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Malaria is a major cause of morbidity and mortality in many areas of the world, particularly in sub-Saharan Africa and southeast Asia. The number of malaria infections reach 200 million annually, resulting in 1 to 3 million deaths per year. Children are the most frequent victims, comprising 85% of all malaria related mortality. (1) Even worse, widespread drug resistance and the lack of novel antimalarials present major challenges in our future fight against malaria.
The causative agent of human malaria is the protozoan parasite Plasmodium of which Plasmodium falciparum is the most virulent. The lifecycle of Plasmodium includes its insect vector, the female Anopheles mosquito, and the human host. Some unusual metabolic pathways can be found within P. falciparum. Most notably, the heme detoxification pathway of P. falciparum is unique, making this pathway an attractive drug target. The goal of our laboratory is to study the mechanism of heme detoxification in P. falciparum. P. falciparum spends a portion of its life cycle inside the host's erythrocytes. During the intraerythrocytic cycle, P. falciparum ingests 25 - 75% of the host cell hemoglobin. The hemoglobin is degraded inside the parasite's food vacuole (pH 4.5-5.5) by specific proteases, and the amino acids from the degraded globin are used as the building blocks for the parasite's own intermediary metabolism. Upon hemoglobin cleavage, free heme is released. As free heme is cytotoxic, detoxification of the liberated heme is critical for plasmodia survival. In mammals, free heme is degraded via the heme oxygenase / biliverdin reductase pathway. In P. falciparum, heme detoxification is achieved by polymerizing free heme into insoluble crystalline material called hemozoin (also termed malaria pigment). (2,3) Hemozoin is believed to be structurally identical to that of b-hematin in which ferric iron of one heme is coordinated to the propionate carboxylate group of the next heme. (4) Due to its uniqueness, the heme polymerization pathway is a very attractive drug target and is the focus of our work.  The mechanism of heme polymerization by P. falciparum is still a mystery. Several hypotheses have been proposed: Heme polymerization (i) is a protein mediated process (mediated by an enzyme "heme polymerase" or a scaffold protein); (ii) requires a non-protein component of the parasite; (iii) is a spontaneous process occurring in the acidic environment of the food vacuole; (iv) is an autocatalytic process in which hemozoin, once formed, may seed more hemozoin formation. Slater and Cerami have demonstrated that unfractionated plasmodia lysate can mediate hemozoin formation in vitro (5). Work by Dan Goldberg's lab (Washington University) has offered Histidine-Rich Proteins (HRPs) as the putative heme polymerase (6). While heme polymerization has been observed in the absence of any protein, the necessary reaction conditions are far from physiologic, requiring high concentration of acetic acid and high temperature (70 °C) (4). The exact role HRPs play
in hemozoin formation is unknown. Catalytic as well as scaffolding roles
have been proposed. The goal of our laboratory is to gain molecular and
biochemical understanding of the mechanism of HRP2-mediated heme polymerization.
Furthermore, we are interested in studying the mechanism of action of quinoline
antimalarials such as chloroquine.
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