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

Item Type:	Article
Title:	A constitutive pan-hexose permease for the Plasmodium life cycle and transgenic models for screening of antimalarial sugar analogs
Creators Name:	Blume, M. and Hliscs, M. and Rodriguez-Contreras, D. and Sanchez, M. and Landfear, S. and Lucius, R. and Matuschewski, K. and Gupta, N.
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 muM), mannose (K(i)~93 muM), 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 muM; Man, K(i)~276 muM; Fru, K(i)~1.25 mM; Gal, K(i)~5.86 mM). Notably, a glucose analog, C3361, attenuated hepatic (IC(50)~15 muM) 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.
Keywords:	Sugar Transport, Metabolic Drug Target, High-Throughput Screening, Animals, Mice, Xenopus Laevis
Source:	FASEB Journal
ISSN:	0892-6638
Publisher:	Federation of American Societies for Experimental Biology
Volume:	25
Number:	4
Page Range:	1218-1229
Date:	April 2011
Official Publication:	https://doi.org/10.1096/fj.10-173278
PubMed:	View item in PubMed

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