Histidine-rich protein 2 of the malaria parasite, Plasmodium falciparum, is involved in detoxification of the by-products of haemoglobin degradation

Papalexis, Vicki; Siomos, Mary-Anne; Campanale, Naomi Vittoria; Guo, Xian‐Guo; Kocak, Gulcan; Foley, Michael; Tilley, Leann

doi:10.1016/s0166-6851(01)00271-7

Cited by 67 publications

(58 citation statements)

References 34 publications

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“…1). As previously shown (11,13,26), endogenous PfHRPII is detected in the infected erythrocyte cytoplasm of ring and schizont stages ( Fig. 2A).…”

Section: Characterization Of the Expression And Distribution Of Endogsupporting

confidence: 82%

“…Histidine-rich proteins have been shown to function as heme polymerases in vitro, and the best characterized of these proteins is P. falciparum HRPII (or PfHRPII) (11)(12)(13). This protein has been detected in the red cell as well as the fv, leading to the suggestion that it is ingested from the red cell by the cytostome along with hemoglobin and subsequently delivered to the fv.…”

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confidence: 99%

“…Although the heme polymerase activity (which is ascribed to the histidine-rich sequences of this protein and other histidine-rich proteins and peptides) has been demonstrated in vitro (11,13), a laboratory cell line with a natural deletion in HRPII and HRPIII can still produce hemozoin (11). Thus, additional histidine-rich proteins may contribute to hemozoin production.…”

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confidence: 99%

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trans Expression of a Plasmodium falciparum Histidine-rich Protein II (HRPII) Reveals Sorting of Soluble Proteins in the Periphery of the Host Erythrocyte and Disrupts Transport to the Malarial Food Vacuole

Akompong¹,

Kadekoppala²,

Harrison³

et al. 2002

Journal of Biological Chemistry

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The heme polymer hemozoin is produced in the food vacuole (fv) of the parasite after hemoglobin proteolysis and is the target of the drug chloroquine. A candidate heme polymerase, the histidine-rich protein II (HRPII), is proposed to be delivered to the fv by ingestion of the infected-red cell cytoplasm. Here we show that 97% of endogenous Plasmodium falciparum (Pf) HRPII (PfHR-PII) is secreted as soluble protein in the periphery of the red cell and avoids endocytosis by the parasite, and 3% remains membrane-bound within the parasite. Transfected cells release 90% of a soluble transgene PfHRPIImyc into the red cell periphery and contain 10% membrane bound within the parasite. Yet these cells show a minor reduction in hemozoin production and IC 50 for chloroquine. They also show decreased transport of resident fv enzyme PfPlasmepsin I, the endoplasmic reticulum (ER) marker PfBiP, and parasite-associated HRPII to fvs. Instead, all three proteins accumulate in the ER, although there is no defect in protein export from the parasite. The data suggest that novel mechanisms of sorting (i) soluble antigens like HRPII in the red cell cytoplasm and (ii) fv-bound membrane complexes in the ER regulate parasite digestive processes.Plasmodium falciparum is a protozoan parasite that causes the most virulent of human malarias (1, 2). During the blood stages of infection, it invades and develops within a parasitophorous vacuolar membrane (PVM) 1 in a red cell (3). The parasite exports numerous proteins to the cytoplasm and membrane of the red cell (4). Association with the host skeleton or insertion across its membrane is thought to be required to keep the protein in the periphery of the red cell. Soluble exported proteins are expected to be ingested with hemoglobin and delivered to the fv within the parasite (3, 5). The parasite ingests and degrades ϳ80% of the hemoglobin in the red cell (3, 5). Ingestion occurs via a specialized organelle called the cytostome, which is a double membrane invagination of the parasite plasma membrane (PPM) and PVM (see Fig. 1). The cytostome pinches off to form a large, double membrane vesicle containing hemoglobin that fuses with the fv where hemoglobin is degraded (Fig. 1). The released, toxic-free heme is detoxified by polymerization to hemozoin (6, 7). Heme polymerization is also likely to be the main target of chloroquine, of which the emergence of drug resistance is a major problem in controlling malaria (8 -10).Histidine-rich proteins have been shown to function as heme polymerases in vitro, and the best characterized of these proteins is P. falciparum HRPII (or PfHRPII) (11-13). This protein has been detected in the red cell as well as the fv, leading to the suggestion that it is ingested from the red cell by the cytostome along with hemoglobin and subsequently delivered to the fv. Early studies also suggest that resident fv proteases synthesized in a membrane-bound pro-form are transported to the PVM and then retrieved into the newly developing cytostome, which ingests hemoglobin (11,1...

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“…1). As previously shown (11,13,26), endogenous PfHRPII is detected in the infected erythrocyte cytoplasm of ring and schizont stages ( Fig. 2A).…”

Section: Characterization Of the Expression And Distribution Of Endogsupporting

confidence: 82%

mentioning

confidence: 99%

mentioning

confidence: 99%

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trans Expression of a Plasmodium falciparum Histidine-rich Protein II (HRPII) Reveals Sorting of Soluble Proteins in the Periphery of the Host Erythrocyte and Disrupts Transport to the Malarial Food Vacuole

Akompong¹,

Kadekoppala²,

Harrison³

et al. 2002

Journal of Biological Chemistry

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“…We thus propose the occurrence of an electron transfer between the redox couple Fe[II]PPIX/Fe[III]PPIX and the quinoline ring [16,17], to generate highly reactive radicals. That this transfer exists is corroborated by the observation that chloroquine protects Fe[II]PPIX/Fe[III]PPIX from oxidative degradation by reactive oxygen species (see [18] and Pasini et al, unpublished results). This hypothesis would explain the importance of stereoelectronic features for chloroquine antimalarial activity [19], since an electron transfer is linked to the electron density in position 4 and in the secondary nitrogen of the side chain, which in turn depends on the substituent in position 7 of the quinoline ring [3] (Fig.…”

