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Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A simple, efficient, sensitive, reproducible and high throughput assay for measuring the cytoadhesion of Plasmodium falciparum-infected red blood cells (human malaria) is described. The assay format uses 96-well microplates, with the number of P. falciparum parasitized erythrocytes bound determined by measuring Plasmodium specific lactic dehydrogenase activity colorimetrically (absorbance at 655 nm) using the 3-acetylpyridine analog of nicotinamide adenine dinucleotide, nitro blue tetrazolium and diaphorase. The results of the described microplate assay were found to be comparable to those using microscopic analysis but much less time consuming.
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PMID:A high capacity in vitro assay for measuring the cytoadherence of Plasmodium falciparum-infected erythrocytes. 1055 1

Mitochondria of the malaria parasite Plasmodium falciparum are morphologically different between the asexual and sexual blood stages (gametocytes). In this paper recent findings of mitochondrial heterogeneity are reviewed based on their ultrastructural characteristics, metabolic activities and the differential expression of their genes in these 2 blood stages of the parasite. The existence of NADH dehydrogenase (complex I), succinate dehydrogenase (complex II), cytochrome c reductase (complex III) and cytochrome c oxidase (complex IV) suggests that the biochemically active electron transport system operates in this parasite. There is also an alternative electron transport branch pathway, including an anaerobic function of complex II. One of the functional roles of the mitochondrion in the parasite is the coordination of pyrimidine biosynthesis, the electron transport system and oxygen utilization via dihydroorotate dehydrogenase and coenzyme Q. Complete sets of genes encoding enzymes of the tricarboxylic acid cycle and the ATP synthase complex are predicted from P. falciparum genomics information. Other metabolic roles of this organelle include membrane potential maintenance, haem and coenzyme Q biosynthesis, and oxidative phosphorylation. Furthermore, the mitochondrion may be a chemotherapeutic target for antimalarial drug development. The antimalarial drug atovaquone targets the mitochondrion.
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PMID:The multiple roles of the mitochondrion of the malarial parasite. 1555 97

Kielmeyera coriacea Mart is a medicinal plant of the Clusiacea (Guttiferae) family used by the native population of Brazil in the treatment of several tropical diseases such as malaria, schistosomiasis, leishmaniasis, and fungal or bacterial infections. Kielmeyera coriacea is also effective as an antidepressant drug. Extracts of the plant are rich in xanthones. Compounds of this class have been reported to inhibit mitochondrial energy metabolism. For this reason the action of the Kielmeyera coriacea extract on hepatic energy metabolism was investigated in the present work, using isolated rat liver mitochondria and the perfused rat liver. In perfused livers the extract (20-80 microg/ml) caused stimulation of oxygen consumption, inhibition of gluconeogenesis and stimulation of glycogenolysis and glycolysis. In isolated mitochondria the Kielmeyera coriacea extract (5-20 microg/ml) stimulated state IV respiration, reduced the ADP/O ratio and decreased the respiratory coefficient. The activities of succinate-oxidase, NADH-oxidase, NADH dehydrogenase and succinate dehydrogenase were inhibited. The ATPase of intact mitochondria was stimulated and the ATPase of uncoupled mitochondria was inhibited. The results of this investigation suggest that the Kielmeyera coriacea extract impairs the hepatic energy metabolism by acting as mitochondrial uncoupler and inhibitor of enzymatic activities linked to the respiratory chain. The impairment of mitochondrial energy metabolism could lead to adverse metabolic effects by the use of the crude extract, but it could equally be the basis of its antiprotozoan and antifungal effects.
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PMID:Effects of the Kielmeyera coriacea extract on energy metabolism in the rat liver. 1624 61

