The protein-phosphatome of the human malaria parasite Plasmodium falciparum.
BACKGROUND
Malaria, caused by the parasitic protist Plasmodium falciparum, represents a major public health problem in the developing world. The P. falciparum genome has been sequenced, which provides new opportunities for the identification of novel drug targets. We report an exhaustive analysis of the P. falciparum genomic database (PlasmoDB) aimed at identifying and classifying all protein phosphatases (PP) in this organism.


RESULTS
Using a variety of bioinformatics tools, we identified 27 malarial putative PP sequences within the four major established PP families, plus 7 sequences that we predict to dephosphorylate "non-protein" substrates. We constructed phylogenetic trees to position these sequences relative to PPs from other organisms representing all major eukaryotic phyla except Cercozoans (for which no full genome sequence is available). Predominant observations were: (i) P. falciparum possessed the smallest phosphatome of any of the organisms investigated in this study; (ii) no malarial PP clustered with the tyrosine-specific subfamily of the PTP group (iii) a cluster of 7 closely related members of the PPM/PP2C family is present, and (iv) some P. falciparum protein phosphatases are present in clades lacking any human homologue.


CONCLUSIONS
The considerable phylogenetic distance between Apicomplexa and other Eukaryotes is reflected by profound divergences between the phosphatome of malaria parasites and those of representative organisms from all major eukaryotic phyla, which might be exploited in the context of efforts for the discovery of novel targets for antimalarial chemotherapy.
Wilkes
Jonathan M
JM
INSERM U609, Wellcome Centre for Molecular Parasitology, University of Glasgow, Glasgow, Scotland, UK. jw149j@udcf.gla.ac.uk
Doerig
Christian
C
D000818:Animals; D023281:Genomics; D006801:Humans; D008390:Markov Chains; D010749:Phosphoprotein Phosphatases / Q000302:isolation & purification*; D010802:Phylogeny; D010963:Plasmodium falciparum / Q000201:enzymology* / Q000235:genetics*
D010749:Phosphoprotein Phosphatases
Proc Natl Acad Sci U S A. 2005 Nov 29;102(48):17314-9
16301539
Genes Dev. 2004 Feb 15;18(4):448-60
14977918
Proteins. 2007 Sep 1;68(4):893-914
17557329
Int J Parasitol. 2002 Dec 4;32(13):1575-85
12435442
Mol Cancer Ther. 2005 Nov;4(11):1653-61
16275986
Biochim Biophys Acta. 2002 Sep 13;1577(2):261-275
12213657
BMC Genomics. 2005 Mar 07;6:30
15752424
Curr Opin Cell Biol. 2005 Apr;17(2):197-202
15780597
Science. 2003 Oct 24;302(5645):639-42
14576433
Mol Microbiol. 2001 Feb;39(4):973-81
11251817
Trends Cell Biol. 2000 Jan;10(1):17-24
10603472
Curr Issues Mol Biol. 2005 Jan;7(1):57-79
15580780
Mol Biochem Parasitol. 1998 Sep 15;95(2):287-95
9803420
Mol Biol Evol. 2001 Mar;18(3):448-52
11230548
Mol Biochem Parasitol. 2008 Mar;158(1):1-10
18096253
Cell Mol Life Sci. 2002 Jun;59(6):941-9
12169024
Biochem J. 1995 Oct 1;311 ( Pt 1):17-29
7575450
Nat Protoc. 2007;2(4):953-71
17446895
Trends Biochem Sci. 1996 Nov;21(11):413-7
8987394
Nucleic Acids Res. 2002 Jan 1;30(1):276-80
11752314
J Bacteriol. 2005 May;187(10):3511-20
