H+-coupled pantothenate transport in the intracellular malaria parasite.
Pantothenate, the precursor of coenzyme A, is an essential nutrient for the intraerythrocytic stage of the malaria parasite Plasmodium falciparum. Pantothenate enters the malaria-infected erythrocyte via new permeation pathways induced by the parasite in the host cell membrane (Saliba, K. J., Horner, H. A., and Kirk, K. (1998) J. Biol. Chem. 273, 10190-10195). We show here that pantothenate is taken up by the intracellular parasite via a novel H(+)-coupled transporter, quite different from the Na(+)-coupled transporters that mediate pantothenate uptake into mammalian cells. The plasmodial H(+):pantothenate transporter has a low affinity for pantothenate (K(m) approximately 23 mm) and a stoichiometry of 1 H(+):1 pantothenate. It is inhibited by low concentrations of the bioflavonoid phloretin and the thiol-modifying agent p-chloromercuribenzene sulfonate. On entering the parasite, pantothenate is phosphorylated (and thereby trapped) by an unusually high affinity pantothenate kinase (K(m) approximately 300 nm). The combination of H(+)-coupled transporter and kinase provides the parasite with an efficient, high affinity pantothenate uptake system, which is distinct from that of the host and is therefore an attractive target for antimalarial chemotherapy.
Saliba
K J
KJ
School of Biochemistry and Molecular Biology, Australian National University, Canberra, Australian Capital Territory 0200, Australia.
Kirk
K
K
D000818:Animals; D001692:Biological Transport; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D004912:Erythrocytes / Q000378:metabolism / Q000469:parasitology; D016778:Malaria, Falciparum / Q000378:metabolism* / Q000469:parasitology; D008565:Membrane Proteins / Q000378:metabolism; D010205:Pantothenic Acid / Q000378:metabolism*; D010963:Plasmodium falciparum / Q000378:metabolism*; D051381:Rats; D029701:Saccharomyces cerevisiae Proteins; D027981:Symporters
D002352:Carrier Proteins; C436246:FEN2 protein, S cerevisiae; D008565:Membrane Proteins; D029701:Saccharomyces cerevisiae Proteins; D027981:Symporters; C119982:pantothenate transporter; D010205:Pantothenic Acid