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, S
dc.contributor.author Donnelly, SM
dc.contributor.author Robinson, MW
dc.contributor.author Skinner-Adams, T
dc.contributor.author Trenholme, KR
dc.contributor.author Gardiner, DL
dc.contributor.author Dalton, JP
dc.contributor.author Stack, CM
dc.contributor.author Lowther, J
dc.date.accessioned 2010-05-28T09:45:28Z
dc.date.issued 2009-06-16
dc.identifier.citation Biochemistry, 2009, 48 (23), pp. 5435 - 5439
dc.identifier.issn 0006-2960
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 a 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 1 is readily exchangeable with several divalent metal ions and displays a preference in the order of preference Zn 2+ > Mn 2+ > Co 2+ > Mg 2+. While it is likely that native PfLAP contains a Zn 2+ 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. © 2009 American Chemical Society.
dc.language eng
dc.relation.isbasedon 10.1021/bi9003638
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
dc.type Journal Article
dc.parent Biochemistry
dc.journal.volume 23
dc.journal.volume 48
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 0605 Microbiology
dc.personcode 995262
dc.personcode 995261
dc.personcode 030896
dc.personcode 996591
dc.personcode 100777
dc.personcode 100775
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
pubs.embargo.period Not known
pubs.organisational-group /University of Technology Sydney
pubs.organisational-group /University of Technology Sydney/Faculty of Science
pubs.organisational-group /University of Technology Sydney/Strength - i3
pubs.organisational-group /University of Technology Sydney/Strength - i3
utslib.copyright.status Closed Access
utslib.copyright.date 2015-04-15 12:17:09.805752+10
pubs.consider-herdc true
utslib.collection.history School of Medical and Molecular Sciences (ID: 341)
utslib.collection.history Closed (ID: 3)


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