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.
Highlights
Maintenance of a high glycolytic flow rate is critical for the rapid growth and virulence of malarial parasites
Erythrocytes infected with Plasmodium spp. consume glucose up to two orders of magnitude faster than uninfected cells, generating lactic acid as the anaerobic end product[1]
Glucose uptake from the host serum is facilitated by the erythrocyte glucose transporter 1, and, consecutively, by the plasmodial hexose transporter (HT)[3]
Summary
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. Erythrocytes infected with Plasmodium spp. consume glucose up to two orders of magnitude faster than uninfected cells, generating lactic acid as the anaerobic end product[1]. Erythrocytes release lactic acid into the blood via a lactate/proton symporter Monocarboxylate Transporter 1 (MCT1)[4] and parasite-induced permeation pathways[5]. The abundance of glucose in the host blood allows the parasites to thrive rapidly despite inefficient energy generation by anaerobic glycolysis (Fig. 1a). Plasmodial lactate transport has been characterized using living parasites and revealed a low-affinity and high-capacity lactate/proton symport mechanism[5,7,8]. We show the molecular identity of a plasmodial lactate/ proton symporter (PFC0725c) whose properties match those obtained with living parasites before
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