Molecular characterization and inhibition of a Plasmodium falciparum aspartic hemoglobinase.
Intraerythrocytic malaria parasites rapidly degrade virtually all of the host cell hemoglobin. We have cloned the gene for an aspartic hemoglobinase that initiates the hemoglobin degradation pathway in Plasmodium falciparum. It encodes a protein with 35% homology to human renin and cathepsin D, but has an unusually long pro-piece that includes a putative membrane spanning anchor. Immunolocalization studies place the enzyme in the digestive vacuole and throughout the hemoglobin ingestion pathway, suggesting an unusual protein targeting route. A peptidomimetic inhibitor selectively blocks the aspartic hemoglobinase, prevents hemoglobin degradation and kills the organism. We conclude that Plasmodium hemoglobin catabolism is a prime target for antimalarial chemotherapy and have identified a lead compound towards this goal.
Francis
S E
SE
Department of Molecular Microbiology, Washington University School of Medicine, St Louis, MO.
Gluzman
I Y
IY
Oksman
A
A
Knickerbocker
A
A
Mueller
R
R
Bryant
M L
ML
Sherman
D R
DR
Russell
D G
DG
Goldberg
D E
DE
D000595:Amino Acid Sequence; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D003001:Cloning, Molecular; D016054:DNA, Protozoan; D004151:Dipeptides / Q000494:pharmacology; D005091:Exons; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D016253:Microscopy, Immunoelectron; D008969:Molecular Sequence Data; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology*; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D014617:Vacuoles / Q000201:enzymology
D000962:Antimalarials; D016054:DNA, Protozoan; D004151:Dipeptides; D006454:Hemoglobins; D015800:Protozoan Proteins; C085835:SC 50083; D016282:Aspartic Acid Endopeptidases; C089643:plasmepsin