Abstract
Maintenance of a high glycolytic flow rate is critical for the rapid growth and virulence of malarial parasites. The parasites release two moles of lactic acid per mole of glucose as the anaerobic end product. However, the molecular identity of the Plasmodium lactate transporter is unknown. Here we show that a member of the microbial formate-nitrite transporter family, PfFNT, acts as a lactate/proton symporter in Plasmodium falciparum. Besides L-lactate, PfFNT transports physiologically relevant D-lactate, as well as pyruvate, acetate and formate, and is inhibited by the antiplasmodial compounds phloretin, furosemide and cinnamate derivatives, but not by p-chloromercuribenzene sulfonate (pCMBS). Our data on PfFNT monocarboxylate transport are consistent with those obtained with living parasites. Moreover, PfFNT is the only transporter of the plasmodial glycolytic pathway for which structure information is available from crystals of homologous proteins, rendering it amenable to further evaluation as a novel antimalarial drug target.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Biological Transport / drug effects
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Cell Membrane / drug effects
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Cell Membrane / metabolism
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Erythrocytes / drug effects
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Erythrocytes / parasitology
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Fluorescence
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Glycolysis / drug effects
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Green Fluorescent Proteins / metabolism
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Humans
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Lactic Acid / metabolism*
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Malaria, Falciparum / parasitology
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Monocarboxylic Acid Transporters / antagonists & inhibitors
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Monocarboxylic Acid Transporters / metabolism*
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Mutation / genetics
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Parasites / drug effects
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Parasites / metabolism
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Plasmodium falciparum / drug effects
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Plasmodium falciparum / metabolism*
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Protons
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Protozoan Proteins / antagonists & inhibitors
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Protozoan Proteins / chemistry
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Protozoan Proteins / metabolism*
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Saccharomyces cerevisiae / metabolism
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Small Molecule Libraries / chemistry
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Small Molecule Libraries / pharmacology
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Symporters / chemistry
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Symporters / metabolism*
Substances
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Monocarboxylic Acid Transporters
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Protons
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Protozoan Proteins
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Small Molecule Libraries
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Symporters
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Green Fluorescent Proteins
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Lactic Acid