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)

In vitro studies have shown that exogenously supplied amino acids are transferred into the malaria-infected cell, where they are incorporated into proteins. Most amino acids appear to enter the cell by facilitated or simple diffusion; however, the high distribution ratios seen in Plasmodium knowlesi-infected cells are difficult to explain on this basis. The changes (leakiness) observed in amino acid transport in P. lophurae infected cells are probably the result of ATP depletion in the host cell as well as the elaboration of plasmodial substances. Depletion of isoleucine, methionine, and cysteine from the medium strikingly depresses the in vitro growth of P. knowlesi. The degree of amino acid incorporation into the malaria-infected cell is not correlated with the amount of a particular amino acid in the host cell haemoglobin, the decline of that amino acid in the plasma of infected animals, or the ratio of free amino acids of the erythrocyte to those of the plasma. In erythrocyte-"free" P. lophurae, carrier-mediated transport is apparently limited to a small number of amino acids; all others seem to enter by simple diffusion.Malaria-infected erythrocytes transport exogenously supplied purines at substantially higher rates than uninfected red cells. The preferred purines are adenosine, hypoxanthine, and inosine. The only pyrimidine incorporated is orotic acid. Thymidine, cytidine, and uridine do not readily enter the red cell, and incorporation does not take place because the parasites lack the appropriate enzyme for conversion to nucleotides. Erythrocyte-"free" P. berghei and P. lophurae take up purines and orotic acid. It has been suggested that in vivo the preferred purines are hypoxanthine and inosine, and that the transport locus for erythrocytes is specific for 6-oxopurines. Similar results of purine incorporation are reported for the insect stages of P. cynomolgi and P. berghei, although transport studies have not been carried out.
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PMID:Transport of amino acids and nucleic acid precursors in malarial parasites. 33 80

Rhesus monkey erythrocytes when incubated in vitro under similar conditions to those used for the cultivation of Plasmodium knowlesi-infected erythrocytes in vitro, exhibit an increase both in their osmotic fragility and in the activity of their acetylthiocholinesterase. No effect was observed on the catabolism of glucose through the glycolytic pathway or through the primary dehydrogenases of the pentose phosphate pathway. The ATP content of normal monkey erythrocytes was also unchanged during incubation in vitro. These observations indicate that incubation of erythrocytes in vitro primarily causes membrane changes. Infection of normal erythrocytes by P. knowlesi was reduced markedly by preincubation in vitro at 37 degrees C for 24 and 48 h. These results suggest that the maintenance of integrity of the surface of the erythrocyte in vitro is a necessary prerequisite for an efficient culture system for the malaria parasite.
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PMID:The effect of incubation in vitro on the susceptibility of monkey erythrocytes to invasion by Plasmodium knowlesi. 82 5

The extracellular development in vitro of the avian malaria Plasmodium lophurae is favored by addition to the medium of coenzyme A at 0.05 mM. Coenzyme A can be replaced by dephospho-coenzyme A and to some extent by phosphopantetheine, but not by phosphopantothenoylcysteine or by phosphopantothenic acid. The activity of the two former precursors results from their conversion to coenzyme A by enzymes in the erythrocyte extract of the culture medium in the presence of ATP, also an essential ingredient of the medium. Hence, P. lophurae in its erythrocytic stage has an absolute requirement for an exogenous source of coenzyme A.
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PMID:Coezyme A requirement of malaria parasites: effects of coenzyme A precursors on extracellular development in vitro of Plasmodium lophurae. 105 72

Chloroquine inhibits the growth of susceptible malaria parasites at low (nanomolar) concentrations because of an energy-requiring drug-concentrating mechanism in the parasite secondary lysosome (food vacuole) which is dependent on the acidification of that vesicle. Chloroquine resistance results from another energy-requiring process: efflux of chloroquine from the resistant parasite with a half-time of 2 min. Chloroquine efflux is inhibited reversibly by the removal of metabolizable substrate (glucose); it is also reduced by the ATPase inhibitor vanadate. These results suggest that chloroquine efflux is an energy-requiring process dependent on the generation and hydrolysis of ATP. Chloroquine efflux cannot be explained by differences in drug accumulation between chloroquine-susceptible and -resistant parasites because the 40-50-fold difference in initial efflux rates between -susceptible and -resistant parasites is unchanged when both parasites contain the same amount of chloroquine. Although chloroquine efflux is phenotypically similar to the efflux of anticancer drugs from multidrug-resistant (mdr) mammalian cells, it is not linked to either of the mdr-like genes of the parasite.
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PMID:Energy dependence of chloroquine accumulation and chloroquine efflux in Plasmodium falciparum. 153 Nov 76

