Identification and functional analysis of the primary pantothenate transporter, PfPAT, of the human malaria parasite Plasmodium falciparum
| Autor: | Abhisek Ghosal, Yoann Augagneur, Sidney Altman, Donna Wesolowski, Niseema Pachikara, Hamid M. Said, Aprajita Garg, Priti Kumar, Lise Jaubert, Skye Zeller, Choukri Ben Mamoun, Emmanuel Cornillot, Sahar Usmani-Brown, Matthieu Schiavoni |
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| Rok vydání: | 2013 |
| Předmět: |
Erythrocytes
Saccharomyces cerevisiae Proteins Morpholines Saccharomyces cerevisiae Mutant Molecular Sequence Data Plasmodium falciparum Drug Resistance Protozoan Proteins medicine.disease_cause Biochemistry Pantothenic Acid Host-Parasite Interactions Antimalarials Chloroquine parasitic diseases medicine Animals Humans Amino Acid Sequence Malaria Falciparum Microscopy Immunoelectron Molecular Biology Phylogeny Mutation biology Sequence Homology Amino Acid Symporters HEK 293 cells Cell Membrane Genetic Complementation Test Transporter Cell Biology biology.organism_classification HEK293 Cells Pyrimethamine Metabolism Microscopy Fluorescence Symporter medicine.drug |
| Zdroj: | The Journal of biological chemistry. 288(28) |
| ISSN: | 1083-351X |
| Popis: | The human malaria parasite Plasmodium falciparum is absolutely dependent on the acquisition of host pantothenate for its development within human erythrocytes. Although the biochemical properties of this transport have been characterized, the molecular identity of the parasite-encoded pantothenate transporter remains unknown. Here we report the identification and functional characterization of the first protozoan pantothenate transporter, PfPAT, from P. falciparum. We show using cell biological, biochemical, and genetic analyses that this transporter is localized to the parasite plasma membrane and plays an essential role in parasite intraerythrocytic development. We have targeted PfPAT to the yeast plasma membrane and showed that the transporter complements the growth defect of the yeast fen2Δ pantothenate transporter-deficient mutant and mediates the entry of the fungicide drug, fenpropimorph. Our studies in P. falciparum revealed that fenpropimorph inhibits the intraerythrocytic development of both chloroquine- and pyrimethamine-resistant P. falciparum strains with potency equal or better than that of currently available pantothenate analogs. The essential function of PfPAT and its ability to deliver both pantothenate and fenpropimorph makes it an attractive target for the development and delivery of new classes of antimalarial drugs. Background: Pantothenate transport is essential for Plasmodium development. The transporter that mediates entry of pantothenate is unknown. Results: PfPAT encodes the primary pantothenate transporter of P. falciparum. Conclusion: PfPAT plays an essential function in parasite development and thus is a valid target for antimalarial therapy. Significance: PfPAT is the first pantothenate transporter identified and characterized in protozoan parasites and a valid target for therapy. |
| Databáze: | OpenAIRE |
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