title: Structural and functional attributes of malaria parasite diadenosine tetraphosphate hydrolase.
abstract: Malaria symptoms are driven by periodic multiplication cycles of Plasmodium parasites in human red blood corpuscles (RBCs). Malaria infection still accounts for ~600,000 annual deaths, and hence discovery of both new drug targets and drugs remains vital. In the present study, we have investigated the malaria parasite enzyme diadenosine tetraphosphate (Ap4A) hydrolase that regulates levels of signalling molecules like Ap4A by hydrolyzing them to ATP and AMP. We have tracked the spatial distribution of parasitic Ap4A hydrolase in infected RBCs, and reveal its unusual localization on the infected RBC membrane in subpopulation of infected cells. Interestingly, enzyme activity assays reveal an interaction between Ap4A hydrolase and the parasite growth inhibitor suramin. We also present a high resolution crystal structure of Ap4A hydrolase in apo- and sulphate- bound state, where the sulphate resides in the enzyme active site by mimicking the phosphate of substrates like Ap4A. The unexpected infected erythrocyte localization of the parasitic Ap4A hydrolase hints at a possible role of this enzyme in purinerigic signaling. In addition, atomic structure of Ap4A hydrolase provides insights for selective drug targeting.
authors.affiliation: Structural and Computational Biology Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), Aruna Asaf Ali Road, New Delhi, 110067, India.
authors.forename: Arvind
authors.initials: A
authors.lastname: Sharma
authors.affiliation: Structural and Computational Biology Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), Aruna Asaf Ali Road, New Delhi, 110067, India.
authors.forename: Manickam
authors.initials: M
authors.lastname: Yogavel
authors.affiliation: Structural and Computational Biology Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), Aruna Asaf Ali Road, New Delhi, 110067, India.
authors.forename: Amit
authors.initials: A
authors.lastname: Sharma
mesh_terms: D017766:Acid Anhydride Hydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology; D016503:Drug Delivery Systems; D004912:Erythrocytes / Q000469:parasitology*; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000201:enzymology; D010963:Plasmodium falciparum / Q000201:enzymology*; D000072417:Protein Domains; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000962:Antimalarials; D015800:Protozoan Proteins; D017766:Acid Anhydride Hydrolases; C020023:bis(5'-nucleosyl)tetraphosphatase (asymmetrical)
references.citation: Nat Commun. 2011;2:530
references.pmid: 22068597
references.citation: J Biol Chem. 2009 Mar 6;284(10):6260-9
references.pmid: 19131328
references.citation: FASEB J. 2006 Jan;20(1):133-5
references.pmid: 16267125
references.citation: J Biol Chem. 1996 Oct 11;271(41):25059-62
references.pmid: 8810257
references.citation: J Biol Chem. 2003 Nov 28;278(48):47670-7
references.pmid: 13679371
references.citation: Structure. 2002 Apr;10(4):589-600
references.pmid: 11937063
references.citation: Exp Eye Res. 2011 Feb;92(2):96-7
references.pmid: 21163257
references.citation: Nucleic Acids Res. 2015 Jan;43(Database issue):D257-60
references.pmid: 25300481
references.citation: Int J Biochem Cell Biol. 2007;39(5):943-54
references.pmid: 17344088
references.citation: J Appl Crystallogr. 2007 Aug 1;40(Pt 4):658-674
references.pmid: 19461840
references.citation: Acta Crystallogr D Biol Crystallogr. 2010 Jan;66(Pt 1):12-21
references.pmid: 20057044
references.citation: Cell Mol Life Sci. 2006 Jan;63(2):123-43
references.pmid: 16378245
references.citation: Mol Cell. 2009 Jun 12;34(5):603-11
