Phylogenetic profiles of all membrane transport proteins of the malaria parasite highlight new drug targets

Abstract

In order to combat the on-going malaria epidemic, discovery of new drug targets remains vital. Proteins that are essential to survival and specific to malaria parasites are key candidates. To survive within host cells, the parasites need to acquire nutrients and dispose of waste products across multiple membranes. Additionally, like all eukaryotes, they must redistribute ions and organic molecules between their various internal membrane bound compartments. Membrane transport proteins mediate all of these processes and are considered important mediators of drug resistance as well as drug targets in their own right. Recently, using advanced experimental genetic approaches and streamlined life cycle profiling, we generated a large collection of Plasmodium berghei gene deletion mutants and assigned essential gene functions, highlighting potential targets for prophylactic, therapeutic, and transmission-blocking anti-malarial drugs. Here, we present a comprehensive orthology assignment of all Plasmodium falciparum putative membrane transport proteins and provide a detailed overview of the associated essential gene functions obtained through experimental genetics studies in human and murine model parasites. Furthermore, we discuss the phylogeny of selected potential drug targets identified in our functional screen. We extensively discuss the results in the context of the functional assignments obtained using gene targeting available to date.

A comparative transcriptomic analysis of replicating and dormant liver stages of the relapsing malaria parasite Plasmodium cynomolgi

“…Plasmodium parasite survival and replication depends on the import of nutrients and solutes from its host cell and some transporters have been proposed to be tractable drug targets for malaria ( Hapuarachchi et al, 2017 ; Pain et al, 2016 ; Slavic et al, 2011 ; Weiner and Kooij, 2016 ). Consistently, we observe high FPKM values for a broad range of transporters in both liver schizonts (35 putative transporters with FPKM values > 10) and hypnozoites (seven transporters with FPKM values > 10 and 25 transporters with FPKM values > 1 ( Supplementary file 4 , Supplementary file 10 ).…”

“…In order to survive, malaria parasites utilize membrane transport proteins that allow the uptake of nutrients, disposal of waste products and maintenance of ion homeostasis ( Weiner and Kooij, 2016 ). While some of these transporters have been implicated in drug resistance, recent experimental work has also supported their potential as anti-malarial drug targets ( Weiner and Kooij, 2016 ).…”

“…In order to survive, malaria parasites utilize membrane transport proteins that allow the uptake of nutrients, disposal of waste products and maintenance of ion homeostasis ( Weiner and Kooij, 2016 ). While some of these transporters have been implicated in drug resistance, recent experimental work has also supported their potential as anti-malarial drug targets ( Weiner and Kooij, 2016 ). Recent evidence has emerged for important roles of heavy metal homeostasis in sporozoite transmission and liver-stage development ( Kenthirapalan et al, 2016 ; Sahu et al, 2014 ; Slavic et al, 2016 ; Stahel et al, 1988 ).…”

A genetic screen in rodent malaria parasites identifies five new apicoplast putative membrane transporters, one of which is essential in human malaria parasites

“…On the basis of phylogenetic data showing the absence of a DMT2 orthologue in Cryptosporidium and the localisation of Pb DMT2 to an unknown intracellular structure (Kenthirapalan et al, ), Weiner and Kooij () proposed that DMT2 might be an apicoplast‐localised transport protein perhaps involved in IPP transport or the import of iron or sulfur for the iron–sulfur cluster biosynthesis pathway. Our analysis suggests that Pf DMT2 has a function in apicoplast maintenance rather than being solely an IPP transporter.…”

Targeting Channels and Transporters in Protozoan Parasite Infections

“…The establishment and maintenance of ion gradients across the parasite plasma membrane is vital for the membrane potential, osmotic balance, as well as for driving transport processes. P-type ATPases are single protein units that convert energy from ATP hydrolysis into cation transport (Weiner and Kooij, 2016 ). ATP4 of P. falciparum was recently shown to act as a sodium pump at the plasma membrane (Dyer et al, 1996 ; Spillman et al, 2013 ).…”