Glycerophospholipid acquisition in Plasmodium – A puzzling assembly of biosynthetic pathways

Déchamps, Sandrine; Shastri, Shilpa; Wengelnik, Kai; Vial, Henri

doi:10.1016/j.ijpara.2010.05.008

Cited by 70 publications

(91 citation statements)

References 209 publications

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“…Plasmodium generates PL from polar heads, like choline, ethanolamine or serine (S), which are mainly taken up from the serum (reviewed in Ben Mamoun et al, 2010;Déchamps et al, 2010), whereas phosphatidylinositol (PI) is made by the parasite from inositol that is either taken up from the serum or generated de novo from glucose-6-phosphate via inositol-3-phosphate (reviewed in Ramakrishnan et al, 2013). Phosphatidylethanolamine (PE) is synthesized by the parasite via the phosphorylation of ethanolamine obtained from plasma or through decarboxylation of S (Fig.…”

Section: Membrane Dynamics and Lipid Turnover In Plasmodial Parasitesmentioning

confidence: 99%

“…The amount of SM (∼15%) in the parasites is comparable to that of uRBCs, while PS (∼5%) and PE plasmalogen (∼10%) are found at lower concentrations (Botté et al, 2013;Gulati et al, 2015;reviewed in Vial et al, 2003). Cholesterol is almost absent in the membranes of Plasmodium parasites, related to its inability to synthesize sterols (reviewed in Déchamps et al, 2010;Vial et al, 2003;Vial and Ancelin, 1992). In iRBCs, relative membrane cholesterol levels decrease inwardly from the RBC membrane (RBCM) via the MC/TVN to the PPM, with cholesterol appearing to travel from RBCM to PVM, but not vice versa (Tokumasu et al, 2014).…”

Section: Membrane Dynamics and Lipid Turnover In Plasmodial Parasitesmentioning

confidence: 99%

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Phospholipases during membrane dynamics in malaria parasites

Flammersfeld

Lang

Flieger

et al. 2018

International Journal of Medical Microbiology

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A B S T R A C TPlasmodium parasites, the causative agents of malaria, display a well-regulated lipid metabolism required to ensure their survival in the human host as well as in the mosquito vector. The fine-tuning of lipid metabolic pathways is particularly important for the parasites during the rapid erythrocytic infection cycles, and thus enzymes involved in lipid metabolic processes represent prime targets for malaria chemotherapeutics. While plasmodial enzymes involved in lipid synthesis and acquisition have been studied in the past, to date not much is known about the roles of phospholipases for proliferation and transmission of the malaria parasite. These phospholipid-hydrolyzing esterases are crucial for membrane dynamics during host cell infection and egress by the parasite as well as for replication and cell signaling, and thus they are considered important virulence factors. In this review, we provide a comprehensive bioinformatic analysis of plasmodial phospholipases identified to date. We further summarize previous findings on the lipid metabolism of Plasmodium, highlight the roles of phospholipases during parasite life-cycle progression, and discuss the plasmodial phospholipases as potential targets for malaria therapy.

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Section: Membrane Dynamics and Lipid Turnover In Plasmodial Parasitesmentioning

confidence: 99%

Section: Membrane Dynamics and Lipid Turnover In Plasmodial Parasitesmentioning

confidence: 99%

Phospholipases during membrane dynamics in malaria parasites

Flammersfeld

Lang

Flieger

et al. 2018

International Journal of Medical Microbiology

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“…Each merozoite then begins a cycle of schizogonic development inside erythrocytes. As a consequence, a 500 to 700% increase in membrane lipids is observed in infected erythrocytes compared to uninfected ones (6).…”

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confidence: 99%

“…It has long been considered that Apicomplexa scavenge their fatty acids and glycerolipids from the host (5)(6)(7)(8). However, the existence of biosynthetic pathways has been demonstrated, leading to the consensus that Apicomplexa meet their actual demand by a combination of scavenging and de novo synthesis (9).…”

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confidence: 99%

Discovery of Compounds Blocking the Proliferation of Toxoplasma gondii and Plasmodium falciparum in a Chemical Space Based on Piperidinyl-Benzimidazolone Analogs

