Biochemical and cellular characterisation of the Plasmodium falciparum M1 alanyl aminopeptidase (PfM1AAP) and M17 leucyl aminopeptidase (PfM17LAP)

The Plasmodium falciparum M1 alanyl aminopeptidase and M17 leucyl aminopeptidase, PfM1AAP and PfM17LAP, are potential targets for novel anti-malarial drug development. Inhibitors of these aminopeptidases have been shown to kill malaria parasites in culture and reduce parasite growth in murine models...

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Published in:	Scientific reports 2021-02, Vol.11 (1), p.2854-2854, Article 2854
Main Authors:	Mathew, Rency, Wunderlich, Juliane, Thivierge, Karine, Cwiklinski, Krystyna, Dumont, Claire, Tilley, Leann, Rohrbach, Petra, Dalton, John P
Format:	Article
Language:	eng
Subjects:	Aminopeptidase Animal models Animals Antimalarials - pharmacology Antimalarials - therapeutic use CD13 Antigens - antagonists & inhibitors CD13 Antigens - chemistry CD13 Antigens - isolation & purification CD13 Antigens - metabolism Cell culture Cell Fractionation Cells, Cultured Cytoplasm Cytosol Cytosol - enzymology Drug Development Enzyme Assays Enzyme kinetics Enzymes Erythrocytes - parasitology Hemoglobin Humans Hydrogen-Ion Concentration Leucyl aminopeptidase Leucyl Aminopeptidase - antagonists & inhibitors Leucyl Aminopeptidase - chemistry Leucyl Aminopeptidase - isolation & purification Leucyl Aminopeptidase - metabolism Malaria Malaria, Falciparum - drug therapy Malaria, Falciparum - parasitology Parasites pH effects Plasmodium falciparum Plasmodium falciparum - drug effects Plasmodium falciparum - enzymology Protein biosynthesis Protozoan Proteins - antagonists & inhibitors Protozoan Proteins - chemistry Protozoan Proteins - isolation & purification Protozoan Proteins - metabolism Rabbits Recombinant Proteins - chemistry Recombinant Proteins - isolation & purification
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Summary:	The Plasmodium falciparum M1 alanyl aminopeptidase and M17 leucyl aminopeptidase, PfM1AAP and PfM17LAP, are potential targets for novel anti-malarial drug development. Inhibitors of these aminopeptidases have been shown to kill malaria parasites in culture and reduce parasite growth in murine models. The two enzymes may function in the terminal stages of haemoglobin digestion, providing free amino acids for protein synthesis by the rapidly growing intra-erythrocytic parasites. Here we have performed a comparative cellular and biochemical characterisation of the two enzymes. Cell fractionation and immunolocalisation studies reveal that both enzymes are associated with the soluble cytosolic fraction of the parasite, with no evidence that they are present within other compartments, such as the digestive vacuole (DV). Enzyme kinetic studies show that the optimal pH of both enzymes is in the neutral range (pH 7.0-8.0), although PfM1AAP also possesses some activity (
ISSN:	2045-2322 2045-2322