Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cyclobuxine is a steroidal alkaloid which was extracted from Buxus microphylla var. koreana Nakai. Extracts of Buxus microphylla var. koreana Nakai have been used as folk remedies of several diseases, including malaria and venereal diseases. In the present study, the possible protective effects of cyclobuxine against 60 min ischemia and subsequent 30 min reperfusion in isolated rat hearts were investigated. Ischemia induced a marked decline in contractile force and a gradual rise in resting tension. Reperfusion of the heart for 30 min resulted in a poor recovery of contractile force. When the heart was perfused in the presence of cyclobuxine (100 and 1000 ng/ml), a significant suppression of mechanical failure was seen. Ischemia also induced an immediate release of ATP metabolites and a release of creatine phosphokinase during reperfusion. Cyclobuxine inhibited the release of ATP metabolites, and slightly prevented the release of creatine phosphokinase during reperfusion. The ultrastructural damages induced by ischemia and subsequent reperfusion were significantly suppressed by cyclobuxine.
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PMID:Cyclobuxine protects the isolated rat heart from the myocardial injuries produced by ischemia and reperfusion. 837 42

Non-mitochondrial calcium deposits were investigated in the intraerythrocytic malaria parasite Plasmodium chabaudi at the trophozoite stage by means of arsenazo III in the presence of ATP and the mitochondrial poisons, antimycin and oligomycin. Addition of vanadate and 2,5-di-(t-butyl)-1,4-hydroquinone (BHQ), both known to interact with SERCA pump, induced calcium release by permeabilized parasites when the medium free calcium concentration was kept at 3.5 microM. The tumor promoter thapsigargin also caused elevation of the free calcium concentration in permeabilized parasites. Our results support the view that P. chabaudi sequesters calcium in an exchangeable form and maintains its calcium homeostasis by way of an endoplasmic reticulum Ca2+ pump.
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PMID:Characterization of Ca2+ transport activity associated with a non-mitochondrial calcium pool in the rodent malaria parasite P. chabaudi. 928 59

Malaria-infected red blood cells are under a substantial oxidative stress. Glutathione metabolism may play an important role in antioxidant defense in these cells, as it does in other eukaryotes. In this work, we have determined the levels of reduced and oxidized glutathione (GSH and GSSG, respectively) and their distributions in the parasite, and in the host-cell compartments of human erythrocytes infected with the malaria parasite Plasmodium falciparum. In intact trophozoite-infected erythrocytes, [GSH] is low and [GSSG] is high, compared with the levels in normal erythrocytes. Normal erythrocytes and the parasite compartment display high GSH/GSSG ratios of 321.6 and 284.5, respectively, indicating adequate antioxidant defense. This ratio drops to 26.7 in the host-cell compartment, indicating a forceful oxidant challenge, the low ratios resulting from an increase in GSSG and a decline in GSH concentrations. On the other hand, the concentrations of GSH and GSSG in the parasite compartment remain physiological and comparable to their concentrations in normal red blood cells. This results from de novo glutathione synthesis and its recycling, assisted by the intensive activity of the hexose monophosphate shunt in the parasite. A large efflux of GSSG from infected cells has been observed, its rate being similar from free parasites and from intact infected cells. This result suggests that de novo synthesis by the parasite is the dominating process in infected cells. GSSG efflux from the intact infected cell is more than 60-fold higher than the rate observed in normal erythrocytes, and is mediated by permeability pathways that the parasite induces in the erythrocyte's membrane. The main route for GSSG efflux through the cytoplasmic membrane of the parasite seems to be due to a specific transport system and occurs against a concentration gradient. Gamma-glutamylcysteine [Glu(-Cys)] and GSH can penetrate through the pathways from the extracellular space into the host cytosol, but not into that of the parasite. This implies that the parasite membrane is impermeable to these peptides, and that the host cannot supply GSH to the parasite as suggested previously. Exogenous Glu(-Cys) is not converted into GSH in the host cell, arguing that GSH synthetase may not be functional. Compartment analysis of Mg2+ in infected erythrocytes revealed that the host compartment exhibits a low concentration of Mg2+ (0.5 mM) in comparison with the parasite compartment (4 mM) and the normal erythrocytes (1.5-3 mM). The drop in [Mg2+] results in cessation of Glu(-Cys) synthesis, and hence of GSH synthesis in the host-cell compartment. The decrease in [Mg2+] can affect other Mg2+-ATP-dependent functions, such as Na+ and Ca2+ active efflux. The present investigation confirms that the host-cell compartment is oxidatively distressed, whereas the parasite is efficiently equipped with anti-oxidant means that protect the parasite from the oxidative injury. The parasite has a huge capacity for de novo synthesis of GSH and for the reduction of GSSG. Part of the GSSG that is actively extruded from the parasite is reduced to GSH in the host cell whose own GSH synthesis is crippled.
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PMID:The malaria parasite supplies glutathione to its host cell--investigation of glutathione transport and metabolism in human erythrocytes infected with Plasmodium falciparum. 946 Dec 89