Saïdani

Botté

Deligny

et al. 2014

Antimicrob Agents Chemother

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A piperidinyl-benzimidazolone scaffold has been found in the structure of different inhibitors of membrane glycerolipid metabolism, acting on enzymes manipulating diacylglycerol and phosphatidic acid. Screening a focus library of piperidinyl-benzimidazolone analogs might therefore identify compounds acting against infectious parasites. We first evaluated the in vitro effects of (S)-2-(dibenzylamino)-3-phenylpropyl 4-(1,2-dihydro-2-oxobenzo[d]imidazol-3-yl)piperidine-1-carboxylate (compound 1) on Toxoplasma gondii and Plasmodium falciparum. In T. gondii, motility and apical complex integrity appeared to be unaffected, whereas cell division was inhibited at compound 1 concentrations in the micromolar range. In P. falciparum, the proliferation of erythrocytic stages was inhibited, without any delayed death phenotype. We then explored a library of 250 analogs in two steps. We selected 114 compounds with a 50% inhibitory concentration (IC 50 ) cutoff of 2 M for at least one species and determined in vitro selectivity indexes (SI) based on toxicity against K-562 human cells. We identified compounds with high gains in the IC 50 (in the 100 nM range) and SI (up to 1,000 to 2,000) values. Isobole analyses of two of the most active compounds against P. falciparum indicated that their interactions with artemisinin were additive. Here, we propose the use of structureactivity relationship (SAR) models, which will be useful for designing probes to identify the target compound(s) and optimizations for monotherapy or combined-therapy strategies.T he phylum Apicomplexa comprises a group of unicellular eukaryotes, including obligate intracellular parasites that cause diseases ranging from benign to serious (1). In humans, the most devastating of these infections is malaria, caused by Plasmodium parasites, with Plasmodium falciparum being the deadliest. Malaria affects about 225 million humans and results in 650,000 deaths every year (2). Toxoplasma gondii is another Apicomplexa organism that causes toxoplasmosis, affecting one-third of the world population (3). Other parasites, such as Babesia spp., Neospora spp., and Eimeria spp., cause diseases of veterinary importance (4). Apicomplexa require large amounts of glycerolipids to build up membrane compartments throughout their life cycle. Plasmodium asexual proliferation illustrates this demand. Once invading a hepatocyte, a single sporozoite divides, producing 40,000 merozoites (5). Each merozoite then begins a cycle of schizogonic development inside erythrocytes. As a consequence, a 500 to 700% increase in membrane lipids is observed in infected erythrocytes compared to uninfected ones (6).The structure of glycerolipids is obtained by the assembly of (i) a 3-carbon glycerol backbone originating from glycerol-3-phosphate (G3P), (ii) fatty acids (FA) esterified at positions sn Ϫ1 and sn Ϫ2 in glycerol, and (iii) a polar head at position sn Ϫ3. It has long been considered that Apicomplexa scavenge their fatty acids and glycerolipids from the host (5-8). However, the existence of bi...

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“…At its blood stage, phospholipids, which constitute the bulk of malarial lipids (5)(6)(7)(8)(9), mostly originate from the Plasmodium-encoded enzymatic machinery (7,10). In this setting, the inhibition of phospholipid biosynthesis has been proposed as a novel therapeutic strategy (11)(12)(13).…”

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confidence: 99%

New Insight into the Mechanism of Accumulation and Intraerythrocytic Compartmentation of Albitiazolium, a New Type of Antimalarial

Wein

Maynadier

et al. 2014

Antimicrob Agents Chemother

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c Bis-thiazolium salts constitute a new class of antihematozoan drugs that inhibit parasite phosphatidylcholine biosynthesis. They specifically accumulate in Plasmodium-and Babesia-infected red blood cells (IRBC). Here, we provide new insight into the choline analogue albitiazolium, which is currently being clinically tested against severe malaria. Concentration-dependent accumulation in P. falciparum-infected erythrocytes reached steady state after 90 to 120 min and was massive throughout the blood cycle, with cellular accumulation ratios of up to 1,000. This could not occur through a lysosomotropic effect, and the extent did not depend on the food vacuole pH, which was the case for the weak base chloroquine. Analysis of albitiazolium accumulation in P. falciparum IRBC revealed a high-affinity component that was restricted to mature stages and suppressed by pepstatin A treatment, and thus likely related to drug accumulation in the parasite food vacuole. Albitiazolium also accumulated in a second high-capacity component present throughout the blood cycle that was likely not related to the food vacuole and also observed with Babesia divergens-infected erythrocytes. Accumulation was strictly glucose dependent, drastically inhibited by H ؉ /K ؉ and Na ؉ ionophores upon collapse of ionic gradients, and appeared to be energized by the proton-motive force across the erythrocyte plasma membrane, indicating the importance of transport steps for this permanently charged new type of antimalarial agent. This specific, massive, and irreversible accumulation allows albitiazolium to restrict its toxicity to hematozoa-infected erythrocytes. The intraparasitic compartmentation of albitiazolium corroborates a dual mechanism of action, which could make this new type of antimalarial agent resistant to parasite resistance.

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Glycerophospholipid acquisition in Plasmodium – A puzzling assembly of biosynthetic pathways

Cited by 70 publications

References 209 publications

Phospholipases during membrane dynamics in malaria parasites

Phospholipases during membrane dynamics in malaria parasites

Discovery of Compounds Blocking the Proliferation of Toxoplasma gondii and Plasmodium falciparum in a Chemical Space Based on Piperidinyl-Benzimidazolone Analogs

New Insight into the Mechanism of Accumulation and Intraerythrocytic Compartmentation of Albitiazolium, a New Type of Antimalarial

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