Membrane transport proteins of the malaria parasite

Abstract

SummaryThe malaria parasite-infected erythrocyte is a multicompartment structure, incorporating numerous different membrane systems. The movement of nutrients, metabolites and inorganic ions into and out of the intraerythrocytic parasite, as well as between subcellular compartments within the parasite, is mediated by transporters and channels -integral membrane proteins that facilitate the movement of solutes across the membrane bilayer. Proteins of this type also play a key role in antimalarial drug resistance. Genes encoding transporters and channels account for at least 2.5% of the parasite genome. However, ascribing functions and physiological roles to these proteins, and defining their roles in drug resistance, is not straightforward. For any given membrane transport protein, a full understanding of its role(s) in the parasitized erythrocyte requires a knowledge of its subcellular localization and substrate specificity, as well as some knowledge of the effects on the parasite of modifying the sequence and/or level of expression of the gene involved. Here we consider recent work in this area, describe a number of newly identified transport proteins, and summarize the likely subcellular localization and putative substrate specificity of all of the candidate membrane transport proteins identified to date.

Biosynthesis of GDP-fucose and Other Sugar Nucleotides in the Blood Stages of Plasmodium falciparum

“…The localization of both enzymes in the cytoplasmic compartment (Fig. 6), as aldolase and other enzymes involved in the metabolism of carbohydrates (68), agrees well with the identification of a putative GDP-Fuc transporter in the P. falciparum endoplasmic reticulum/Golgi apparatus (69), where N-and O-glycosylation processes occur. The location and function of a putative fucosecontaining glycan in P. falciparum remain enigmatic, and biosynthetic labeling with tritiated fucose is not feasible, because there is no prominent GDP-Fuc salvage pathway in the parasite, and/or hexose transporters do not efficiently take up fucose (Fig.…”

Novel cinnamic acid/4-aminoquinoline conjugates bearing non-proteinogenic amino acids: Towards the development of potential dual action antimalarials

“…A higher uptake of HEDICINs 8, as compared to HECINs 9, could arise from: a) a more efficient transport by passive diffusion, as HEDICINs are more lipophilic than HECINs; globally, HEDICINs and HECINs have similar acidebase properties (average estimated pKa w 4 for deprotonation of the quinolinic nitrogen), but differ by almost two units in their estimated logP values (4.2 < logP < 5.1 for HECINs; 5.8 < log P < 7.9 for HEDICINs; cf. Table 1) [33], with the most lipophilic, 8c, being also the most active anti-plasmodial; amino acid and dipeptide esters are known to cross cell membranes by passive diffusion [38], so it is possible that the presence of the dipeptide spacer in HEDICINs augments cell permeation of these compounds by such process; b) recognition of the dipeptide motif by specific transporters from the P. falciparum ABC transporter super-family, many of which have been taken as putative drug transporting proteins [39] and found to be directly implicated in drugresistance mechanisms [40,41]; c) increased permeability of dipeptide derivatives due to the new permeation pathways created in P. falciparum-infected RBCs to promote uptake of nutrients such as sugars or nucleosides [42], as well as amino acids and oligopeptides [31]; II. Alternatively, a difference in the respective mechanism of action (MOA) may be operating in addition, or in alternative, to a difference in uptake of HEDICINs versus HECINs: a) due to their dipeptide moiety, HEDICINs might be able to inhibit plasmodial cytosolic proteases like aminopeptidases PfA-M1 and PfA-M17, which function in regulating the intracellular pool of amino acids required for parasite growth and development inside the red blood cell [43,44]; b) HEDICINs anti-plasmodial activity could otherwise be related to the cinnamoyl moiety, as it has been shown that cinnamic acid derivatives inhibit the growth of intraerythrocytic P. falciparum in culture by inhibiting monocarboxylate (e.g.…”

A female gametocyte-specific ABC transporter plays a role in lipid metabolism in the malaria parasite

“…ABC transporters play a key role in multidrug resistance (MDR), both in human cancer cells and in pathogenic microbes 5,6 . The P. falciparum genome encodes 11 putative ABC transporter proteins 7 . Thus far, Plasmodium ABC proteins have been studied in the context of their prominent roles in conferring drug resistance.…”