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)

10-(4'-Chlorophenyl)-3-methylflavin has antimalarial activity in vitro and in vivo (Cowden et al., J Med Chem 31: 799, 1988). This flavin analog and two of its derivatives were found to inhibit the antioxidant flavoenzyme glutathione reductase from human erythrocytes in its isolated form as well as in hemolysates. The mixed-type inhibition was completely reversible, the Ki-values being of the order of 1 microM. Surprisingly, the drugs were not competitive with FAD, but with GSSG, one of the enzyme's substrates. Malaria parasite glutathione reductase, extracted from Plasmodium falciparum, could also be inhibited by the compounds. Studies on the effects of the substances on P. falciparum in vitro, which were demonstrated morphologically and by growth inhibition, confirmed previous observations with 10-(4'-chlorophenyl)-3-methylflavin and showed similar parasiticidal characteristics for the two new derivatives. The activities of five other erythrocytic enzymes tested were not impaired by the drugs, nor was the nucleotide metabolism of erythrocytes and/or parasites significantly changed. Permeation into red blood cells was demonstrated for one compound by 19F-NMR-spectroscopy. Inhibition of glutathione reductase might contribute to, or account for, the antimalarial activity of this group of flavin analogs.
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PMID:Flavin analogs with antimalarial activity as glutathione reductase inhibitors. 240 94

In 18 beta-thalassaemia families from the Ferrara area the incidence of an inherited low flavin mononucleotide (FMN)-dependent pyridoxine phosphate (PNP) oxidase activity, a sensitive indicator of red-cell FMN deficiency, is higher in related members in these families than in the unrelated spouses and controls subjects without family history of thalassaemia. This suggests slower red-cell riboflavin metabolism in thalassaemia families, which may have resulted from selection in combination with thalassaemia by malaria. However, there was a markedly higher incidence of red-cell flavin adenine dinucleotide (FAD) deficiency in thalassaemia heterozygotes than in their normal relatives. This was indicated by higher stimulation of FAD-dependent glutathione reductase (GR) activity by FAD and lower GR activity per red cell, and suggests a marked additive effect by thalassaemia on the red cell FAD deficiency that results from the inherited slow riboflavin metabolism. There is evidence that diversion of FAD to other FAD-dependent enzymes might be an important factor.
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PMID:Genetic and other influences on red-cell flavin enzymes, pyridoxine phosphate oxidase and glutathione reductase in families with beta-thalassaemia. 272 60

BCNU [1,3-bis(2-chloroethyl)-1-nitrosourea] and its less toxic derivative HeCNU [1-(2-chloroethyl)-3-(2-hydroxyethyl)-1-nitrosourea] are clinically-used antitumour drugs. In erythrocytes BCNU is a highly specific inhibitor of the enzyme glutathione reductase [H. Frischer and T. Ahmad, J. Lab. clin. Med. 89, 1080 (1977)]. When treating erythrocytes in vitro, 50% enzyme inhibition was obtained with 1 microM BCNU or 3 microM HeCNU within 2 hr. The two drugs were used for preparing red cell populations with various levels of glutathione reductase activity; complete inhibition (greater than or equal to 98%) was only achieved when the medium contained glucose as a source of reducing equivalents. The erythrocytes were then tested in drug-free media as host cells for the malaria parasite Plasmodium falciparum. In the range of 0-300 mU/ml cells, there was a correlation between glutathione reductase activity and parasite growth; erythrocytes with an activity of less than 20 mU/ml did not serve as host cells for P. falciparum at all although these erythrocytes were viable. When the culture medium was supplemented with 20 mM glutathione (GSH), parasite growth was normal irrespective of the glutathione reductase level in the erythrocytes. This is consistent with the finding that poisoning glutathione reductase led to a 10-fold decrease of the cytosolic GSH level. Our results corroborate the concept that intraerythrocytic inhibition of glutathione reductase mimicks the biochemistry of drug-sensitive glucose-6-phosphate dehydrogenase deficiency (favism), an inherited condition which confers protection from malaria.
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PMID:Glutathione reductase-deficient erythrocytes as host cells of malarial parasites. 327 13

The riboflavin status of 64 children suffering from malarial infection was assessed by measuring the activation coefficient of erythrocyte glutathione reductase. Thirty-five children were found to be deficient in riboflavin whereas in 29 children riboflavin status was within the normal range. The median parasite count and its range on admission in the deficient group (2.7 per cent, range 0.3-13.6) was lower than that in the non-deficient group (5.3 per cent, range 0.6-30.2). The correlation between activity coefficient and parasite count was significant (R = -0.49). The recovery process was slower in the deficient group even though they had a relatively lower parasite count. It is inferred that riboflavin deficiency leads to inhibition of growth and multiplication of plasmodia. Its beneficial effects in malaria infection needs further evaluation.
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PMID:Riboflavin deficiency and severity of malaria. 329 96

The glutathione metabolism of Plasmodium falciparum, P. vinckei and P. berghei has been investigated. Human erythrocytes with low glutathione reductase and synthetase activity are still capable of harbouring P. falciparum. Both enzymes have been demonstrated in Plasmodium spp. Moreover, evidence is given for a selenium-independent glutathione peroxidase in malaria parasites.
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PMID:Glutathione and peroxide metabolism in malaria-parasitized erythrocytes. 332 Oct 43

