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 isolated and characterised the gene encoding the glycolytic enzyme enolase (2-phospho-D-glycerate hydrolase) from the human malaria parasite Plasmodium falciparum. This was achieved using a combination of cDNA sequencing and inverse-PCR techniques. The gene maps to chromosome 10 of the parasite. We have also mapped two further glycolytic enzyme genes, glyceraldehyde-3-phosphate dehydrogenase and triose-phosphate isomerase, to chromosome 14. The enolase gene encodes a protein of 446 amino acids (48.7 kDa), and all amino acid residues implicated in substrate/cofactor binding and catalysis are conserved in the malarial enolase molecule. The predicted protein sequence displays approximately 60-70% identity to enolase molecules of other eukaryotes, the closest relationship with its homologues seen amongst the seven fully described glycolytic pathway enzymes of P. falciparum. Of particular significance in this well conserved molecule is a characteristic 5-amino-acid insertion sequence that is identical in position and virtually identical in primary structure to that which is otherwise found uniquely in plant enolase proteins. This pentapeptide, together with other features of the plasmodial sequence, points to a common ancestry with photosynthetic organisms at the level of a protein-encoding nuclear gene, thus extending earlier analyses of nuclear small-subunit ribosomal RNA genes, and of an extrachromosomal circular 35-kb DNA element found in P. falciparum, which have also indicated such a relationship.
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PMID:Molecular characterisation of the enolase gene from the human malaria parasite Plasmodium falciparum. Evidence for ancestry within a photosynthetic lineage. 812 9

In 1998, we reported that Plasmodium falciparum (Pf) enolase was useful as the capture antigen for the immunodiagnosis of malaria. In the present study, we modified a fluorescence-ELISA for the diagnosis of malaria by applying yeast enolase or rabbit muscle enolase as antigen. Sera from 67 falciparum malaria patients and 15 vivax malaria patients were tested by the method. Positivity rates of the former was 82.1% against yeast enolase antigen and 90.5% against rabbit muscle enolase antigen, and those of latter was 93.3% against both enolase antigens. Mean antibody level (RFU values) of sera from falciparum and vivax malaria patients were significantly higher than those from healthy individuals. There was a significant correlation between anti-yeast and anti-rabbit muscle enolase antibody level (RFU values) in the group of falciparum subjects (r = 0.401, p<0.001). A significant correlation between RFU values against yeast enolase antigen and indirect fluorescent antibody titers against crude Pf antigen in the same subjects was recognized (r = 0.518, p<0.001). Longitudinal changes of RFU values against yeast enolase for the following 4 weeks after admission were also examined for sera from falciparum malaria patients. Patients with more severe malaria showed increasing RFU values as the clinical courses progressed. However, in the mild cases, each RFU value stayed unchanged during the course. We concluded that yeast and rabbit muscle enolase could be appropriately used as antigen for the immunodiagnosis of malaria.
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PMID:Application of yeast enolase as antigen for immunodiagnosis of malaria. 1141 65

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

Patterns of expression of the 2-Cys and 1-Cys peroxiredoxin (Prx) proteins of the rodent malaria parasite Plasmodium yoelii during its life cycle were observed by immunofluorescent antibody staining and confocal laser scanning microscopy. 2-Cys Prx was expressed in the parasite cytoplasm throughout the life cycle, and the thioredoxin (Trx)-peroxidase activity of 2-Cys Prx revealed with the recombinant protein suggested that the Prx is constitutively expressed and, thus, likely plays a housekeeping role in the parasite's intracellular redox control. In contrast, 1-Cys Prx showed stage-specific expression in blood-stage parasites. The limited expression of 1-Cys Prx in the trophozoite cytoplasm suggests that 1-Cys Prx may be involved in haemoglobin metabolism by the parasite, which generates a prooxidative haem iron and increases intracellular oxidative stress. The antioxidant activity of 1-Cys Prx was tested for its ability to protect yeast enolase against inactivation of the mixed-function oxidation system. Differential expression of the two Prx proteins during the erythrocytic and insect stages suggests the importance of these proteins in protecting parasites against oxidative stress, which is generated by the parasite's metabolism and also from the environment.
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PMID:Expression profiles of peroxiredoxin proteins of the rodent malaria parasite Plasmodium yoelii. 1457 8

In the past, several unsuccessful attempts have been made to dissociate homodimeric enolases into their active monomeric forms. The main objective of these studies had been to understand whether intersubunit interactions are essential for the catalytic and structural stability of enolases. Further motivation to investigate the properties of monomeric enolase has arisen from several recent reports on the involvement of enolase in diverse nonglycolytic (moonlighting) functions, where it may occur in monomeric form. Here, we report successful dissociation of dimeric enolases from Plasmodium falciparum, yeast and rabbit muscle into active and isolatable monomers. Dimeric enolases could be dissociated into monomers by high concentrations ( approximately 250 mm) of imidazole and/or hydrogen ions. Two forms were separated using Superdex-75 gel filtration chromatography. A detailed comparison of the kinetic and structural properties of monomeric and dimeric forms of recombinant P. falciparum enolase showed differences in specific activity, salt-induced inhibition and inactivation, thermal stability, etc. Furthermore, we found that enolases from the three species differ in their dimer dissociation profiles. Specifically, on challenge with imidazole, Mg(II) protected the enolases of yeast and rabbit muscle but not of P. falciparum from dissociation. The observed differential stability of the P. falciparum enolase dimer interface with respect to mammalian enolases could be exploited to selectively dissociate the dimeric parasite enzyme into its catalytically inefficient, thermally unstable monomeric form. Thus enolase could be a novel therapeutic target for malaria.
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PMID:Differential susceptibility of Plasmodium falciparum versus yeast and mammalian enolases to dissociation into active monomers. 1737 7

