Updated List of Transport Proteins in Plasmodium falciparum

Abstract

Malaria remains a leading cause of death and disease in many tropical and subtropical regions of the world. Due to the alarming spread of resistance to almost all available antimalarial drugs, novel therapeutic strategies are urgently needed. As the intracellular human malaria parasite Plasmodium falciparum depends entirely on the host to meet its nutrient requirements and the majority of its transmembrane transporters are essential and lack human orthologs, these have often been suggested as potential targets of novel antimalarial drugs. However, membrane proteins are less amenable to proteomic tools compared to soluble parasite proteins, and have thus not been characterised as well. While it had been proposed that P. falciparum had a lower number of transporters (2.5% of its predicted proteome) in comparison to most reference genomes, manual curation of information from various sources led to the identification of 197 known and putative transporter genes, representing almost 4% of all parasite genes, a proportion that is comparable to well-studied metazoan species. This transporter list presented here was compiled by collating data from several databases along with extensive literature searches, and includes parasite-encoded membrane-resident/associated channels, carriers, and pumps that are located within the parasite or exported to the host cell. It provides updated information on the substrates, subcellular localisation, class, predicted essentiality, and the presence or absence of human orthologs of P. falciparum transporters to quickly identify essential proteins without human orthologs for further functional characterisation and potential exploitation as novel drug targets.

Structural basis of the substrate recognition and inhibition mechanism of Plasmodium falciparum nucleoside transporter PfENT1

“…Targeting transporters and channels of Plasmodium parasites to eliminate malaria has attracted much attention from researchers 25 , 51 . Here, we report the structure of PfENT1 in complex with the antimalarial compound, which uncovers the inhibition mechanism of the small molecule.…”

Basic Nitrogen (BaN) Is a Key Property of Antimalarial Chemical Space

“…94 A long list of transporters is known to interact with other antimalarials, and many transporters remain uncharacterized. 85,86 In addition, several protozoans, including Plasmodium, uptake certain exogenous polyamine compounds such as spermidine, spermine, and putrescine. 95−100 These cationic compounds are critical for Plasmodium's metabolism, especially during the intraerythrocytic development of the parasite.…”

“…Inside the host, three membrane barriers surround the malarial parasite: the RBC membrane, parasitophorous vacuolar membrane (PVM), and parasite plasma membrane. , The parasite induces new permeation pathways in the host RBCs for salvaging essential nutrients. ,− Plasmodium enables efficient permeation of diverse molecules by inducing ion channels localized at the infected erythrocytic membranes . For instance, large, lipophilic, and charged molecules are transported by the plasmodial surface anion channel (PSAC) linked to the clag multigene family. , The BaN containing antimalarials blasticidin S and leupeptin require PSAC-mediated uptake in the infected erythrocytes. , Similar results were observed with bisthizolium antimalarials with permanent positive charges .…”

“…A yeast homologue of amino acid transporter Tat2 protein (PF3D7_0629500) has also been shown to import several quinoline antimalarials in FV . A long list of transporters is known to interact with other antimalarials, and many transporters remain uncharacterized. , …”

Plasmodium falciparum ZIP1 Is a Zinc-Selective Transporter with Stage-Dependent Targeting to the Apicoplast and Plasma Membrane in Erythrocytic Parasites

“…Two Zrt-/Irt-like protein (ZIP) transporters are encoded in P. falciparum . ZIPs belong to the SLC39A family, which regulates the flux of zinc into the cytosol from outside of the cell and from intracellular vesicles .…”