The structure of the glycolytic enzyme class I fructose-1, 6-bisphosphate aldolase from the human malaria parasite Plasmodium falciparum has been determined by X-ray crystallography. Homotetrameric P. falciparum aldolase (PfALDO) crystallizes in space group P3221 with one 80 kDa dimer per asymmetric unit. The final refined PfALDO model has an R-factor of 0.239 and an R-free of 0.329 with respect to data from 8 to 3.0 A resolution. PfALDO is potentially a target for antimalarial drug design as the intraerythrocytic merozoite lifestage of P. falciparum is completely dependent upon glycolysis for its ATP production. Thus, inhibitors directed against the glycolytic enzymes in P. falciparum may be effective in killing the parasite. The structure of PfALDO is compared with the previously determined structure of human aldolase in order to determine possible targets for the structure-based design of selective PfALDO ligands. The salient structural differences include a hydrophobic pocket on the surface of PfALDO, which results from some amino acid changes and a single residue deletion compared with human aldolase, and the overall quaternary structure of the PfALDO tetramer, which buries less surface area than human aldolase.
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PMID:Crystal structure of fructose-1,6-bisphosphate aldolase from the human malaria parasite Plasmodium falciparum. 952 58

Movement of the malaria parasite into a host erythrocyte during invasion is thought to involve polymerization of parasite actin. We have used F-actin affinity chromatography to isolate actin-binding proteins from Plasmodium knowlesi merozoites, in an attempt to identify proteins responsible for regulating parasite actin polymerization during invasion. Five major proteins, of molecular masses 75, 70, 48, 40 and 34 kDa, were reproducibly eluted from the F-actin columns. The 70 kDa actin-binding protein was identified by tryptic peptide microsequencing as heat shock protein-70 kDa (HSC70); this identification was confirmed by Western blotting with anti-HSC70 antibody, and binding of the protein to ATP-agarose. A doublet of 32/34-kDa proteins coeluted with parasite HSC70 from the F-actin and ATP-agarose columns; a complex of these three proteins was also observed by gel filtration chromatography Highly enriched fractions containing the Plasmodium HSC70/32/34 complex inhibited the polymerization of rabbit skeletal muscle actin, in vitro. This capping activity was calcium-independent, and abrogated by phosphatidylinositol 4,5-bisphosphate. The average length of the actin filaments polymerized in presence of the HSC70/32/34-kDa complex was significantly shorter than in the absence of the complex, consistent with a capping activity. The capping or uncapping of actin filament ends by the HSC70/32/34-kDa complex during invasion could provide a mechanism for localized actin filament growth and movement of the parasite into the host cell.
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PMID:Actin-binding proteins of invasive malaria parasites and the regulation of actin polymerization by a complex of 32/34-kDa proteins associated with heat shock protein 70kDa. 966 13

A major obstacle in the global effort to control malaria is the paucity of anti-malarial drugs. This is compounded by the continuing emergence and spread of resistance to old and new anti-malarial drugs in the malarial parasites. Here we describe the anti-malarial effect of phosphorothioate antisense (AS) oligodeoxynucleotides (ODNs) targeting the aldolase enzyme of Plasmodium falciparum, using the asexual blood stages of the parasite grown in vitro. The blood stages of P. falciparum depend almost entirely on the energy produced by their own glycolysis. Aldolase, the fourth enzyme of the glycolytic pathway, is highly upregulated during the malarial 48-h life cycle. We found that the mRNA of this enzyme can be inhibited, in a sequence specific manner, using AS-ODN to the splice sites on the pre-mRNA of malarial aldolase. At the enzyme level, both specific AS-ODNs for the splice sites, as well as for the translation initiation site on mature mRNA, can inhibit aldolase enzyme activity within the trophozoites of P. falciparum. Furthermore, this downregulation of the malarial aldolase results in a reduction in the production of ATP within the parasite. Finally, the treatment reduces parasitemia. In summary, AS-ODNs targeting the aldolase gene of P. falciparum can interfere with the blood-stage life cycle of this parasite in vitro by inhibiting the expression of the enzyme aldolase which results in decreased malarial glycolysis and energy production. Thus, we conclude that blockade of the expression of malarial glycolytic enzymes using specific AS-ODNs has the potential of a new anti-malarial strategy.
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PMID:Antisense oligonucleotides targeting malarial aldolase inhibit the asexual erythrocytic stages of Plasmodium falciparum. 1047 79

