title: A constitutive pan-hexose permease for the Plasmodium life cycle and transgenic models for screening of antimalarial sugar analogs.
abstract: Glucose is considered essential for erythrocytic stages of the malaria parasite, Plasmodium falciparum. Importance of sugar and its permease for hepatic and sexual stages of Plasmodium, however, remains elusive. Moreover, increasing global resistance to current antimalarials necessitates the search for novel drugs. Here, we reveal that hexose transporter 1 (HT1) of Plasmodium berghei can transport glucose (K(m)~87 μM), mannose (K(i)~93 μM), fructose (K(i)~0.54 mM), and galactose (K(i)~5 mM) in Leishmania mexicana mutant and Xenopus laevis; and, therefore, is functionally equivalent to HT1 of P. falciparum (Glc, K(m)~175 μM; Man, K(i)~276 μM; Fru, K(i)~1.25 mM; Gal, K(i)~5.86 mM). Notably, a glucose analog, C3361, attenuated hepatic (IC(50)~15 μM) and ookinete development of P. berghei. The PbHT1 could be ablated during intraerythrocytic stages only by concurrent complementation with PbHT1-HA or PfHT1. Together; these results signify that PbHT1 and glucose are required for the entire life cycle of P. berghei. Accordingly, PbHT1 is expressed in the plasma membrane during all parasite stages. To permit a high-throughput screening of PfHT1 inhibitors and their subsequent in vivo assessment, we have generated Saccharomyces cerevisiae mutant expressing codon-optimized PfHT1, and a PfHT1-dependent Δpbht1 parasite strain. This work provides a platform to facilitate the development of drugs against malaria, and it suggests a disease-control aspect by reducing parasite transmission.
authors.affiliation: Department of Molecular Parasitology, Humboldt University, Berlin, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Blume
authors.forename: Marion
authors.initials: M
authors.lastname: Hliscs
authors.forename: Dayana
authors.initials: D
authors.lastname: Rodriguez-Contreras
authors.forename: Marco
authors.initials: M
authors.lastname: Sanchez
authors.forename: Scott
authors.initials: S
authors.lastname: Landfear
authors.forename: Richard
authors.initials: R
authors.lastname: Lucius
authors.forename: Kai
authors.initials: K
authors.lastname: Matuschewski
authors.forename: Nishith
authors.initials: N
authors.lastname: Gupta
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology; D001483:Base Sequence; D005632:Fructose / Q000378:metabolism; D005690:Galactose / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007894:Leishmania mexicana; D008018:Life Cycle Stages; D008358:Mannose / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009004:Monosaccharide Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010962:Plasmodium berghei / Q000187:drug effects / Q000378:metabolism*; D010963:Plasmodium falciparum / Q000378:metabolism; D015800:Protozoan Proteins / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics; D014122:Toxoplasma / Q000187:drug effects; D014982:Xenopus laevis
chemical_list: D000962:Antimalarials; D009004:Monosaccharide Transport Proteins; D015800:Protozoan Proteins; D011994:Recombinant Proteins; C118145:hexose transporter 1 protein, Plasmodium falciparum; D005632:Fructose; D005947:Glucose; D008358:Mannose; D005690:Galactose