Controlled mechanical homogenization of Plasmodium falciparum-infected erythrocytes releases parasites of a quality sufficient for studying the export of newly synthesized plasmodial proteins. Protein synthesis occurs within intact released parasites as defined by resistance of acid-insoluble incorporation of radiolabel to high levels of exogenously added EDTA, hexokinase, and RNaseA. While exogenously added ATP and erythrocyte cytosol were not essential for biosynthetic activity at levels comparable to that seen in infected erythrocytes, the addition of an extracellular ATP regenerating system (ARS) stimulated the synthesis of parasite proteins. Conversely, parasite viability and biosynthetic activity are decreased by the addition of a non-hydrolyzable ATP analogue (ATP gamma S), ADP, or ATP in the absence of a regenerating system. These data suggest a metabolic interdependence between extracellular energy metabolism and biosynthetic functions within the parasite. The export of a predominant subset of proteins was retarded in the presence of Brefeldin A, indicating the existence of a classical secretory pathway characteristic of that seen in higher eukaryotic cells. Interestingly, a Brefeldin A-insensitive component of export was also consistently observed; this may suggest the existence of an additional alternative secretory mechanism in malaria.
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PMID:Synthesis and secretion of proteins by released malarial parasites. 162 Jan 61

Multiplication of the human malaria parasite Plasmodium falciparum within red blood cells is an energy-dependent process and glucose consumption increases dramatically in infected red blood cells (IRBC) versus normal red blood cells (NRBC). The major pathway for glucose metabolism in P. falciparum IRBC is anaerobic glycolysis. Phosphoglycerate kinase (PGK) is one of the key enzymes of this pathway as it generates ATP. We found that the PGK specific activity in P. falciparum IRBC is seven times higher than that in NRBC. The parasitic origin of the increase in PGK activity is confirmed by isoelectric focusing. Indeed, two P. falciparum isoenzymes with neutral isoelectric points were detected. P. falciparum PGK in purified form has a molecular mass of 48 kDa. Antiserum raised against purified P. falciparum PGK specifically recognizes the 48-kDa protein band in P. falciparum and also reacts with P. berghei and P. yoelii IRBC lysates but does not cross-react with PGK associated with NRBC.
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PMID:Plasmodium falciparum: identification and purification of the phosphoglycerate kinase of the malaria parasite. 163 56

Chloroquine is thought to act against falciparum malaria by accumulating in the acid vesicles of the parasite and interfering with their function. Parasites resistant to chloroquine expel the drug rapidly in an unaltered form, thereby reducing levels of accumulation in the vesicles. The discovery that verapamil partially reverses chloroquine resistance in vitro led to the proposal that efflux may involve an ATP-driven P-glycoprotein pump similar to that in mammalian multidrug-resistant (mdr) tumor cell lines. Indeed, Plasmodium falciparum contains at least two mdr-like genes, one of which has been suggested to confer the chloroquine resistant (CQR) phenotype. To determine if either of these genes is linked to chloroquine resistance, we performed a genetic cross between CQR and chloroquine-susceptible (CQS) clones of P. falciparum. Examination of 16 independent recombinant progeny indicated that the rapid efflux phenotype is controlled by a single gene or a closely linked group of genes. But, there was no linkage between the rapid efflux, CQR phenotype and either of the mdr-like P. falciparum genes or amplification of those genes. These data indicate that the genetic locus governing chloroquine efflux and resistance is independent of the known mdr-like genes.
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PMID:Chloroquine resistance not linked to mdr-like genes in a Plasmodium falciparum cross. 218 23

