Plasmodium falciparum Ensures Its Amino Acid Supply with Multiple Acquisition Pathways and Redundant Proteolytic Enzyme Systems

Degradation of host hemoglobin by the human malaria parasite Plasmodium falciparum is a massive metabolic process. What role this degradation plays and whether it is essential for parasite survival have not been established, nor have the roles of the various degradative enzymes been clearly defined....

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Published in:Proceedings of the National Academy of Sciences - PNAS 2006-06, Vol.103 (23), p.8840-8845
Main Authors: Liu, Jun, Istvan, Eva S., Gluzman, Ilya Y., Gross, Julia, Goldberg, Daniel E.
Format: Article
Language:English
Subjects:
Amino acids
Amino Acids - metabolism
Animals
Antimalarials
Biological Sciences
Cells, Cultured
Chromosomes - genetics
Culture Media
Doubling time
Enzymes
Genomics
Hemoglobin
Hemoglobins
Hemoglobins - metabolism
Humans
Inhibitory Concentration 50
Malaria
Parasitemia
Parasites
Parasitism
Pepstatins
Peptide Hydrolases - metabolism
Plasmodium falciparum
Plasmodium falciparum - enzymology
Plasmodium falciparum - metabolism
Protease Inhibitors
Proteases
Time Factors
Vacuoles
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Summary:Degradation of host hemoglobin by the human malaria parasite Plasmodium falciparum is a massive metabolic process. What role this degradation plays and whether it is essential for parasite survival have not been established, nor have the roles of the various degradative enzymes been clearly defined. We report that P. falciparum can grow in medium containing a single amino acid (isoleucine, the only amino acid missing from human hemoglobin). In this medium, growth of hemoglobin-degrading enzyme gene knockout lines (missing falcipain-2 and plasmepsins alone or in combination) is impaired. Blockade of plasmepsins with the potent inhibitor pepstatin A has a minimal effect on WT parasite growth but kills falcipain-2 knockout parasites at low concentrations and is even more potent on falcipain-2, plasmepsin I and IV triple knockout parasites. We conclude that: (i) hemoglobin degradation is necessary for parasite survival; (ii) hemoglobin degradation is sufficient to supply most of the parasite's amino acid requirements; (iii) external amino acid acquisition and hemoglobin digestion are partially redundant nutrient pathways; (iv) hemoglobin degradation uses dual protease families with overlapping function; and (v) hemoglobin-degrading plasmepsins are not promising drug targets.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0601876103