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)

We have evaluated 3 molecularly defined polypeptides encoded by encloned Plasmodium falciparum genes for their ability to serve as antigens for detecting antimalaria antibodies. The recombinant proteins correspond to (i) a conserved part of 190-200 kDa schizont merozoite surface component, (ii) the carboxy terminal part of the P. falciparum aldolase, and (iii) the 5.1 antigen. Antibodies were detected using enzyme-linked immunosorbent assays (ELISA) in a high percentage of sera from individuals from a malaria endemic area in The Gambia (up to 99% for some adult groups). These results were further improved, especially for detection of antimalaria antibodies in children, when a pool of all 3 polypeptides (ELISA MIXT) was used as antigen. This ELISA MIXT improves presently available assays for the detection of antimalaria antibodies directed against asexual blood stages in respect of standardization, sensitivity and specificity.
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PMID:Recombinant polypeptides for serology of malaria. 269 65

Immunization with a 41-kilodalton blood stage antigen (p41) of Plasmodium falciparum induces immunity to malaria in monkeys. However, antigenic polymorphism and repetitive amino acids commonly found in protective antigens complicate vaccine development. The gene encoding p41 has now been cloned and analyzed. Sequencing and hybridization studies revealed that the gene structure is highly conserved in 14 parasite isolates from three continents. This finding and the lack of repetitive amino acids in the translated DNA sequence may indicate that p41 has an essential function. In this study the protein was found to be 60 percent homologous to the key glycolytic enzyme aldolase from vertebrates, and the affinity-purified p41 protein from parasites showed aldolase activity.
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PMID:Aldolase activity of a Plasmodium falciparum protein with protective properties. 328 69

A structural study of the type I aldolases has been carried out to examine the isozyme specificity of these enzymes and the potential for designing specific inhibitors. Natural mutations in these aldolase enzymes are associated with haemolytic anaemia and fructose intolerance. It has also been proposed that inhibition of the parasitic version of the enzyme may provide a new lead in the design of drugs against malaria and sleeping sickness. X-ray crystallographic data is used with molecular modelling techniques to investigate the structural properties of these enzymes.
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PMID:Studies with type I aldolase to understand fructose intolerance and combat parasitic disease. 893 75

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

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

Malaria presents a diagnostic challenge to laboratories in most countries. Endemic malaria, population movements, and travelers all contribute to presenting the laboratory with diagnostic problems for which it may have little expertise available. Drug resistance and genetic variation has altered many accepted morphological appearances of malaria species, and new technology has given an opportunity to review available procedures. Concurrently the World Health Organization has opened a dialogue with scientists, clinicians, and manufacturers on the realistic possibilities for developing accurate, sensitive, and cost-effective rapid diagnostic tests for malaria, capable of detecting 100 parasites/microl from all species and with a semiquantitative measurement for monitoring successful drug treatment. New technology has to be compared with an accepted "gold standard" that makes comparisons of sensitivity and specificity between different methods. The majority of malaria is found in countries where cost-effectiveness is an important factor and ease of performance and training is a major consideration. Most new technology for malaria diagnosis incorporates immunochromatographic capture procedures, with conjugated monoclonal antibodies providing the indicator of infection. Preferred targeted antigens are those which are abundant in all asexual and sexual stages of the parasite and are currently centered on detection of HRP-2 from Plasmodium falciparum and parasite-specific lactate dehydrogenase or Plasmodium aldolase from the parasite glycolytic pathway found in all species. Clinical studies allow effective comparisons between different formats, and the reality of nonmicroscopic diagnoses of malaria is considered.
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PMID:Rapid diagnostic tests for malaria parasites. 1236 79

Ferriprotoporphyrin IX (FPIX) is a potentially toxic product of hemoglobin digestion by intra-erythrocytic malaria parasites. It is detoxified by biomineralization or through degradation by glutathione. Both processes are inhibited by the antimalarial drug chloroquine, leading to the accumulation of FPIX in the membranes of the infected cell and their consequent permeabilization. It is shown here that treatment of Plasmodium falciparum-infected erythrocytes with chloroquine also leads to the binding of FPIX to a subset of parasite proteins. Parasite enzymes such as aldolase, pyrimidine nucleaside monophosphate kinase and pyrimidine 5'-nucleotidase were inhibited by FPIX in vitro, but only the activity of 6-phosphogluconate dehydrogenase was reduced significantly in cells after drug treatment. Additional proteins were extracted from parasite cytosol by their ability to bind FPIX. Sequencing of these proteins identified heat shock proteins 90 and 70, enolase, elongation factor 1-alpha, phoshoglycerate kinase, glyceraldehyde 3-phosphate dehydrogenase, L-lactate dehydrogenase and gametocytogenesis onset-specific protein. The possible involvement of these proteins in the antimalarial mode of action of chloroquine is discussed. It is concluded that drug-induced binding of FPIX to parasite glycolytic enzymes could underlie the demonstrable inhibition of glycolysis by chloroquine. The inhibition of 6-phosphogluconate dehydrogenase could explain the reduction of the activity of the hexose monophosphate shunt by the drug. Inhibition of both processes is deleterious to parasite survival. Binding of FPIX to other proteins is probably inconsequential to the rapid killing of the parasite by chloroquine.
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PMID:The treatment of Plasmodium falciparum-infected erythrocytes with chloroquine leads to accumulation of ferriprotoporphyrin IX bound to particular parasite proteins and to the inhibition of the parasite's 6-phosphogluconate dehydrogenase. 1266 48

