Plasmodium falciparum falcilysin: an unprocessed food vacuole enzyme.

Five hundred million infections and nearly two million deaths each year are attributed to the protozoan Plasmodium falciparum, a causative agent of human malaria. With the increasing prevalence of drug resistant strains, there is an urgent need to identify new drug targets. Examination of the parasite’s unique metabolic pathways, such as hemoglobin degradation, provides candidates for chemotherapeutic development. Intraerythrocytic development of the parasite is dependent upon degradation of red blood cell hemoglobin. A semi-ordered pathway of proteases mediates this catabolism, which occurs in the acidic organelle called the food vacuole. The aspartic proteases, plasmepsins I and II, are proposed to be responsible for initial cleavage of hemoglobin in a conserved hinge region of the alpha chain [1,2]. Plasmepsins, and a family of cysteine proteases, falcipain-2 and 3, then carry out further degradation of the denatured globin [2–5]. The resulting small globin peptides serve as substrates for falcilysin (FLN) [6]. FLN was first identified in 1999 when analysis of degraded globin fragments from the food vacuole revealed several peptides with cleavage sites that could not be attributed to the known proteases [7]. Specifically, a protease preferring to cleave substrates at polar or charged residues was implicated; this stands in contrast to the other hemoglobin-degrading proteases, which favor cleavage at hydrophobic residues. Purification of the native enzyme from food vacuoles revealed that it is a monomeric enzyme with a molecular weight of 130,000, by far the largest hemoglobin catabolic protease. FLN is a member of the M16 family of metalloproteases, enzymes character-