15866939
Mol Biochem Parasitol. 2001 Jun;115(1):29-39
11377737
Expert Opin Ther Targets. 2007 Mar;11(3):279-90
17298288
Biochemistry. 2007 Mar 27;46(12):3595-604
17328562
Science. 2003 Sep 12;301(5639):1503-8
12893887
Mol Microbiol. 2000 Mar;35(5):1005-16
10712683
Traffic. 2005 Dec;6(12):1063-9
16262718
Mol Biochem Parasitol. 1999 Apr 30;99(2):167-81
10340482
J Mol Biol. 2000 Sep 8;302(1):205-17
10964570
Curr Med Chem. 2005;12(1):1-22
15638728
J Biol Chem. 1999 Oct 15;274(42):29912-20
10514473
Biochemistry. 1995 Feb 14;34(6):1988-96
7531497
Mol Biol Evol. 2006 Feb;23(2):254-67
16221896
Genome Biol. 2003;4(5):111
12734000
FEBS Lett. 2005 Jun 13;579(15):3278-86
15913612
Future Microbiol. 2006 Jun;1(1):127-41
17661691
Mol Biochem Parasitol. 2003 Feb;126(2):239-50
12615323
Curr Opin Cell Biol. 2006 Dec;18(6):623-31
17030123
J Biol Chem. 1998 May 1;273(18):11241-7
9556615
Methods Mol Biol. 2007;365:287-98
17200569
Eur J Biochem. 1994 Feb 15;220(1):225-37
8119291
BMC Genomics. 2004 Oct 12;5:79
15479470
FEBS Lett. 1990 Nov 26;275(1-2):44-8
2175718
Trends Biochem Sci. 1997 Jul;22(7):245-51
9255065
Science. 2004 Dec 10;306(5703):1934-7
15591203
BMC Evol Biol. 2004 Nov 19;4:47
15555063
Nature. 2002 Oct 3;419(6906):498-511
12368864
J Cell Sci. 1996 Dec;109 ( Pt 12):2865-74
9013334
EMBO J. 1996 Dec 16;15(24):6798-809
9003755
Oncogene. 2007 May 14;26(22):3203-13
17496916
BMC Genomics. 2005 Sep 15;6:127
16164760
Int J Parasitol. 2002 Jun;32(6):739-47
12062492
Trends Parasitol. 2006 Dec;22(12):543-6
17029963
Proteins. 2005 Jan 1;58(1):180-9
15515182
Nucleic Acids Res. 2006 Jan 1;34(Database issue):D247-51
16381856
Clin Transl Oncol. 2006 Mar;8(3):153-60
16648114
Bioinformatics. 1998;14(9):755-63
9918945
J Mol Biol. 2007 Dec 7;374(4):899-909
17976645
Mol Biochem Parasitol. 2002 Apr 9;120(2):257-68
11897131
Science. 2003 Jun 13;300(5626):1703-6
12805537
Mol Biochem Parasitol. 2004 Feb;133(2):297-310
14698441
Cell Signal. 2002 Sep;14(9):745-50
12034355
Annu Rev Biophys Biomol Struct. 1998;27:133-64
9646865
J Exp Bot. 2007;58(13):3503-11
17951602
Malar J. 2002 Apr 26;1:5
12057017
Nucleic Acids Res. 1997 Sep 1;25(17):3389-402
9254694
Biochim Biophys Acta. 2005 Dec 30;1754(1-2):291-5
16194631
J Biol Chem. 2003 Apr 18;278(16):13627-32
12556522
BMC Genomics. 2007 Nov 26;8:434
18039372
Trends Biochem Sci. 2001 Jun;26(6):369-76
11406410
Nucleic Acids Res. 2002 Apr 1;30(7):1575-84
11917018
BMC Microbiol. 2001;1:31
11737864
Eur J Biochem. 1997 Oct 1;249(1):98-106
9363759
BMC Mol Biol. 2004 Jul 01;5:6
15230980
Trends Biochem Sci. 2001 Jul;26(7):426-31
11440854
J Biol Chem. 2003 Jul 11;278(28):26078-85
12721286
Trends Plant Sci. 2004 May;9(5):236-43
15130549
Curr Cancer Drug Targets. 2006 Sep;6(6):519-32
17017875
Curr Opin Cell Biol. 2006 Apr;18(2):185-91
16488126
Mol Microbiol. 2005 Jan;55(1):184-96
15612927
Adv Pharmacol. 1996;36:67-89
8783555
Science. 2004 Dec 10;306(5703):1930-3
15591202
Int J Parasitol. 2008 Sep;38(11):1279-95
18547579
Nucleic Acids Res. 1994 Nov 11;22(22):4673-80
7984417
Methods Enzymol. 1991;200:38-62
1956325
Methods Mol Biol. 2007;365:335-46
17200573
Science. 2003 Jan 31;299(5607):705-8
12560551