A constitutive pan-hexose permease for the Plasmodium life cycle and transgenic models for screening of antimalarial sugar analogs

Martin Blume, Marion Hliscs, Dayana Rodriguez-Contreras, Marco Sanchez, Scott Landfear, Richard Lucius, Kai Matuschewski, Nishith Gupta

Research output: Contribution to journalArticle

28 Scopus citations

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 (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.

Original languageEnglish (US)
Pages (from-to)1218-1229
Number of pages12
JournalFASEB Journal
Volume25
Issue number4
DOIs
StatePublished - Apr 2011

Keywords

  • Highthroughput screening
  • Metabolic drug target
  • Sugar transport

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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    Blume, M., Hliscs, M., Rodriguez-Contreras, D., Sanchez, M., Landfear, S., Lucius, R., Matuschewski, K., & Gupta, N. (2011). A constitutive pan-hexose permease for the Plasmodium life cycle and transgenic models for screening of antimalarial sugar analogs. FASEB Journal, 25(4), 1218-1229. https://doi.org/10.1096/fj.10-173278