The Pathway of Hemoglobin Degradation in the Malaria Parasite Plasmodium falciparum

Daniel E. Goldberg, M.D., Ph.D.
Washington University

Seminar Hosts : UCSF Molecular Design Institute  and Department of Pharmaceutical Chemistry

2:00
January 30, 1998
S 214

Abstract

Our laboratory is interested in the biochemistry of parasitic diseases. Parasites have evolved many clever ways to infect their hosts and develop within them. Study of these processes at a molecular level should lead to treatment or prevention of parasitic infections which afflict most of humanity. We study an organism that causes malaria, Plasmodium falciparum.  P. Falciparum develops within human erythrocytes by using host hemoglobin as a nutrient source. We are studying the mechanism of hemoglobin catabloism. Our data suggest that this takes place in a specialized acidic vacuole. These two specific aspartic proteases, plasmepsins I and II, are responsible for the initial steps in hemoglobin breakdown, making strategic clips of the hemoglobin alpha chain causing the hemoglobin to unravel so that other proteases can then degrade the molecule efficiently. The plasmepsin genes have homology to human renin and cathepsin D.  ImmunoEM data suggest an unusual targeting route for the newly synthesized enzymes whereby they come to the surface as integral membrane proteins and get internalized with the host hemoglobin they are destined to degrade. When the plamepsins reach the digestive vacuole, they are cleaved and activated by a novel processing activity that we are presently studying. Current efforts focus on understanding protease specificity, designing specific protease inhibitors as antimalarial agents, following the targeting of proteases to the digestive vacuole, and defining other components of this organelle.

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