The permeability of simian erythrocytes to choline was found to be considerably increased after infection by the malaria parasite, Plasmodium knowlesi. Choline entry occurs by a facilitated-diffusion system involving a carrier, which displays temperature-dependence, saturability with choline (Km = 8.5 +/- 0.7 microM) and specificity. This carrier can also be inhibited by a thiol reagent, N-ethylmaleimide, at an inactivation rate which is, in the absence of choline, the same as in normal erythrocytes. Inactivation by N-ethylmaleimide can be accelerated by external choline and prevented by decamethonium, which acts as an inhibitor of choline entry in infected cells (as with dodecyltrimethylammonium). Both ethanolamine and imidazole act as inhibitors or activators of choline entry in infected erythrocytes, depending on the relative concentrations of choline and of the competing compound (i.e. ethanolamine or imidazole). After infection, the maximum velocity reached 2.84 +/- 0.5 nmol/min per 10(10) infected cells, which is more than 10 times the Vmax. of normal erythrocytes. Impairing the biosynthesis of phosphatidylcholine de novo in Plasmodium-infected erythrocytes by various methods (glucose or ATP depletion, high ethanolamine concentrations) did not result in any alteration of choline transport (Km or Vmax.), indicating that the constant triggering and transformation of choline into phosphatidylcholine by the parasite is not directly responsible for the increase in the choline transport rate after infection. This high increase in choline transport activity is more likely related to modifications in choline carriers and/or in their environment after Plasmodium infection.
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PMID:Increased permeability to choline in simian erythrocytes after Plasmodium knowlesi infection. 199 67

Energy metabolism of malaria parasites was investigated in P. berghei infected red blood cells of rat. Although Plasmodia contain mitochondria most of their ATP is formed by glycolysis. Lactate formation is two orders of magnitude higher than in noninfected erythrocytes. The coupling of respiration and glycolysis is very loose, a Pasteur-effect was not found. The key enzymes of glycolysis hexokinase and phosphofructokinase have been partially purified and kinetically characterized. The kinetic properties of both enzymes significantly differ from those of erythrocytes. They are less efficiently inhibited and PFK is activated only by PEP, Fru6P and Pi. The high rate of glycolytic proton formation in Plasmodia inhibits the PFK and thus the anaerobic energy metabolism of the host cell but not that of the parasite. Nevertheless the ATP concentrations in the host and the parasite compartment were found to be nearly identical. This supports the assumption that the parasites make ATP available to their host cell, probably by an adenine nucleotide translocator.
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PMID:Regulation of the energy metabolism of Plasmodium berghei. 214 51

The energy metabolism of the blood stage form of the human malaria parasite Plasmodium falciparum is adapted to the host cell. Like erythrocytes, P. falciparum merozoites lack a functional citric acid cycle. Generation of ATP depends therefore fully on the glycolytic pathway. Aldolase is a key enzyme of this pathway and a high degree of sequence diversity between parasite and host makes it a potential drug target. We have expressed the enzyme in its tetrameric form in Escherichia coli and the catalytic constants Vmax and Km of the recombinant enzyme correspond to the constants of parasite-derived aldolase. Rabbit antibodies against the recombinant P. falciparum aldolase inhibit the natural enzyme and no cross-reaction with human aldolase is detectable. Both the recombinant and the natural protein bind to the cytosolic domain of the band 3 membrane protein in vitro. A 19-residue synthetic peptide corresponding to the sequence of the binding domain of band 3 is an inhibitor when included in the binding assay. In addition, this peptide inhibits the catalytic activity of recombinant P. falciparum aldolase when assayed in a buffer system devoid of anions such as chloride or phosphate. The band 3-derived peptides compete with the aldolase substrate fructose-1,6-diphosphate for binding, suggesting that both reagents have a high affinity for the substrate pocket. A similar sequence motif exists in P. falciparum actin II. A 19-residue peptide corresponding to this sequence is also an inhibitor which could suggest that the P. falciparum aldolase can associate with the cytoskeleton of the parasite or of the host.
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PMID:Expression, purification, biochemical characterization and inhibition of recombinant Plasmodium falciparum aldolase. 220 32


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