-57
references: 19726565
references: Biochem J. 1995 Aug 15;310 ( Pt 1):255-61
references: 7646454
references: J Biol Chem. 1997 Apr 11;272(15):9809-17
references: 9092515
references: J Biol Chem. 1991 Dec 15;266(35):23670-5
references: 1748644
references: Mem Inst Oswaldo Cruz. 2002 Jul;97(5):603-12
references: 12219120
references: Biochim Biophys Acta. 2008 Mar;1780(3):362-9
references: 17976917
references: J Biol Chem. 1992 Apr 5;267(10):6820-8
references: 1532392
references: J Lipid Res. 1986 Dec;27(12):1294-303
references: 3559392
references: J Biol Chem. 1996 Jul 12;271(28):16877-87
references: 8663209
references: EMBO Rep. 2004 Aug;5(8):777-82
references: 15289826
references: Exp Mol Pathol. 2002 Apr;72(2):132-41
references: 11890722
references: Biochem Biophys Res Commun. 1995 Jun 15;211(2):396-403
references: 7794249
references: Biochem J. 2005 Apr 15;387(Pt 2):519-29
references: 15569002
references: EMBO J. 1997 Jun 16;16(12):3506-18
references: 9218793
references: J Biol Chem. 1995 Mar 31;270(13):7241-50
references: 7706263
references: J Antibiot (Tokyo). 1995 May;48(5):349-56
references: 7797434
references: J Lipid Res. 2007 May;48(5):993-1011
references: 17361015
references: Mol Biochem Parasitol. 1993 Jun;59(2):293-303
references: 8341326
references: Mol Microbiol. 2007 Sep;65(6):1493-502
references: 17714445
references: Mol Microbiol. 2008 Jan;67(1):202-12
references: 18036137
references: Microbes Infect. 2002 Jul;4(9):1007-13
references: 12106795
references: FEBS Lett. 2010 May 3;584(9):1670-7
references: 19883648
references: Br Med Bull. 1985 Apr;41(2):105-14
references: 3928017
references: Mol Microbiol. 2005 Mar;55(5):1566-78
references: 15720561
references: Mol Biol Cell. 2007 Apr;18(4):1497-506
references: 17314402
references: J Biol Chem. 1998 May 1;273(18):11062-8
references: 9556590
references: Mol Biol Cell. 2001 Nov;12(11):3417-27
references: 11694577
references: Biochem J. 2000 Jan 1;345 Pt 1:77-84
references: 10600641
references: Trends Parasitol. 2001 Aug;17(8):381-7
references: 11685899
references: Mol Syst Biol. 2009;5:261
references: 19357640