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Falcipains and Other Cysteine Proteases of Malaria Parasites

  • Philip J. Rosenthal
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 712)

Abstract

A number of cysteine proteases of malaria parasites have been described and many more are suggested by analysis of the Plasmodium falciparum genome sequence. The best characterized of these proteases are the falcipains, a family of four papain-family enzymes. Falcipain-2 and falcipain-3 act in concert with other proteases to hydrolyze host erythrocyte hemoglobin in the parasite food vacuole. Disruption of the falcipain-2 gene led to a transient block in hemoglobin hydrolysis and parasites with increased sensitivity to protease inhibitors. Disruption of the falcipain-3 gene was not possible, strongly suggesting that this protease is essential for erythrocytic parasites. Disruption of the falcipain-1 gene did not alter development in erythrocytes, but led to decreased production of oocysts in mosquitoes. other papain-family proteases predicted by the genome sequence include dipeptidyl peptidases, a calpain homolog and serine-repeat antigens (SERAs). Dipeptidyl aminopeptidase 1 appears to be essential and localized to the food vacuole, suggesting a role in hemoglobin hydrolysis. Dipeptidyl aminopeptidase 3 appears to play a role in the rupture of erythrocytes by mature parasites. the P. falciparum calpain homolog gene could not be disrupted, suggesting that the protein is essential and a role in the parasite cell cycle has been suggested. Nine P. falciparum SERAs have cysteine protease motifs, but in some the active site cys is replaced by a Ser. Gene disruption studies suggested that SERA-5 and SERA-6 are essential. activation of SERA-5 by a serine protease seems to be required for merozoite egress from the erythrocyte. New drugs for malaria are greatly needed and cysteine proteases represent potential drug targets. cysteine protease inhibitors have demonstrated potent antimalarial effects and the optimization and testing of falcipain inhibitor antimalarials is underway.

Keywords

Plasmodium Falciparum Cysteine Protease Aspartic Protease Cysteine Protease Inhibitor Parasitophorous Vacuole 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Landes Bioscience and Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Philip J. Rosenthal
    • 1
  1. 1.Department of Medicine, San Francisco General HospitalUniversity of CaliforniaSan FranciscoUSA

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