Riboflavin deficiency suppresses parasitic growth in malaria. Three possible mechanisms have been proposed previously to explain the survival advantage of riboflavin-deficient hosts: a) enhanced fragility of red blood cells (RBC), b) decreased formation of reticulocytes and/or c) decreased concentrations of reduced glutathione (GSH) and ATP. The validity of these proposed mechanisms was tested by investigating whether riboflavin deficiency alters the hemolytic response to three stimuli: hydrogen peroxide (H2O2), a hypotonic medium or ferriprotoporphyrin IX (FP). Reticulocyte counts and concentrations of ATP and GSH were also determined. The percentage of hemolysis induced by H2O2 or FP was significantly less in riboflavin-deficient than in control animals. By contrast, hemolytic response to a hypotonic medium was enhanced during riboflavin deficiency. Despite diminished activity of glutathione reductase and normal glutathione peroxidase activity during riboflavin deficiency, the erythrocyte concentration of GSH was increased over that in control animals. Concentrations of ATP and hemoglobin in erythrocytes as well as the reticulocyte count were unaltered during riboflavin deficiency. Thus, diminished malarial parasitemia in riboflavin-deficient animals occurs despite greater resistance of RBC to either H2O2- or FP-induced hemolysis, and in the presence of a normal reticulocyte count and erythrocytes ATP concentration. Results of this study raise the possibility that Plasmodium parasites have greater requirements for flavin coenzymes, GSH or ATP than those of host erythrocytes, which may explain the apparent protection of the riboflavin-deficient host from malaria.
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PMID:Riboflavin deficiency and glutathione metabolism in rats: possible mechanisms underlying altered responses to hemolytic stimuli. 341 22

Many parasites--including the causative agents of malaria, Chagas' disease and schistosomiasis--are more susceptible to reactive oxygen species (ROS) than their hosts are. This is manifested by one or more of the following criteria: 1. Susceptibility of the parasite to ROS in vitro; 2. macrophage-based defense mechanisms against the parasite in vivo; 3. successful therapy using agents which lead to oxidative stress; 4. selection advantage (with respect to parasite infections) of human populations whose antioxidant capacity is impaired by a gene defect or by strong oxidants in their staple food. Our laboratory is involved in developing inhibitors against antioxidant enzymes thus mimicking natural experiments. Since glutathione reductase is a protein of known atomic structure the methods of drug design by receptor fit (DDRF) can be applied for this enzyme. Another promising target enzyme is trypanothione reductase which was found so far only in trypanosomatids, and specifically, not in their hosts. Consequently the trypanothione pathway may be a general target in the design of drugs against diseases caused by trypanosomes and leishmanias.
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PMID:Oxidative stress as a defense mechanism against parasitic infections. 350 42

An improved protein-blotting procedure and a thin layer isoelectric focusing technique are introduced to study glutathione reductase and methemoglobin (Met-Hb). According to our results, there is only one form of glutathione reductase in normal red blood cells. A similar protein was shown to be present at higher concentration in isolated merozoites. Both proteins have a subunit Mr of ca. 50,000 and react with anti-human glutathione reductase serum. Red cells with schizonts do not possess a higher proportion of Met-Hb than non-parasitized erythrocytes. This finding suggests that Met-Hb is not an indicator of metabolic alterations in malaria-infected erythrocytes.
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PMID:Studies on glutathione reductase and methemoglobin from human erythrocytes parasitized with Plasmodium falciparum. 355 36

Chloroquine acts on erythrocytes parasitized by a P. berghei sensitive strain, inducing a dramatic decrease of the intra erythrocytic reduced glutathione. This reduction follows a decrease of the glutathione reductase activity. Contrarily when erythrocytes are parasitized by a P. berghei resistant strain neither the intra erythrocytic reduced glutathione nor the glutathione reductase activity are modified by the action of chloroquine. Glutathione metabolism could be the main target of action of chloroquine in malaria infection.
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PMID:[Action of chloroquine on glutathione metabolism in erythrocytes parasitized by Plasmodium berghei]. 638 Mar 77

In two areas in Italy where malaria was endemic--in the Po delta and Maremma on the west coast--we have found a high prevalence of an inherited flavin-deficient red cell in the normal population, suggesting selection by malaria. This study in Sardinia enabled a direct comparison of red-cell activities of FAD-dependent glutathione reductase (EGR) and FMN-dependent pyridoxine phosphate (PNP) oxidase in an ethnically homogeneous population, between two coastal villages where malaria was endemic from 300 B.C. and two mountain villages with no history of malaria. Both enzyme activities were significantly lower on the coast, and it did not seem that this could be explained by possible small differences in dietary riboflavin. As was thought to be the case in Ferrara and Grosseto, it is probable that a genetically controlled flavin-deficient red cell was selected for by malaria. Low EGR apoenzyme activity was more common on the coast, usually explaining the accompanying low basic EGR activity, and may also have been selected for by malaria. This adds to evidence from others that the mechanism of defence of a flavin-deficient red cell against malaria may be through EGR deficiency. It could also play a part in the protection given by heterozygous beta-thalassemia. The multifactorial protection of the population against malaria is discussed.
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PMID:Deficiency of two red-cell flavin enzymes in a population in Sardinia: was glutathione reductase deficiency specifically selected for by malaria? 766 97


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