references.pmid: 19524539
references.citation: Infect Immun. 1995 Apr;63(4):1552-62
references.pmid: 7890422
references.citation: J Biol Chem. 2005 Mar 4;280(9):8471-81
references.pmid: 15596429
references.citation: Acta Crystallogr A. 2003 May;59(Pt 3):228-34
references.pmid: 12714773
references.citation: Immunity. 2004 Feb;20(2):145-51
references.pmid: 14975237
references.citation: Nucleic Acids Res. 2015 Jan;43(Database issue):D222-6
references.pmid: 25414356
references.citation: Purinergic Signal. 2010 Dec;6(4):365-72
references.pmid: 21437007
references.citation: FEBS Lett. 1998 May 8;427(2):157-63
references.pmid: 9607303
references.citation: J Comput Chem. 2004 Oct;25(13):1605-12
references.pmid: 15264254
references.citation: J Biol Chem. 2010 Feb 19;285(8):5917-30
references.pmid: 20007323
references.citation: Biochem Biophys Res Commun. 2013 Mar 1;432(1):16-21
references.pmid: 23384440
references.citation: Cell. 1983 Oct;34(3):711-2
references.pmid: 6354469
references.citation: Biochem Biophys Res Commun. 1999 Mar 24;256(3):474-9
references.pmid: 10080922
references.citation: Nucleic Acids Res. 2009 Jan;37(Database issue):D380-6
references.pmid: 19036790
references.citation: Arch Biochem Biophys. 2005 Jan 1;433(1):129-43
references.pmid: 15581572
references.citation: Arch Biochem Biophys. 2000 Jan 1;373(1):218-24
references.pmid: 10620341
references.citation: Mini Rev Med Chem. 2008 Nov;8(13):1384-94
references.pmid: 18991754
references.citation: Mol Cell Biol. 2011 May;31(10):2111-21
references.pmid: 21402779
references.citation: FEBS Lett. 1998 Jun 12;429(2):143-6
references.pmid: 9650578
references.citation: Exp Parasitol. 2013 Nov;135(3):541-5
references.pmid: 24055216
references.citation: Sci Rep. 2011;1:188
references.pmid: 22355703
references.citation: Biochem J. 2015 Feb 1;465(3):459-69
references.pmid: 25391660
references.citation: Parasite. 2009 Sep;16(3):169-82
references.pmid: 19839262
references.citation: J Biol Chem. 1992 Mar 5;267(7):4652-7
references.pmid: 1537848
references.citation: J Biol Chem. 1987 Nov 5;262(31):14855-8
references.pmid: 2822703
references.citation: Mol Biochem Parasitol. 2004 Sep;137(1):13-21
references.pmid: 15279947
references.citation: Structure. 2015 May 5;23(5):819-29
references.pmid: 25817387
references.citation: Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):213-21
references.pmid: 20124702
references.citation: Acta Crystallogr D Biol Crystallogr. 2013 May;69(Pt 5):785-95
references.pmid: 23633587
references.citation: Nature. 2008 Oct 9;455(7214):751-6
references.pmid: 18843360
references.citation: J Parasitol. 1979 Jun;65(3):418-20
references.pmid: 383936
references.citation: Acta Crystallogr D Biol Crystallogr. 2002 Nov;58(Pt 11):1948-54
references.pmid: 12393927
references.citation: Nat Protoc. 2007;2(9):2212-21
references.pmid: 17853878
references.citation: Bioorg Med Chem. 2013 Jul 1;21(13):3667-73
references.pmid: 23680445
references.citation: Biophys J. 2008 Oct;95(7):3222-31
references.pmid: 18599640
references.citation: Acta Crystallogr D Biol Crystallogr. 2004 Dec;60(Pt 12 Pt 1):2126-32
references.pmid: 15572765
references.citation: Acta Crystallogr A. 2008 Jan;64(Pt 1):112-22
references.pmid: 18156677
references.citation: J Struct Funct Genomics. 2014 Jun;15(2):63-71
references.pmid: 24935905
references.citation: BMC Genomics. 2009;10:644
references.pmid: 20042123
references.citation: Nature. 2005 Feb 3;433(7025):531-7
references.pmid: 15690043
references.citation: PLoS One. 2013;8(6):e66224
references.pmid: 23776638
references.citation: Biol Pharm Bull. 2012;35(7):1191-6
references.pmid: 22791172