The M17 Leucine Aminopeptidase of the Malaria Parasite Plasmodium falciparum: Importance of Active Site Metal Ions in the Binding of Substrates and Inhibitors

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dc.contributor.author Maric, Selma en_US
dc.contributor.author Donnelly, Sheila en_US
dc.contributor.author Robinson, Mark en_US
dc.contributor.author Skinner-Adams, Tina en_US
dc.contributor.author Trenholme, Katharine en_US
dc.contributor.author Gardiner, Donald en_US
dc.contributor.author Dalton, John en_US
dc.contributor.author Stack, Colin en_US
dc.contributor.author Lowther, Jonathan en_US
dc.contributor.editor en_US
dc.date.accessioned 2010-05-28T09:45:28Z
dc.date.available 2010-05-28T09:45:28Z
dc.date.issued 2009 en_US
dc.identifier 2008007820 en_US
dc.identifier.citation Maric Selma et al. 2009, 'The M17 Leucine Aminopeptidase of the Malaria Parasite Plasmodium falciparum: Importance of Active Site Metal Ions in the Binding of Substrates and Inhibitors', Amer Chemical Soc, vol. 48, no. 23, pp. 5435-5439. en_US
dc.identifier.issn 0006-2960 en_US
dc.identifier.other C1 en_US
dc.identifier.uri http://hdl.handle.net/10453/8789
dc.description.abstract The M17 leucine aminopeptidase of the intraerythrocytic stages of the malaria parasite Plasmodium falciparum (PfLAP) plays it role in releasing amino acids from host hemoglobin that are used for parasite protein synthesis, growth, and development. This enzyme represents a target at which new antimalarials Could be designed since metalloaminopeptidase inhibitors prevent the growth of the parasites in vitro and in vivo. A study on the metal ion binding characteristics of recombinant P. falciparum M17 leucine aminopeptidase (rPfLAP) shows that the active site of this exopeptidase contains two metal-binding sites, a readily exchangeable site (site 1) and a tight binding site (site 2). The enzyme retains activity when the metal ion is removed from site 1, while removal of metal ions from both sites results in an inactive apoenzyme that cannot be reactivated by the addition of divalent metal cations. The metal Ion at site I is readily exchangeable with several divalent metal ions and displays a preference in the order of preference Zn2+ > Mn2+ > Co2+ > Mg2+. While it is likely that native PfLAP contains a Zn2+ in site 2, the metal ion located in site 1 may be dependent on the type and concentration of metal ions in the cytosolic compartment of the parasite. Importantly, the type of metal ion present at site 1 influences not only the catalytic efficiency of the enzyme for peptide Substrates but also the mode of binding by bestatin, a metal-chelating inhibitor of M17 aminopeptidases with antimalarial activity. en_US
dc.language en_US
dc.publisher Amer Chemical Soc en_US
dc.relation.isbasedon http://dx.doi.org/10.1021/bi9003638 en_US
dc.title The M17 Leucine Aminopeptidase of the Malaria Parasite Plasmodium falciparum: Importance of Active Site Metal Ions in the Binding of Substrates and Inhibitors en_US
dc.parent Biochemistry en_US
dc.journal.volume 48 en_US
dc.journal.number 23 en_US
dc.publocation Washington en_US
dc.identifier.startpage 5435 en_US
dc.identifier.endpage 5439 en_US
dc.cauo.name SCI.Faculty of Science en_US
dc.conference Verified OK en_US
dc.for 060500 en_US
dc.personcode 100775 en_US
dc.personcode 995261 en_US
dc.personcode 100777 en_US
dc.personcode 0000027738 en_US
dc.personcode 0000022368 en_US
dc.personcode 0000022367 en_US
dc.personcode 030896 en_US
dc.personcode 995262 en_US
dc.personcode 996591 en_US
dc.percentage 100 en_US
dc.classification.name Microbiology en_US
dc.classification.type FOR-08 en_US
dc.edition en_US
dc.custom en_US
dc.date.activity en_US
dc.location.activity ISI:000266860400044 en_US
dc.description.keywords NA en_US
dc.staffid 996591 en_US


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