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Chapter 16 : Proteases and Hemoglobin Degradation

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Abstract:

This chapter reviews the current understanding of the reasons for hemoglobin degradation, the mechanism of hemoglobin breakdown, the proteases that contribute to this process, and the potential for new antimalarial therapies that block hemoglobin hydrolysis. A large body of work suggests that a principal source of amino acids for erythrocytic parasites is the hydrolysis of globin. De novo synthesis of amino acids appears to play only a small role in supplying parasite amino acids. In , ring-stage parasites pinocytose the hemoglobin-rich erythrocyte cytosol into small vesicles. Upon its delivery to the food vacuole, and perhaps during vesicular transit to this organelle, hemoglobin is subjected to an acidic pH. Proteases of multiple catalytic classes appear to contribute to hemoglobin degradation. Biochemical characterizations of food vacuole aspartic and cysteine proteases and metalloproteases have shown that these enzymes hydrolyze hemoglobin or globin in vitro, supporting roles in hemoglobin hydrolysis. Evidence for a role for cysteine proteases in hemoglobin hydrolysis came from the observation that cysteine protease inhibitors cause a dramatic morphological abnormality in trophozoites, whereby food vacuoles swell and fill with undegraded hemoglobin. The processing of hemoglobin peptides in the cytosol is probably performed, at least in part, by a neutral metalloaminopeptidase. Homologs of proteases have been identified in other plasmodial species. Considering the selection of drug resistance, a recent study showed that parasites resistant to vinyl sulfone cysteine protease inhibitors could be selected by incubation of cultured parasites with stepwise increases in concentrations of inhibitor.

Citation: Rosenthal P. 2005. Proteases and Hemoglobin Degradation, p 311-326. In Sherman I (ed), Molecular Approaches to Malaria. ASM Press, Washington, DC. doi: 10.1128/9781555817558.ch16

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Tables

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TABLE 1

Features of proteases that may play roles in hemoglobin hydrolysis

Citation: Rosenthal P. 2005. Proteases and Hemoglobin Degradation, p 311-326. In Sherman I (ed), Molecular Approaches to Malaria. ASM Press, Washington, DC. doi: 10.1128/9781555817558.ch16

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