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J. Biol. Chem., Vol. 283, Issue 19, 12870-12876, May 9, 2008

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Plasmodium Food Vacuole Plasmepsins Are Activated by Falcipains^*

Mark E. Drew, Ritu Banerjee, Eric W. Uffman^¶, Scott Gilbertson^||, Philip J. Rosenthal^**1, and Daniel E. Goldberg²

From the Departments of Medicine and Molecular Microbiology, Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, Missouri 63110, the Division of Infectious Diseases, Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94143, ^¶Chemir Analytical Services, St. Louis, Missouri 63043, the ^||Department of Pharmacology and Toxicology, Chemical Biology Program, University of Texas Medical Branch, Galveston, Texas 77555-0650, and the ^**Department of Medicine, San Francisco General Hospital, University of California, San Francisco, California 94143-0811

Intraerythrocytic malaria parasites use host hemoglobin as a major nutrient source. Aspartic proteases (plasmepsins) and cysteine proteases (falcipains) function in the early steps of the hemoglobin degradation pathway. There is extensive functional redundancy within and between these protease families. Plasmepsins are synthesized as integral membrane proenzymes that are activated by cleavage from the membrane. This cleavage is mediated by a maturase activity whose identity has been elusive. We have used a combination of cell biology, chemical biology, and enzymology approaches to analyze this processing event. These studies reveal that plasmepsin processing occurs primarily via the falcipains; however, if falcipain activity is blocked, autoprocessing can take place, serving as an alternate activation system. These results establish a further level of redundancy between the protease families involved in Plasmodium hemoglobin degradation.

Received for publication, October 31, 2007 , and in revised form, February 1, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants AI-47798 (to D. E. G.) and AI-035800 (to P. J. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Doris Duke Charitable Foundation Distinguished Clinical Scientist.

² To whom correspondence should be addressed: Howard Hughes Medical Institute, Depts. of Molecular Microbiology and Medicine, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, Missouri 63110. Tel.: 314-362-1514; Fax: 314-367-3214; E-mail: goldberg{at}borcim.wustl.edu.

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