The M18 aspartyl aminopeptidase of the human malaria parasite Plasmodium falciparum

Teuscher, F; Lowther, J; Skinner-Adams, TS; Spielmann, T; Dixon, MWA; Stack, CM; Donnelly, S; Mucha, A; Kafarski, P; Vassiliou, S; Gardiner, DL; Dalton, JP; Trenholme, KR

The M18 aspartyl aminopeptidase of the human malaria parasite Plasmodium falciparum

Teuscher, F Lowther, J Skinner-Adams, TS Spielmann, T Dixon, MWA Stack, CM Donnelly, S

Mucha, A Kafarski, P Vassiliou, S Gardiner, DL Dalton, JP Trenholme, KR

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Publication Type:: Journal Article
Citation:: Journal of Biological Chemistry, 2007, 282 (42), pp. 30817 - 30826
Issue Date:: 2007-10-19

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Field	Value	Language
dc.contributor.author	Teuscher, F	en_US
dc.contributor.author	Lowther, J	en_US
dc.contributor.author	Skinner-Adams, TS	en_US
dc.contributor.author	Spielmann, T	en_US
dc.contributor.author	Dixon, MWA	en_US
dc.contributor.author	Stack, CM	en_US
dc.contributor.author	Donnelly, S https://orcid.org/0000-0003-2005-3698	en_US
dc.contributor.author	Mucha, A	en_US
dc.contributor.author	Kafarski, P	en_US
dc.contributor.author	Vassiliou, S	en_US
dc.contributor.author	Gardiner, DL	en_US
dc.contributor.author	Dalton, JP	en_US
dc.contributor.author	Trenholme, KR	en_US
dc.date.issued	2007-10-19	en_US
dc.identifier.citation	Journal of Biological Chemistry, 2007, 282 (42), pp. 30817 - 30826	en_US
dc.identifier.issn	0021-9258	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.	en_US
dc.relation.ispartof	Journal of Biological Chemistry	en_US
dc.relation.isbasedon	10.1074/jbc.M704938200	en_US
dc.subject.classification	Biochemistry & Molecular Biology	en_US
dc.subject.mesh	Erythrocytes	en_US
dc.subject.mesh	Vacuoles	en_US
dc.subject.mesh	Cytosol	en_US
dc.subject.mesh	Animals	en_US
dc.subject.mesh	Humans	en_US
dc.subject.mesh	Plasmodium falciparum	en_US
dc.subject.mesh	Phosphinic Acids	en_US
dc.subject.mesh	Metals	en_US
dc.subject.mesh	Glutamyl Aminopeptidase	en_US
dc.subject.mesh	Amino Acids	en_US
dc.subject.mesh	Peptides	en_US
dc.subject.mesh	Hemoglobins	en_US
dc.subject.mesh	Protozoan Proteins	en_US
dc.subject.mesh	Recombinant Proteins	en_US
dc.subject.mesh	DNA, Antisense	en_US
dc.subject.mesh	Enzyme Inhibitors	en_US
dc.subject.mesh	Antimalarials	en_US
dc.subject.mesh	Gene Expression Regulation, Enzymologic	en_US
dc.subject.mesh	Structure-Activity Relationship	en_US
dc.subject.mesh	Substrate Specificity	en_US
dc.subject.mesh	Protein Transport	en_US
dc.subject.mesh	Phenotype	en_US
dc.subject.mesh	Hydrogen-Ion Concentration	en_US
dc.title	The M18 aspartyl aminopeptidase of the human malaria parasite Plasmodium falciparum	en_US
dc.type	Journal Article
utslib.citation.volume	42	en_US
utslib.citation.volume	282	en_US
utslib.for	0605 Microbiology	en_US
utslib.for	03 Chemical Sciences	en_US
utslib.for	06 Biological Sciences	en_US
utslib.for	11 Medical and Health Sciences	en_US
dc.location.activity	ISI:000250136300050	en_US
dc.location.activity	Sacramento, CA
pubs.embargo.period	Not known	en_US
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 Life Sciences
utslib.copyright.status	closed_access
pubs.issue	42	en_US
pubs.publication-status	Published	en_US
pubs.volume	282	en_US

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.

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http://hdl.handle.net/10453/3521