The mechanism by which the intra-erythrocytic form of the human malaria parasite, Plasmodium falciparum, extrudes H(+) ions and thereby regulates its cytosolic pH (pH(i)), was investigated using saponin-permeabilized parasitized erythrocytes. The parasite was able both to maintain its resting pH(i) and to recover from an imposed intracellular acidification in the absence of extracellular Na(+), thus ruling out the involvement of a Na(+)/H(+) exchanger in both processes. Both phenomena were ATP-dependent. Amiloride and the related compound ethylisopropylamiloride caused a substantial reduction in the resting pH(i) of the parasite, whereas EMD 96785, a potent and allegedly selective inhibitor of Na(+)/H(+) exchange, had relatively little effect. The resting pH(i) of the parasite was also reduced by the sulfhydryl reagent N-ethylmaleimide, by the carboxyl group blocker N,N'-dicyclohexylcarbodiimide, and by bafilomycin A(1), a potent inhibitor of V-type H(+)-ATPases. Bafilomycin A(1) blocked pH(i) recovery in parasites subjected to an intracellular acidification and reduced the rate of acidification of a weakly buffered solution by parasites under resting conditions. The data are consistent with the hypothesis that the malaria parasite, like other parasitic protozoa, has in its plasma membrane a V-type H(+)-ATPase, which serves as the major route for the efflux of H(+) ions.
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PMID:pH regulation in the intracellular malaria parasite, Plasmodium falciparum. H(+) extrusion via a V-type H(+)-ATPase. 1055 94

The asexual development of the malaria parasite takes place inside the host's erythrocyte, an environment that is different from that of most other eukaryotic organisms. The intense and rapid development of the parasite, as well as the homeostatic regulation of its cellular composition, require an extensive exchange of material between the parasite and its immediate surroundings. Studies on free murine parasite species suggest that a plasma membrane H+ pump is responsible for the maintenance of membrane potential and pH gradient, which are used as driving forces for the uptake of glucose and extrusion of Ca2+ by means of a symporter and an antiporter, respectively. In Plasmodium falciparum, a similar transport of Ca2+ may prevail. Several other transporters have been assigned to the plasma membrane of this parasite, either by direct measurements or by inference: D-glucose, nucleosides, L-amino acids, L-lactate and pantothenic acid. A Na+/H+ antiporter has been demonstrated, and implicated in the regulation of pH, and an ATP/ADP antiporter, whose function remains controversial, has been characterized. The presence of Mg2+ and Na+/K+ pumps and an active extrusion of oxidized glutathione can be inferred from the composition of the parasite cytosol vs. that of the host cell. Several genes coding for cation pumps have been cloned and their functions await characterization.
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PMID:The permeability properties of the parasite cell membrane. 1064 41

Respiration, oxidative phosphorylation, calcium uptake, and the mitochondrial membrane potential of trophozoites of the malaria parasite Plasmodium berghei were assayed in situ after permeabilization with digitonin. ADP promoted an oligomycin-sensitive transition from resting to phosphorylating respiration. Respiration was sensitive to antimycin A and cyanide. The capacity of trophozoites to sustain oxidative phosphorylation was additionally supported by the detection of an oligomycin-sensitive decrease in mitochondrial membrane potential induced by ADP. Phosphorylation of ADP could be obtained in permeabilized trophozoites in the presence of succinate, citrate, alpha-ketoglutarate, glutamate, malate, dihydroorotate, alpha-glycerophosphate, and N,N,N',N'-tetramethyl-p-phenylenediamine. Ca(2+) uptake caused membrane depolarization compatible with the existence of an electrogenically mediated Ca(2+) transport system in these mitochondria. An uncoupling effect of fatty acids was partly reversed by bovine serum albumin, ATP, or GTP and not affected by atractyloside, ADP, glutamate, or malonate. Evidence for the presence of a mitochondrial uncoupling protein in P. berghei was also obtained by using antibodies raised against plant uncoupling mitochondrial protein. Together these results provide the first direct biochemical evidence of mitochondrial function in ATP synthesis and Ca(2+) transport in a malaria parasite and suggest the presence of an H(+) conductance in trophozoites similar to that produced by a mitochondrial uncoupling protein.
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PMID:Oxidative phosphorylation, Ca(2+) transport, and fatty acid-induced uncoupling in malaria parasites mitochondria. 1073 23

Plasmodium species have the capacity to fix carbon dioxide during intracellular development. This process contributes to the pool of free amino acids and metabolites, which are the end products of glucose metabolism in the malaria parasite. A gene encoding phosphoenolpyruvate carboxykinase (PEPCK), an enzyme known to catalyze CO(2) fixation was identified in the genome of the human parasite Plasmodium falciparum by DNA microarray analysis experiments and was cloned and characterized. PfPEPCK is a 66.2 kDa, ATP-dependent enzyme which is closely related to PEPCK from plants and yeast but markedly different from the host enzyme human PEPCK. PfPEPCK transcript and active enzyme levels are upregulated in the transmissible and zygote stages of parasite development relative to the asexual blood stages. Elevated expression of PfPEPCK during the extracellular zygote phase of P. falciparum development within the microenvironment of the mosquito midgut may reflect a glucose-rare medium and suggests a possible switch in carbohydrate metabolism to a gluconeogenesis pathway.
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PMID:Plasmodium falciparum phosphoenolpyruvate carboxykinase is developmentally regulated in gametocytes. 1077 99


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