Phylogenetic studies of the genus Plasmodium have been performed using sequences of the nuclear, mitochondrial and plastid genes. Here we have analyzed the adenylosuccinate lyase (ASL) gene, which encodes an enzyme involved in the salvage of host purines needed by malaria parasites for DNA synthesis. The ASL gene is present in several eukaryotic as well as prokaryotic organisms and does not have repeat regions, which facilitates the accuracy of the alignment. Furthermore, it has been shown that ASL is not subject to positive natural selection. We have sequenced the ASL gene of several different Plasmodium species infecting humans, rodents, monkeys and birds and used the obtained sequences along with the previously known P. falciparum ASL sequence, for structural and phylogenetic analysis of the genus Plasmodium. The genetic divergence of ASL is comparable with that observed in other nuclear genes such as cysteine proteinase, although ASL cannot be considered conserved when compared to aldolase or superoxide dismutase, which exhibit a slower rate of evolution. Nevertheless, a protein like ASL has a rate of evolution that provides enough information for elucidating evolutionary relationships. We modeled 3D structures of the ASL protein based on sequences used in the phylogenetic analysis and obtained a consistent structure for four different species despite the divergence observed. Such models would facilitate alignment in further studies with a greater number of plasmodial species or other Apicomplexa.
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PMID:Phylogenetic analysis of the genus Plasmodium based on the gene encoding adenylosuccinate lyase. 1279 8

Malaria remains a major disease of mankind, and resistance to existing therapeutics is rapidly emerging. Limited financial investment to develop new therapeutics requires the careful selection of well-defined targets from the causative parasite, Plasmodium falciparum. In these circumstances, protein crystallography can provide valuable structural detail to facilitate both the selection of suitable targets and the development of compounds to provide novel drug candidates. This review summarises the current involvement of crystallographic studies in anti-malarial drug development programmes. Protein crystallography is increasingly central to the exploitation of a number of potential Plasmodial targets. including the aspartic acid proteases (plasmepsins) and cysteine proteases (falcipains) involved in haem degradation within the parasite food vacuole. Lead compounds are being identified from collections previously synthesised against homologous human enzymes. Plasmodium have an unusual dependence on the glycolytic pathway relative to their human hosts, and this is reflected in subtle structural differences identified in the crystal structures of a number of parasite glycolytic enzymes including aldolase and lactate dehydrogenase. Other enzymes from a range of biosynthetic pathways have also been targeted in crystallographic studies. These include dihydrofolate reductase, the target of existing anti-folate therapeutics, and enoyl reductase from the fatty acid biosynthesis pathway which is already the target of effective bacteriocides. Crystal structures of these drug-enzyme complexes not only allow visualisation and improvement of inhibitor-protein contacts, but in the former case have also been used to probe the molecular basis of emerging anti-malarial drug resistance. Crystallography is similarly proving valuable as a tool to facilitate the development of inhibitors of purine salvage, isoprenoid synthesis and utilisation, and protein processing mechanisms.
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PMID:Structure-based approaches to the development of novel anti-malarials. 1501 47

The combined immuno-chromographic-malaria dipstick (ICT) for the rapid diagnosis of malaria detects both Plasmodium falciparum (P.f.)-specific, histidine-rich protein 2 (HRP-2) and a plasmodial aldolase expressed by all Plasmodium species pathogenic to humans. ICT was applied in 674 febrile returnees from malaria-endemic regions attending our Tropical Diseases Unit. Microscopy confirmed malaria in 69/674 cases, of whom 67/69 had returned from Africa or Madagascar, and 2/69 from the Caribbean. Monoparasitic P.f. infection occurred in 52/69, mixed infection was due to P.f.+ P. ovale (P.o.) in 3/69, and P.f.+P. malariae (P.m.) in 1/69 cases. Monoparasitic P. vivax (P.v.) infection occurred in 8/69 , P.o. in 3/69, and P.m. in 2/69 cases . Whereas a positive HRP-2 band on the test was a highly sensitive indicator for P.f. infection (52/52 patients; sensitivity 100%), this was not the case for a positive aldolase band (25/52 patients; sensitivity 48.1%). Sensitivity of aldolase band for non-falciparum plasmodia was even lower: aldolase was positive in only 3/8 (37.5%) of patients with vivax malaria, and in 0/5 cases with P.o.- or P.m. infection. Co-reaction of both bands occurred more frequently in patients with P.f. parasitaemia of > or =40,000/microl (20/25, 80.0%) as compared to patients with P.f. parasitaemia <40,000/microl (5/27, 18.5%; P<0.00005), and to patients with mixed infection (P.f.+ P.o., P.f.+ P.m.: 2/4, 50.0%; diff. n.s.). In our series, co-reaction of HRP-2 and aldolase indicated monoparasitic falciparum malaria with high P.f. parasitaemia, rather than mixed infection. Whereas the aldolase band is not a reliable qualitative marker for malaria, co-reaction of HRP-2 and aldolase band may have a potential for indicating high parasitaemia in falciparum malaria.
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PMID:Co-reactivity of plasmodial histidine-rich protein 2 and aldolase on a combined immuno-chromographic-malaria dipstick (ICT) as a potential semi-quantitative marker of high Plasmodium falciparum parasitaemia. 1554 88


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