Parasites have exploited unique energy metabolic pathways as adaptations to the natural host habitat. In fact, the respiratory systems of parasites typically show greater diversity in electron transfer pathways than do those of host animals. These unique aspects of parasite mitochondria and related enzymes may represent promising targets for chemotherapy. Natural products have been recognized as a source of the candidates of the specific inhibitors for such parasite respiratory chains. Chalcones was recently evaluated for its antimalarial activity in vitro and in vivo. However, its target is still unclear in malaria parasites. In this study, we investigated that licochalcone A inhibited the bc1 complex (ubiquinol-cytochrome c reductase) as well as complex II (succinate ubiquinone reductase, SQR) of Plasmodium falciparum mitochondria. In particular, licochalcone A inhibits bc1 complex activity at very low concentrations. Because the property of the P. falciparum bc1 complex is different from that of the mammalian host, chalcones would be a promising candidate for a new antimalarial drug.
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PMID:Parasite mitochondria as a target of chemotherapy: inhibitory effect of licochalcone A on the Plasmodium falciparum respiratory chain. 1638 76

In the intraerythrocytic stages of malaria parasites, mitochondria lack obvious cristae and are assumed to derive energy through glycolysis. For understanding of parasite energy metabolism in mammalian hosts, we isolated rodent malaria mitochondria from Plasmodium yoelii yoelii grown in mice. As potential targets for antiplasmodial agents, we characterized two respiratory dehydrogenases, succinate:ubiquinone reductase (complex II) and alternative NADH dehydrogenase (NDH-II), which is absent in mammalian mitochondria. We found that P. y. yoelii complex II was a four-subunit enzyme and that kinetic properties were similar to those of mammalian enzymes, indicating that the Plasmodium complex II is favourable in catalysing the forward reaction of tricarboxylic acid cycle. Notably, Plasmodium complex II showed IC(50) value for atpenin A5 three-order of magnitudes higher than those of mammalian enzymes. Divergence of protist membrane anchor subunits from eukaryotic orthologs likely affects the inhibitor resistance. Kinetic properties and sensitivity to 2-heptyl-4-hydroxyquinoline-N-oxide and aurachin C of NADH: ubiquinone reductase activity of Plasmodium NDH-II were similar to those of plant and fungus enzymes but it can oxidize NADPH and deamino-NADH. Our findings are consistent with the notion that rodent malaria mitochondria are fully capable of oxidative phosphorylation and that these mitochondrial enzymes are potential targets for new antiplasmodials.
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PMID:Mitochondrial dehydrogenases in the aerobic respiratory chain of the rodent malaria parasite Plasmodium yoelii yoelii. 1906 Mar 9

Tafenoquine (TFQ), an 8-aminoquinoline analogue of primaquine, which is currently under clinical trial (phase IIb/III) for the treatment and prevention of malaria, may represent an alternative treatment for leishmaniasis. In this work, we have studied the mechanism of action of TFQ against Leishmania parasites. TFQ impaired the overall bioenergetic metabolism of Leishmania promastigotes, causing a rapid drop in intracellular ATP levels without affecting plasma membrane permeability. TFQ induced mitochondrial dysfunction through the inhibition of cytochrome c reductase (respiratory complex III) with a decrease in the oxygen consumption rate and depolarization of mitochondrial membrane potential. This was accompanied by ROS production, elevation of intracellular Ca(2+) levels and concomitant nuclear DNA fragmentation. We conclude that TFQ targets Leishmania mitochondria, leading to an apoptosis-like death process.
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PMID:Tafenoquine, an antiplasmodial 8-aminoquinoline, targets leishmania respiratory complex III and induces apoptosis. 2083 58

It is a continuing quest to uncover the principal molecular targets of malarial parasites to understand the antimalarial activity and mechanism of action of artemisinin, a potent antimalarial. A series of parasite proteins are experimentally validated as potential targets, such as translationally controlled tumor protein (TCTP) and sarco/endoplasmic reticulum membrane calcium ATP-ase (SERCA). The present study addressed the development of a theoretical model of Plasmodium falciparum NADH dehydrogenase with inference from artemisinin in vivo inhibitory activity. We report here the predicted binding modes of artemisinin and its derivatives. The modeled protein resembled the structural architecture of flavoproteins and oxidoreductases, consisting of two Rossmann folds and dedicated binding sites for its cofactors. Docked poses of the ligand dataset revealed its interactions at or near the si face, indicating being activated. This may aid in generation of reactive oxygen species, thereby disrupting the membrane potential of parasite mitochondria and leading to the clearance from the blood. These observations open up new strategies for development of novel therapeutics, or improvement of existing pharmacotherapies against malaria, a major burden for global health.
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PMID:Structural insights into the theoretical model of Plasmodium falciparum NADH dehydrogenase and its interaction with artemisinin and derivatives: towards global health therapeutics. 2363 80

