Comparative structural and functional features of folate salvage transporters in Plasmodium falciparum and humans

摘要

Folic acids are essential cofactors for synthesis of DNA, RNA, membrane lipids, methionine metabolism and neurotransmitter synthesis. P. falciparum is capable of synthesizing folate de novo or obtaining it through salvage, whereas humans can only obtain folate from their diet, making the folate pathway products important targets for chemotherapy. Although P. falciparum folate pathway enzymes and metabolites have been studied extensively, the structure and function of transporters that underpin folate salvage are lacking. Plasmodium falciparum 3D7 and Homo sapiens folate transporter protein sequences were queried by using BLAST and sequences retrieved from PlasmoDB and NCBI databases respectively. This was followed by structural and functional prediction of the transporters. P. falciparum possesses two folate transporters that are structurally and functionally different from one another, and also from that found in humans. The P. falciparum folate transporter 1 has 12 transmembrane helices with a predicted upright funnel shaped structure, whereas the P. falciparum folate transporter 2 and H. sapiens folate transporter have 11 transmembrane helices and predicted inverted funnel shaped structures. A significant portion of the transporters lay in the cytoplasmic space, with little protrusion on the extracellular space. The differences observed in the parasite protein in comparison to the human version may offer possibilities in the effort to develop newer antimalarials against folate transport in P. falciparum.