The Molecular Basis of Folate Salvage in Plasmodium falciparum
| Autor: | Sanjeev Krishna, David J. Johnson, Stephen A. Ward, Alexis Nzila, Edwin Ochong, Susan Beveridge, Paul M. O'Neill, J. Enrique Salcedo-Sora, Giancarlo A. Biagini, Patrick G. Bray, Paul A. Stocks |
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| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Plasmodium
Plasmodium falciparum Catabolite repression Protozoan Proteins Biological Transport Active Tetrahydrofolates Biochemistry 03 medical and health sciences chemistry.chemical_compound Folic Acid Escherichia coli Humans Molecular Biology Nucleotide salvage 030304 developmental biology 0303 health sciences biology 030306 microbiology Probenecid Cell Biology Metabolism Membrane transport Uricosuric Agents biology.organism_classification Folate Membrane Transporters 3. Good health Malaria Transporters Methotrexate chemistry Membrane Transport Antifolate Folic Acid Antagonists p-Amino Benzoic Acid (pABA) Folic Acid Transporters Folate Metabolism |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 1083-351X 0021-9258 |
| Popis: | Background: Antifolates have been effective antimalarial drugs. Results: Two proteins of P. falciparum facilitate membrane transport of folates but also of pABA, a precursor of folates. Conclusion: At the concentration that pABA is in the human plasma it would have a higher impact on the parasite's fitness. Significance: pABA metabolism could be a valuable target in the effort to further antimalarial chemotherapy. Tetrahydrofolates are essential cofactors for DNA synthesis and methionine metabolism. Malaria parasites are capable both of synthesizing tetrahydrofolates and precursors de novo and of salvaging them from the environment. The biosynthetic route has been studied in some detail over decades, whereas the molecular mechanisms that underpin the salvage pathway lag behind. Here we identify two functional folate transporters (named PfFT1 and PfFT2) and delineate unexpected substrate preferences of the folate salvage pathway in Plasmodium falciparum. Both proteins are localized in the plasma membrane and internal membranes of the parasite intra-erythrocytic stages. Transport substrates include folic acid, folinic acid, the folate precursor p-amino benzoic acid (pABA), and the human folate catabolite pABAGn. Intriguingly, the major circulating plasma folate, 5-methyltetrahydrofolate, was a poor substrate for transport via PfFT2 and was not transported by PfFT1. Transport of all folates studied was inhibited by probenecid and methotrexate. Growth rescue in Escherichia coli and antifolate antagonism experiments in P. falciparum indicate that functional salvage of 5-methyltetrahydrofolate is detectable but trivial. In fact pABA was the only effective salvage substrate at normal physiological levels. Because pABA is neither synthesized nor required by the human host, pABA metabolism may offer opportunities for chemotherapeutic intervention. |
| Databáze: | OpenAIRE |
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