The M18 aspartyl aminopeptidase of the human malaria parasite Plasmodium falciparum

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dc.contributor.author Teuscher, F
dc.contributor.author Lowther, J
dc.contributor.author Skinner-Adams, TS
dc.contributor.author Spielmann, T
dc.contributor.author Dixon, MWA
dc.contributor.author Stack, CM
dc.contributor.author Donnelly, S
dc.contributor.author Mucha, A
dc.contributor.author Kafarski, P
dc.contributor.author Vassiliou, S
dc.contributor.author Gardiner, DL
dc.contributor.author Dalton, JP
dc.contributor.author Trenholme, KR
dc.date.accessioned 2009-12-21T02:28:43Z
dc.date.issued 2007-10-19
dc.identifier.citation Journal of Biological Chemistry, 2007, 282 (42), pp. 30817 - 30826
dc.identifier.issn 0021-9258
dc.identifier.other C1 en_US
dc.identifier.uri http://hdl.handle.net/10453/3521
dc.description.abstract A member of the M18 family of aspartyl aminopeptidases is expressed by all intra-erythrocytic stages of the human malaria parasite Plasmodium falciparum (PfM18AAP), with highest expression levels in rings. Functionally active recombinant enzyme, rPfM18AAP, and native enzyme in cytosolic extracts of malaria parasites are 560-kDa octomers that exhibit optimal activity at neutral pH and require the presence of metal ions to maintain enzymatic activity and stability. Like the human aspartyl aminopeptidase, the exopeptidase activity of PfM18AAP is exclusive to N-terminal acidic amino acids, glutamate and aspartate, making this enzyme of particular interest and suggesting that it may function alongside the malaria cytosolic neutral aminopeptidases in the release of amino acids from host hemoglobin-derived peptides. Whereas immunocytochemical studies using transgenic P. falciparum parasites show that PfM18AAP is expressed in the cytosol, immunoblotting experiments revealed that the enzyme is also trafficked out of the parasite into the surrounding parasitophorous vacuole. Antisense-mediated knockdown of PfM18AAP results in a lethal phenotype as a result of significant intracellular damage and validates this enzyme as a target at which novel antimalarial drugs could be directed. Novel phosphinic derivatives of aspartate and glutamate showed modest inhibition of rPfM18AAP but did not inhibit malaria growth in culture. However, we were able to draw valuable observations concerning the structure-activity relationship of these inhibitors that can be employed in future inhibitor optimization studies. © 2007 by The American Society for Biochemistry and Molecular Biology, Inc.
dc.language eng
dc.relation.isbasedon 10.1074/jbc.M704938200
dc.title The M18 aspartyl aminopeptidase of the human malaria parasite Plasmodium falciparum
dc.type Journal Article
dc.description.version Published
dc.parent Journal of Biological Chemistry
dc.journal.volume 42
dc.journal.volume 282
dc.journal.number 42 en_US
dc.publocation Bethesda en_US
dc.identifier.startpage 30817 en_US
dc.identifier.endpage 30826 en_US
dc.cauo.name SCI.Medical and Molecular Biosciences 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.percentage 100 en_US
dc.classification.name Microbiology en_US
dc.classification.type FOR-08 en_US
dc.location.activity ISI:000250136300050 en_US
dc.location.activity Sacramento, CA
dc.description.keywords Matrix Metalloproteases; Hemoglobin Degradation; Antimalarial Activity; Inhibition; Identification; Digestion; Bestatin; Culture; Acid; Gene en_US
dc.description.keywords Science & Technology
dc.description.keywords Technology
dc.description.keywords Physical Sciences
dc.description.keywords Engineering, Electrical & Electronic
dc.description.keywords Physics, Applied
dc.description.keywords Engineering
dc.description.keywords Physics
dc.description.keywords ENGINEERING, ELECTRICAL & ELECTRONIC
dc.description.keywords PHYSICS, APPLIED
dc.description.keywords Claw-pole permanent magnet motor
dc.description.keywords finite element analysis of magnetic field
dc.description.keywords improved phase variable model
dc.description.keywords molded SMC core
dc.description.keywords soft magnetic composite (SMC)
dc.description.keywords FINITE-ELEMENT-ANALYSIS
dc.description.keywords MODEL
dc.description.keywords Erythrocytes
dc.description.keywords Vacuoles
dc.description.keywords Cytosol
dc.description.keywords Animals
dc.description.keywords Humans
dc.description.keywords Plasmodium falciparum
dc.description.keywords Phosphinic Acids
dc.description.keywords Metals
dc.description.keywords Glutamyl Aminopeptidase
dc.description.keywords Amino Acids
dc.description.keywords Peptides
dc.description.keywords Hemoglobins
dc.description.keywords Protozoan Proteins
dc.description.keywords Recombinant Proteins
dc.description.keywords DNA, Antisense
dc.description.keywords Enzyme Inhibitors
dc.description.keywords Antimalarials
dc.description.keywords Gene Expression Regulation, Enzymologic
dc.description.keywords Structure-Activity Relationship
dc.description.keywords Substrate Specificity
dc.description.keywords Protein Transport
dc.description.keywords Phenotype
dc.description.keywords Hydrogen-Ion Concentration
dc.description.keywords Animals
dc.description.keywords Humans
dc.description.keywords Erythrocytes
dc.description.keywords Vacuoles
dc.description.keywords Cytosol
dc.description.keywords Plasmodium falciparum
dc.description.keywords Phosphinic Acids
dc.description.keywords Metals
dc.description.keywords Peptides
dc.description.keywords Glutamyl Aminopeptidase
dc.description.keywords DNA, Antisense
dc.description.keywords Amino Acids
dc.description.keywords Protozoan Proteins
dc.description.keywords Recombinant Proteins
dc.description.keywords Enzyme Inhibitors
dc.description.keywords Substrate Specificity
dc.description.keywords Protein Transport
dc.description.keywords Phenotype
dc.description.keywords Gene Expression Regulation, Enzymologic
dc.description.keywords Antimalarials
dc.description.keywords Hydrogen-Ion Concentration
dc.description.keywords Structure-Activity Relationship
dc.description.keywords Hemoglobins
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/Faculty of Science/School of Medical and Molecular Sciences
pubs.organisational-group /University of Technology Sydney/Strength - i3


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