TY - JOUR
T1 - A constitutive pan-hexose permease for the Plasmodium life cycle and transgenic models for screening of antimalarial sugar analogs
AU - Blume, Martin
AU - Hliscs, Marion
AU - Rodriguez-Contreras, Dayana
AU - Sanchez, Marco
AU - Landfear, Scott
AU - Lucius, Richard
AU - Matuschewski, Kai
AU - Gupta, Nishith
PY - 2011/4
Y1 - 2011/4
N2 - 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 (Km∼87 μM), mannose (K i∼93 μM), fructose (Ki∼0.54 mM), and galactose (Ki∼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, Ki∼276 μM; Fru, K i∼1.25 mM; Gal, Ki∼5.86mM). Notably, a glucose analog, C3361, attenuated hepatic (IC50∼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 Apbht1 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.
AB - 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 (Km∼87 μM), mannose (K i∼93 μM), fructose (Ki∼0.54 mM), and galactose (Ki∼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, Ki∼276 μM; Fru, K i∼1.25 mM; Gal, Ki∼5.86mM). Notably, a glucose analog, C3361, attenuated hepatic (IC50∼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 Apbht1 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.
KW - Highthroughput screening
KW - Metabolic drug target
KW - Sugar transport
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U2 - 10.1096/fj.10-173278
DO - 10.1096/fj.10-173278
M3 - Article
C2 - 21169382
AN - SCOPUS:79954618684
SN - 0892-6638
VL - 25
SP - 1218
EP - 1229
JO - FASEB Journal
JF - FASEB Journal
IS - 4
ER -