Analysis of Plasmodium vivax hexose transporters and effects of a parasitocidal inhibitor.
Plasmodium vivax is the second most common species of malaria parasite and causes up to 80 million episodes of infection each year. New drug targets are urgently needed because of emerging resistance to current treatments. To study new potential targets, we have functionally characterized two natural variants of the hexose transporter of P. vivax (PvHT) after heterologous expression in Xenopus oocytes. We show that PvHT transports both glucose and fructose. Differences in the affinity for fructose between the two variants of PvHT establishes that sequence variation is associated with phenotypic plasticity. Mutation of a single glutamine residue, Gln(167), predicted to lie in transmembrane helix 5, abolishes fructose transport by PvHT, although glucose uptake is preserved. In contrast, the exofacial site located between predicted helices 5 and 6 of PvHT is not an important determinant of substrate specificity, despite exhibiting sequence polymorphisms between hexose transporters of different Plasmodium spp. Indeed, replacement of twelve residues located within this region of PvHT by those found in the orthologous Plasmodium falciparum sequence (PfHT) is functionally silent with respect to affinity for hexoses. All PvHT variants are inhibited by compound 3361, a long-chain O-3 derivative of D-glucose effective against PfHT. Furthermore, compound 3361 kills short term cultures of P. vivax isolated from patients. These data provide unique insights into the function of hexose transporters of Plasmodium spp. as well as further evidence that they could be targeted by drugs.
Joët
Thierry
T
Department of Cellular and Molecular Medicine - Infectious Diseases, St. George's Hospital Medical School, Cranmer Terrace, London SW17 ORE, UK.
Chotivanich
Kesinee
K
Silamut
Kamolrat
K
Patel
Asha P
AP
Morin
Christophe
C
Krishna
Sanjeev
S
D000595:Amino Acid Sequence; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology; D005947:Glucose / Q000031:analogs & derivatives / Q000494:pharmacology; D006601:Hexoses / Q000378:metabolism; D008969:Molecular Sequence Data; D009004:Monosaccharide Transport Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000502:physiology; D016297:Mutagenesis, Site-Directed / Q000502:physiology; D009865:Oocytes / Q000737:chemistry; D010966:Plasmodium vivax / Q000187:drug effects / Q000254:growth & development; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000502:physiology; D020539:Sequence Analysis, Protein / Q000379:methods; D013379:Substrate Specificity / Q000502:physiology; D014981:Xenopus / Q000196:embryology
D000962:Antimalarials; D006601:Hexoses; D009004:Monosaccharide Transport Proteins; D015800:Protozoan Proteins; D005947:Glucose