title: Order and specificity of the Plasmodium falciparum hemoglobin degradation pathway.
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-denatured 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 isobologram 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.
authors.affiliation: Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri 63110.
authors.forename: I Y
authors.initials: IY
authors.lastname: Gluzman
authors.forename: S E
authors.initials: SE
authors.lastname: Francis
authors.forename: A
authors.initials: A
authors.lastname: Oksman
authors.forename: C E
authors.initials: CE
authors.lastname: Smith
authors.forename: K L
authors.initials: KL
authors.lastname: Duffin
authors.forename: D E
authors.initials: DE
authors.lastname: Goldberg
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D003546:Cysteine Endopeptidases / Q000302:isolation & purification; D010450:Endopeptidases / Q000302:isolation & purification* / Q000502:physiology; D006454:Hemoglobins / Q000378:metabolism*; D008969:Molecular Sequence Data; D010963:Plasmodium falciparum / Q000378:metabolism*; D014617:Vacuoles / Q000201:enzymology
chemical_list: D006454:Hemoglobins; D010450:Endopeptidases; D003546:Cysteine Endopeptidases