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

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 similar to 87 mu M), mannose (K-i similar to 93 mu M), fructose (K-i similar to 0.54 mM), and galactose (K-i similar to 5 mM) in Leishmania mexicana mutant and Xenopus laevis; and, therefore, is functionally equivalent to HT1 of P. falciparum (Glc, K-m similar to 175 mu M; Man, K-i similar to 276 mu M; Fru, K-i similar to 1.25 mM; Gal, K-i similar to 5.86 mM). Notably, a glucose analog, C3361, attenuated hepatic (IC50 similar to 15 mu M) 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 Delta pbht1 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.-Blume, M., Hliscs, M., Rodriguez-Contreras, D., Sanchez, M., Landfear, S., Lucius, R., Matuschewski, K., Gupta, N. A constitutive pan-hexose permease for the Plasmodium life cycle and transgenic models for screening of antimalarial sugar analogs. FASEB J. 25, 1218-1229 (2011). www.fasebj.org