Atovaquone, a coenzyme Q analogue has been indicated to specifically target the cytochrome bc1 complex of the mitochondrial respiratory chain in the malarial parasite and other protozoan. Various mutations in the quinone binding site of the cytochrome b gene of Plasmodium spp. such as M133I, L144S, L271V, K272R, Y268C, Y268S, Y268N, and V284F are suggesting to associate with resistance to atovaquone. There is no direct evidence of relation between the mutations and resistance to atovaquone in Plasmodium parasite that has been available. Technical difficulties in isolating active assayable mitochondria in the malarial parasite hinder us to obtain direct biochemical evidence to support the relation between the mutations and drug resistance. The establishment of a mitochondrial isolation method for the malaria parasite has allowed us to test the degree of resistance of Plasmodium berghei isolates to atovaquone directly. We have tested the activity of dihydroorotate (DHO)-cytochrome c reductase in various P. berghei atovaquone resistant clones in the presence of a wide concentration range of atovaquone. Our results show the IC(50) of P. berghei atovaquone resistant clones is much higher (1.5 up to 40 nM) in comparison to the atovaquone sensitive clones (0.132-0.465 nM). The highest IC(50) was revealed in clones carrying Y268C and Y268N mutations (which play an important role in atovaquone resistance in Plasmodium falciparum), with an approximately 100-fold increase. The findings indicate the importance of the mutation in the quinone binding site of the cytochrome b gene and that provide a direct evidence for the atovaquone inhibitory mechanism in the cytochrome bc1 complex of the parasite.
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PMID:Direct evidence for the atovaquone action on the Plasmodium cytochrome bc1 complex. 2526

The battle against malaria has been substantially impeded by the recurrence of drug resistance in Plasmodium falciparum, the deadliest human malaria parasite. To counter the problem, novel antimalarial drugs are urgently needed, especially those that target unique pathways of the parasite, since they are less likely to have side effects. The mitochondrial type II NADH dehydrogenase (NDH2) of P. falciparum, PfNDH2 (PF3D7_0915000), has been considered a good prospective antimalarial drug target for over a decade, since malaria parasites lack the conventional multi-subunit NADH dehydrogenase, or Complex I, present in the mammalian mitochondrial electron transport chain (mtETC). Instead, Plasmodium parasites contain a single subunit NDH2, which lacks proton pumping activity and is absent in humans. A significant amount of effort has been expended to develop PfNDH2 specific inhibitors, yet the essentiality of PfNDH2 has not been convincingly verified. Herein, we knocked out PfNDH2 in P. falciparum via a CRISPR/Cas9 mediated approach. Deletion of PfNDH2 does not alter the parasite's susceptibility to multiple mtETC inhibitors, including atovaquone and ELQ-300. We also show that the antimalarial activity of the fungal NDH2 inhibitor HDQ and its new derivative CK-2-68 is due to inhibition of the parasite cytochrome bc1 complex rather than PfNDH2. These compounds directly inhibit the ubiquinol-cytochrome c reductase activity of the malarial bc1 complex. Our results suggest that PfNDH2 is not likely a good antimalarial drug target.
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PMID:Mitochondrial type II NADH dehydrogenase of Plasmodium falciparum (PfNDH2) is dispensable in the asexual blood stages. 3096 63

Chorismate synthase (Cs) is the last enzyme of the main trunk of shikimate pathway and catalyzes formation of chorismate, a major aromatic metabolite precursor. We have previously reported that Cs is highly conserved across different Plasmodium sp. Here we report that Cs from malaria parasites are bifunctional enzymes through expression and functional studies of two recombinant proteins rPfCs (Cs from P. falciparum) and rPvCs (Cs from P. vivax). We confirm bifunctional activity of both rPfCs and rPvCs based on their ability to catalyze formation of chorismate under aerobic conditions as well as their ability to catalyze generation of reduced flavin mononucleotide (FMN) as assessed through diaphorase assay.
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PMID:Chorismate synthase from malaria parasites is bifunctional enzyme. 3138 47


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