Import of host delta-aminolevulinate dehydratase into the malarial parasite: identification of a new drug target

Nat Med. 2000 Aug;6(8):898-903. doi: 10.1038/78659.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimalarials / pharmacology
  • Biological Transport, Active
  • Cell Membrane / enzymology
  • Erythrocytes / enzymology
  • Erythrocytes / parasitology
  • Heme / biosynthesis
  • Malaria / drug therapy
  • Malaria / enzymology
  • Malaria / parasitology
  • Mice
  • Mice, Inbred BALB C
  • Plasmodium berghei / drug effects
  • Plasmodium berghei / enzymology*
  • Porphobilinogen Synthase / genetics
  • Porphobilinogen Synthase / metabolism*

Substances

  • Antimalarials
  • Heme
  • Porphobilinogen Synthase