title: Cysteine proteinase inhibitors block early steps in hemoglobin degradation by cultured malaria parasites.
abstract: Erythrocytic malaria parasites degrade hemoglobin as a source of amino acids for parasite protein synthesis. Cysteine proteinase inhibitors have been shown to block the hydrolysis of globin by cultured parasites, indicating that a malarial cysteine proteinase is required for this process. In the present study, we have evaluated the role of parasite proteinases in earlier steps of hemoglobin degradation, namely the disassociation of the hemoglobin tetramer and the separation of heme from globin. Hemoglobin did not spontaneously denature or release heme under the pH and reducing conditions of the malarial food vacuole, suggesting that parasite enzymatic activity is necessary for early steps in hemoglobin degradation. The incubation of cultured parasites with cysteine proteinase inhibitors inhibited the denaturation of hemoglobin and the release of heme from globin. These results suggest that, in addition to its role in globin hydrolysis, a malarial cysteine proteinase participates in the dissociation of the hemoglobin tetramer and the release of heme from globin. Thus, the malarial cysteine proteinase is a promising target for antimalarial chemotherapy.
authors.affiliation: Department of Medicine, San Francisco General Hospital, University of California, San Francisco, USA.
authors.forename: N D
authors.initials: ND
authors.lastname: Gamboa de Domínguez
authors.forename: P J
authors.initials: PJ
authors.lastname: Rosenthal
mesh_terms: D000818:Animals; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D004151:Dipeptides / Q000494:pharmacology*; D006418:Heme / Q000378:metabolism; D006454:Hemoglobins / Q000737:chemistry / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis / Q000187:drug effects; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000378:metabolism; D011487:Protein Conformation; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014617:Vacuoles / Q000201:enzymology
chemical_list: D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; D006454:Hemoglobins; D015800:Protozoan Proteins; C092609:benzyloxycarbonyl-phenylalanyl-arginine fluoromethane; D006418:Heme; D003546:Cysteine Endopeptidases; C099607:falcipain; D007930:Leucine; C024974:E 64