The treatment of Plasmodium falciparum-infected erythrocytes with chloroquine leads to accumulation of ferriprotoporphyrin IX bound to particular parasite proteins and to the inhibition of the parasite's 6-phosphogluconate dehydrogenase.
Ferriprotoporphyrin IX (FPIX) is a potentially toxic product of hemoglobin digestion by intra-erythrocytic malaria parasites. It is detoxified by biomineralization or through degradation by glutathione. Both processes are inhibited by the antimalarial drug chloroquine, leading to the accumulation of FPIX in the membranes of the infected cell and their consequent permeabilization. It is shown here that treatment of Plasmodium falciparum-infected erythrocytes with chloroquine also leads to the binding of FPIX to a subset of parasite proteins. Parasite enzymes such as aldolase, pyrimidine nucleaside monophosphate kinase and pyrimidine 5'-nucleotidase were inhibited by FPIX in vitro, but only the activity of 6-phosphogluconate dehydrogenase was reduced significantly in cells after drug treatment. Additional proteins were extracted from parasite cytosol by their ability to bind FPIX. Sequencing of these proteins identified heat shock proteins 90 and 70, enolase, elongation factor 1-alpha, phoshoglycerate kinase, glyceraldehyde 3-phosphate dehydrogenase, L-lactate dehydrogenase and gametocytogenesis onset-specific protein. The possible involvement of these proteins in the antimalarial mode of action of chloroquine is discussed. It is concluded that drug-induced binding of FPIX to parasite glycolytic enzymes could underlie the demonstrable inhibition of glycolysis by chloroquine. The inhibition of 6-phosphogluconate dehydrogenase could explain the reduction of the activity of the hexose monophosphate shunt by the drug. Inhibition of both processes is deleterious to parasite survival. Binding of FPIX to other proteins is probably inconsequential to the rapid killing of the parasite by chloroquine.
Famin
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O
Department of Biological Chemistry, Institute of Life Sciences, Hebrew University of Jerusalem, Jerusalem 91904, Israel.
Ginsburg
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H
D000818:Animals; D000962:Antimalarials / Q000494:pharmacology* / Q000627:therapeutic use; D002738:Chloroquine / Q000378:metabolism* / Q000494:pharmacology* / Q000627:therapeutic use; D004910:Erythrocyte Membrane; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology*; D006019:Glycolysis / Q000187:drug effects; D006427:Hemin / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D016778:Malaria, Falciparum / Q000188:drug therapy; D010734:Phosphogluconate Dehydrogenase / Q000037:antagonists & inhibitors*; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D015800:Protozoan Proteins / Q000378:metabolism
D000962:Antimalarials; D015800:Protozoan Proteins; C069269:ferriprotoporphyrin IX-chloroquine complex; D006427:Hemin; D002738:Chloroquine; D010734:Phosphogluconate Dehydrogenase