Overexpression of Leucyl Aminopeptidase in Plasmodium falciparum Parasites. Target for the antimalarial activity of bestatin

Gardiner, Donald L., Trenholme, Katharine R., Skinner-Adams, Tina S., Stack, Colin M. and Dalton, John P. (2006) Overexpression of Leucyl Aminopeptidase in Plasmodium falciparum Parasites. Target for the antimalarial activity of bestatin. Journal of Biological Chemistry, 281 3: 1741-1745. doi:10.1074/jbc.M508955200

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Author Gardiner, Donald L.
Trenholme, Katharine R.
Skinner-Adams, Tina S.
Stack, Colin M.
Dalton, John P.
Title Overexpression of Leucyl Aminopeptidase in Plasmodium falciparum Parasites. Target for the antimalarial activity of bestatin
Journal name Journal of Biological Chemistry   Check publisher's open access policy
ISSN 0021-9258
Publication date 2006-01-20
Sub-type Article (original research)
DOI 10.1074/jbc.M508955200
Open Access Status File (Publisher version)
Volume 281
Issue 3
Start page 1741
End page 1745
Total pages 5
Editor H. Tabor
Place of publication Bethesda, U.S.
Publisher American Society for Biochemistry & Molecular Biology
Language eng
Subject C1
320403 Medical Infection Agents (incl. Prions)
730101 Infectious diseases
730213 Preventive medicine
Abstract Malaria aminopeptidases are important in the generation and regulation of free amino acids that are used in protein anabolism and for maintaining osmotic stability within the infected erythrocyte. The intraerythrocytic development of malaria parasites is blocked when the activity of aminopeptidases is specifically inhibited by reagents such as bestatin. One of the major aminopeptidases of malaria parasites is a leucyl aminopeptidase of the M17 family. We reasoned that, when this enzyme was the target of bestatin inhibition, its overexpression in malaria cells would lead to a reduced sensitivity to the inhibitor. To address this supposition, transgenic Plasmodium falciparum parasites overexpressing the leucyl aminopeptidase were generated by transfection with a plasmid that housed the full-length gene. Transgenic parasites expressed a 65-kDa protein close to the predicted molecule size of 67.831 kDa for the introduced leucyl aminopeptidase, and immunofluorescence studies localized the protein to the cytosol, the location of the native enzyme. The product of the transgene was shown to be functionally active with cytosolic extracts of transgenic parasites exhibiting twice the leucyl aminopeptidase activity compared with wildtype parasites. In vitro inhibitor sensitivity assays demonstrated that the transgenic parasites were more resistant to bestatin (EC50 64 mu M) compared with the parent parasites (EC50 25 mu M). Overexpression of genes in malaria parasites would have general application in the identification and validation of targets for antimalarial drugs.
Keyword Malaria Parasites
Hemoglobin Degradation
Chabaudi Chabaudi
Amino-acids
M1 Family
Cysteine
Proteases
Inhibition
Hydrolysis
Proteins
Biochemistry & Molecular Biology
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
2007 Higher Education Research Data Collection
School of Medicine Publications
 
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Created: Wed, 15 Aug 2007, 19:53:17 EST