Transmembrane solute transport in the apicomplexan parasite Plasmodium

Abstract

Apicomplexa are a large group of eukaryotic, single-celled parasites, with complex life cycles that occur within a wide range of different microenvironments. They include important human pathogens such as Plasmodium, the causal agent of malaria, and Toxoplasma, which causes toxoplasmosis most often in immunocompromised individuals. Despite environmental differences in their life cycles, these parasites retain the ability to obtain nutrients, remove waste products, and control ion balances. They achieve this flexibility by relying on proteins that can deliver and remove solutes. This reliance on transport proteins for essential functions makes these pathways excellent potential targets for drug development programmes. Transport proteins are frequently key mediators of drug resistance by their ability to remove drugs from their sites of action. The study of transport processes mediated by integral membrane proteins and, in particular, identification of their physiological functions and localisation, and differentiation from host orthologues has already established new validated drug targets. Our understanding of how apicomplexan parasites have adapted to changing environmental challenges has also increased through the study of their transporters. This brief introduction to membrane transporters of apicomplexans highlights recent discoveries focusing on Plasmodium and emphasises future directions.

Untargeted Metabolomics Uncovers the Essential Lysine Transporter in Toxoplasma gondii

“…Despite their critical role in the parasite’s metabolism and homeostasis, only a fraction of transporters have been identified and characterized. The critical role of metabolite transporters and their potential as drug targets in parasitic protozoa are increasingly recognized [ 7 , 8 , 33 , 34 ]. The requirements for amino acids and uptake of other metabolites likely differ between tachyzoites and the encysted bradyzoites, but these differences are poorly defined to date [ 35 ].…”

Enzymatic Transition States and Drug Design

“…The purine base and nucleoside transporter PfENT1 provides the link between erythrocyte and parasite purine metabolism. 424–426 P. falciparum PNP ( Pf PNP) differs from the human enzyme. It is a homohexamer with six independent catalytic sites.…”

“…However, P. falciparum also expresses an abundant PNP as a second path for hypoxanthine production. The purine base and nucleoside transporter PfENT1 provides the link between erythrocyte and parasite purine metabolism. − P. falciparum PNP ( Pf PNP) differs from the human enzyme. It is a homohexamer with six independent catalytic sites. − In addition to inosine, Pf PNP also uses 5′-methylthioinosine (MTI) as a substrate, formed in P. falciparum by deamination of 5′-methylthioadenosine (MTA).…”

A Prodrug Strategy to Reposition Atovaquone as a Long-Acting Injectable for Malaria Chemoprotection

“…This includes significant information on systemic human safety and prophylaxis efficacy 36, 47 . One key drawback of ATO compared to ELQ300 40 and more contemporary cytochrome bc1 inhibitors is the emergence of clinical resistance after short periods of dosing 12, 48, 49 . Therefore, drug combinations such as ATO plus proguanil (Malarone) have been used to address resistance, enabling a first-line oral prophylaxis for many years.…”