Import of host delta-aminolevulinate dehydratase into the malarial parasite: identification of a new drug target.
The parasite Plasmodium berghei imports the enzyme delta-aminolevulinate dehydratase (ALAD), and perhaps the subsequent enzymes of the pathway from the host red blood cell to sustain heme synthesis. Here we have studied the mechanism of this import. A 65-kDa protein on the P. berghei membrane specifically bound to mouse red blood cell ALAD, and a 93-amino-acid fragment (ALAD-DeltaNC) of the host erythrocyte ALAD was able to compete with the full-length enzyme for binding to the P. berghei membrane. ALAD-DeltaNC was taken up by the infected red blood cell when added to a culture of P. falciparum and this led to a substantial decrease in ALAD protein and enzyme activity and, subsequently, heme synthesis in the parasite, resulting in its death.
Bonday
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ZQ
Department of Biochemistry, Indian Institute of Science Bangalore: 560 012, India.
Dhanasekaran
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S
Rangarajan
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PN
Padmanaban
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G
D000818:Animals; D000962:Antimalarials / Q000494:pharmacology; D001693:Biological Transport, Active; D002462:Cell Membrane / Q000201:enzymology; D004912:Erythrocytes / Q000201:enzymology / Q000469:parasitology; D006418:Heme / Q000096:biosynthesis; D008288:Malaria / Q000188:drug therapy / Q000201:enzymology / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D010962:Plasmodium berghei / Q000187:drug effects / Q000201:enzymology*; D000623:Porphobilinogen Synthase / Q000235:genetics / Q000378:metabolism*
D000962:Antimalarials; D006418:Heme; D000623:Porphobilinogen Synthase