Biosynthesis and maturation of the malaria aspartic hemoglobinases plasmepsins I and II

Susan E. Francis, Ritu Banerjee, Daniel E. Goldberg

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Abstract

During the intraerythrocytic stage of infection, the malaria parasite Plasmodium falciparum digests most of the host cell hemoglobin. Hemoglobin degradation occurs in the acidic digestive vacuole and is essential for the survival of the parasite. Two aspartic proteases, plasmepsins I and II, have been isolated from the vacuole and shown to make the initial cleavages in the hemoglobin molecule. We have studied the biosynthesis of these two enzymes. Plasmepsin I is synthesized and processed to the mature form soon after the parasite invades the red blood cell, while plasmepsin II synthesis is delayed until later in development. Otherwise, biosynthesis of the plasmepsins is identical. The proplasmepsins are type II integral membrane proteins that are transported through the secretory pathway before cleavage to the soluble form. They are not glycosylated in vivo, despite the presence of several potential glycosylation sites. Proplasmepsin maturation appears to require acidic conditions and is reversibly inhibited by the tripeptide aldehydes N- acetyl-L-leucyl-L-leucyl-nor-leucinal and N-acetyl-L-leucyl-L-leucyl- methional. These compounds are known to inhibit cysteine proteases and the chymotryptic activity of proteasomes but not aspartic proteases. However, proplasmepsin processing is not blocked by other cysteine protease inhibitors, nor by the proteasome inhibitor lactacystin. Processing is also not blocked by aspartic protease inhibitors. This inhibitor profile suggests that unlike most other aspartic proteases, proplasmepsin maturation may not be autocatalytic in vivo, but instead could require the action of an unusual processing enzyme. Compounds that block processing are expected to be potent antimalarials.

Original languageEnglish (US)
Pages (from-to)14961-14968
Number of pages8
JournalJournal of Biological Chemistry
Volume272
Issue number23
DOIs
StatePublished - Jun 6 1997

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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