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confidence: 70%

Does chloroquine really act through oxidative stress?

et al. 2002

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To assess whether molecular oxygen and oxidative stress contribute to chloroquine activity, we cultivated strains of Plasmodium falciparum in erythrocytes with carboxyhemoglobin and an atmosphere containing 2% CO, 5% CO 2 and 93% N 2 . Results indicate that, contrary to common belief, oxygen is not involved in the activity of chloroquine. Reactive radicals formation is suggested. ß 2002 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved.Key words: Carboxyhemoglobin; Chloroquine; Carbon monoxide ; Oxygen; Malaria; Plasmodium falciparum Malaria continues to be a major health problem in tropical countries. Some 300^500 million clinical cases occur annually and result in 700 000^2.7 million deaths [1]. Chloroquine, a 4-amino 7-chloro quinoline, has been the mainstay of malaria control for decades. Despite years of use, its mode of action and the mechanism by which malaria parasites become resistant are only partly known. We know, however, that they are unrelated and independent [2]. Resistance of Plasmodium falciparum to chloroquine is multigenic and concerns drug accumulation in the parasite. In contrast, chloroquine and other quinoline drugs target a unique, essential metabolic pathway of the parasite, the ingestion and degradation of host cell hemoglobin (Hb) within the parasite's food vacuole. While globin-derived amino acids are used by the parasite, the remaining free heme moiety must be disposed: iron(II)protoporphyrin IX (Fe[II]PPIX) is oxidized to iron(III)protoporphyrin IX (Fe[III]PPIX) and, for the most part, converted into a crystalline pigment called hemozoin [3]. So, although chloroquine resistance is nowadays widely spread, knowing how chloroquine works is important in order to design newer and more e¡ective drugs.It is generally accepted that chloroquine prevents heme disposal through the formation of complexes with Fe[III]PPIX. Nuclear magnetic resonance, UV-visible and Mo « ssbauer spectroscopy data concur to show that Z^Z interaction between the drug and the electronic system of hematin governs the formation of these adducts. The accumulation of free heme and/or of chloroquine^Fe(III)PPIX adducts is thought to generate oxidative stress, leading to peroxidation of parasite membrane lipids and parasitic death [3^5]. However, uncertainties still exist.If the peroxidative damage hypothesis were correct, molecular oxygen would be important and play a key role in the initiation and ampli¢cation of the oxidative reactions. However, our ¢ndings are not supportive of this view. We found no signi¢cant variation in the activity of chloroquine when the oxygen tension in the culture was increased [6]. Also the presence of preformed peroxides was necessary for membranes to react with the drug^Fe[III]PPIX complexes and for lipid peroxidation to occur [7]. To further clarify if molecular oxygen and oxidative stress had a role in the mechanism of action of chloroquine, we compared P. falciparum (chloroquine resistant and susceptible clones) cultured in sta...

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“…SS RBCs produce membrane-associated hemin secondary to repeated formation of sickle hemoglobin polymers. This hemin (free ferriprotoporphyrin IX (FP) moieties) in oxyhemoglobin is oxidized from the Fe(II) state to the Fe(III) state with the consequent production of a half-molar equivalent of H 2 O 2 -a potentially toxic molecule [10,11]. Alternative detoxication pathways, including the binding to FP-binding proteins, reaction with glutathione, and FP degradation, may also contribute to FP detoxification [12].…”

Section: Introductionmentioning

confidence: 99%

Spectrin's E2/E3 ubiquitin conjugating/ligating activity is diminished in sickle cells

2005

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Erythrocyte spectrin contains E2/E3 ubiquitin conjugating/ligating activity in its a subunit. Ankyrin is a target of spectrin's E2/E3 ubiquitin conjugating/ligating activity in vitro and in vivo. We compare the ubiquitination levels of ankyrin mediated by control and sickle cell spectrin using a biotinylated ubiquitin cell-free assay. Sickle cell spectrin has diminished ability to transfer ubiquitin from an intermediate spectrin-ubiquitin thioester adduct (a 0 spectrin) to ankyrin, which may be due to glutathiolation of spectrin's E2 and/ or E3 active site cysteines. There is also a diminished ability of the sickle cell ankyrin to serve as target of spectrin's E2/E3 activity, probably due to oxidative damage to ankyrin. A direct correlation exists between the a 0 /a spectrin ratio and spectrin's ability to ubiquitinate ankyrin. There is also an inverse correlation between severity of the disease and the a 0 /a spectrin ratio in SS erythrocytes. These results suggest that reduced spectrin E2/ E3 activity is an important determinant of sickle cell severity. Am. J. Hematol. 79:89-96, 2005.

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Histidine-rich protein 2 of the malaria parasite, Plasmodium falciparum, is involved in detoxification of the by-products of haemoglobin degradation

Cited by 67 publications

References 34 publications

trans Expression of a Plasmodium falciparum Histidine-rich Protein II (HRPII) Reveals Sorting of Soluble Proteins in the Periphery of the Host Erythrocyte and Disrupts Transport to the Malarial Food Vacuole

trans Expression of a Plasmodium falciparum Histidine-rich Protein II (HRPII) Reveals Sorting of Soluble Proteins in the Periphery of the Host Erythrocyte and Disrupts Transport to the Malarial Food Vacuole

Does chloroquine really act through oxidative stress?

Spectrin's E2/E3 ubiquitin conjugating/ligating activity is diminished in sickle cells

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