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The M18 aspartyl aminopeptidase of the human malaria parasite Plasmodium falciparum.

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.
AuthorsFranka Teuscher, Jonathan Lowther, Tina S Skinner-Adams, Tobias Spielmann, Matthew W A Dixon, Colin M Stack, Sheila Donnelly, Artur Mucha, Paweł Kafarski, Stamatia Vassiliou, Donald L Gardiner, John P Dalton, Katharine R Trenholme
JournalThe Journal of biological chemistry (J Biol Chem) Vol. 282 Issue 42 Pg. 30817-26 (Oct 19 2007) ISSN: 0021-9258 [Print] United States
PMID17720817 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Amino Acids
  • Antimalarials
  • DNA, Antisense
  • Enzyme Inhibitors
  • Hemoglobins
  • Metals
  • Peptides
  • Phosphinic Acids
  • Protozoan Proteins
  • Recombinant Proteins
  • Glutamyl Aminopeptidase
Topics
  • Amino Acids (metabolism)
  • Animals
  • Antimalarials (chemistry, pharmacology, therapeutic use)
  • Cytosol (enzymology)
  • DNA, Antisense (genetics, pharmacology)
  • Enzyme Inhibitors (chemistry, pharmacology, therapeutic use)
  • Erythrocytes (enzymology, parasitology)
  • Gene Expression Regulation, Enzymologic (drug effects, genetics)
  • Glutamyl Aminopeptidase (antagonists & inhibitors, chemistry, genetics)
  • Hemoglobins (metabolism)
  • Humans
  • Hydrogen-Ion Concentration
  • Metals (chemistry, metabolism)
  • Peptides (metabolism)
  • Phenotype
  • Phosphinic Acids (chemistry, pharmacology, therapeutic use)
  • Plasmodium falciparum (enzymology, genetics)
  • Protein Transport (drug effects, genetics)
  • Protozoan Proteins (antagonists & inhibitors, chemistry, genetics)
  • Recombinant Proteins (antagonists & inhibitors, chemistry, genetics)
  • Structure-Activity Relationship
  • Substrate Specificity (drug effects, genetics)
  • Vacuoles (enzymology, parasitology)

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