Order and specificity of the Plasmodium falciparum hemoglobin degradation pathway

Ilya Y. Gluzman, Susan E. Francis, Anna Oksman, Christine E. Smith, Kevin L. Duffin, Daniel E. Goldberg

Research output: Contribution to journalArticlepeer-review

248 Scopus citations

Abstract

The human malaria parasite, Plasmodium falciparum, degrades nearly all its host cell hemoglobin during a short segment of its intraerythrocytic development. This massive catabolic process occurs in an acidic organelle, the digestive vacuole. Aspartic and cysteine proteases have been implicated in this pathway. We have isolated three vacuolar proteases that account for most of the globin-degrading activity of the digestive vacuole. One is the previously described aspartic hemoglobinase that initiates hemoglobin degradation. A second aspartic protease is capable of cleaving hemoglobin with an overlapping specificity, but seems to prefer acid-denaturated globin. The third is a cysteine protease that does not recognize native hemoglobin but readily cleaves denatured globin. It is synergistic with the aspartic hemoglobinase, both by in vitro assay of hemoglobin degradation, and by isohologram analysis of protease inhibitor-treated parasites in culture. The cysteine protease is highly sensitive to chloroquine-heme complex, suggesting a possible mechanism of 4-aminoquinoline antimalarial action. The data suggest an ordered pathway of hemoglobin catabolism that presents an excellent target for chemotherapy.

Original languageEnglish
Pages (from-to)1602-1608
Number of pages7
JournalJournal of Clinical Investigation
Volume93
Issue number4
DOIs
StatePublished - Apr 1994

Keywords

  • aspartic
  • chloroquine
  • hemoglobin
  • plasmodium
  • protease

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