AUTHOR=Won Jeong Yeon , Mazigo Ernest , Cha Seok Ho , Han Jin-Hee 

TITLE=Functional characterization of Plasmodium vivax hexose transporter 1

JOURNAL=Frontiers in Cellular and Infection Microbiology

VOLUME=13

YEAR=2024

URL=https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2023.1321240

DOI=10.3389/fcimb.2023.1321240

ISSN=2235-2988

ABSTRACT=<p><italic>Plasmodium vivax</italic> is the most widely distributed human malaria parasite. The eradication of vivax malaria remains challenging due to transmission of drug-resistant parasite and dormant liver form. Consequently, anti-malarial drugs with novel mechanisms of action are urgently demanded. Glucose uptake blocking strategy is suggested as a novel mode of action that leads to selective starvation in various species of malaria parasites. The role of hexose transporter 1 in <italic>Plasmodium</italic> species is glucose uptake, and its blocking strategies proved to successfully induce selective starvation. However, there is limited information on the glucose uptake properties via <italic>P. vivax</italic> hexose transporter 1 (PvHT1). Thus, we focused on the PvHT1 to precisely identify its properties of glucose uptake. The PvHT1 North Korean strain (PvHT1<sub>NK</sub>) expressed <italic>Xenopus laevis</italic> oocytes mediating the transport of [<sup>3</sup>H] deoxy-D-glucose (ddGlu) in an expression and incubation time-dependent manner without sodium dependency. Moreover, the PvHT1<sub>NK</sub> showed no exchange mode of glucose in efflux experiments and concentration-dependent results showed saturable kinetics following the Michaelis-Menten equation. Non-linear regression analysis revealed a Km value of 294.1 μM and a Vmax value of 1,060 pmol/oocyte/hr, and inhibition experiments showed a strong inhibitory effect by glucose, mannose, and ddGlu. Additionally, weak inhibition was observed with fructose and galactose. Comparison of amino acid sequence and tertiary structure between <italic>P. falciparum</italic> and <italic>P. vivax</italic> HT1 revealed a completely conserved residue in glucose binding pocket. This result supported that the glucose uptake properties are similar to <italic>P. falciparum</italic>, and PfHT1 inhibitor (compound 3361) works in <italic>P. vivax</italic>. These findings provide properties of glucose uptake via PvHT1<sub>NK</sub> for carbohydrate metabolism and support the approaches to vivax malaria drug development strategy targeting the PvHT1 for starving of the parasite.</p>