The enolase protein of the human malarial parasite Plasmodium falciparum has recently been characterized. Apart from its glycolytic function, enolase has also been shown to possess antigenic properties and to be present on the cell wall of certain invasive organisms, such as Candida albicans. In order to assess whether enolase of P. falciparum is also antigenic, sera from residents of a region of Eastern India where malaria is endemic were tested against the recombinant P. falciparum enolase (r-Pfen) protein. About 96% of immune adult sera samples reacted with r-Pfen over and above the seronegative controls. Rabbit anti-r-Pfen antibodies inhibited the growth of in vitro cultures of P. falciparum. Mice immunized with r-Pfen showed protection against a challenge with the 17XL lethal strain of the mouse malarial parasite Plasmodium yoelii. The antibodies raised against r-Pfen were specific for Plasmodium and did not react to the host tissues. Immunofluorescence as well as electron microscopic examinations revealed localization of the enolase protein on the merozoite cell surface. These observations establish malaria enolase to be a potential protective antigen.
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PMID:Protective properties and surface localization of Plasmodium falciparum enolase. 1778 75

Plasmodium falciparum enolase (Pfen) is of photosynthetic lineage as evident from the presence of a plant like pentapeptide insert (104)EWGWS(108) in a highly conserved surface loop of the protein. Such a unique region which is absent in human enolase, constitutes an excellent target for inhibitor design, provided its essentiality for function could be demonstrated. A deletion Pfen lacking this insert was made and the effect of this deletion on activity and structure was assessed. Deletion of insert resulted in approximately 100-fold decrease in k(cat)/K(m) and caused dissociation of dimeric form into monomers. Since the parasite enolase localizes on the merozoite surface and confers partial protection against malaria [I. Pal-Bhowmick, M. Mehta, I. Coppens, S. Sharma, G.K. Jarori, Infect. Immun. 75(11) (2007) 5500-5008], the possibility of the insert being involved in protective response was examined. Serum from Pfen vaccinated mouse which showed prolonged survival to parasite challenge had negligible reactivity against deletion protein as compared to wild type enolase. These results indicate that the insert sequence is required for the full enolase activity and may constitute the protective antigenic epitope in parasite enolase.
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PMID:Effect of deletion of a plant like pentapeptide insert on kinetic, structural and immunological properties of enolase from Plasmodium falciparum. 1926 21

Enolase is the eighth enzyme in the glycolytic pathway, a reaction that generates ATP from phosphoenol pyruvate in cytosolic compartments. Enolase is essential, especially for organisms devoid of the Krebs cycle that depend solely on glycolysis for energy. Interestingly, enolase appears to serve a separate function in some organisms, in that it is also exported to the cell surface via a poorly understood mechanism. In these organisms, surface enolase assists in the invasion of their host cells by binding plasminogen, an abundant plasma protease precursor. Binding is mediated by the interaction between a lysine motif of enolase with Kringle domains of plasminogen. The bound plasminogen is then cleaved by specific proteases to generate active plasmin. Plasmin is a potent serine protease that is thought to function in the degradation of the extracellular matrix surrounding the targeted host cell, thereby facilitating pathogen invasion. Recent work revealed that the malaria parasite Plasmodium also expresses surface enolase, and that this feature may be essential for completion of its life cycle. The therapeutic potential of targeting surface enolases of pathogens is discussed.
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PMID:Surface-expressed enolases of Plasmodium and other pathogens. 2188 61

Ookinete invasion of the mosquito midgut is an essential step for the development of the malaria parasite in the mosquito. Invasion involves recognition between a presumed mosquito midgut receptor and an ookinete ligand. Here, we show that enolase lines the ookinete surface. An antienolase antibody inhibits oocyst development of both Plasmodium berghei and Plasmodium falciparum, suggesting that enolase may act as an invasion ligand. Importantly, we demonstrate that surface enolase captures plasminogen from the mammalian blood meal via its lysine motif (DKSLVK) and that this interaction is essential for midgut invasion, because plasminogen depletion leads to a strong inhibition of oocyst formation. Although addition of recombinant WT plasminogen to depleted serum rescues oocyst formation, recombinant inactive plasminogen does not, thus emphasizing the importance of plasmin proteolytic activity for ookinete invasion. The results support the hypothesis that enolase on the surface of Plasmodium ookinetes plays a dual role in midgut invasion: by acting as a ligand that interacts with the midgut epithelium and, further, by capturing plasminogen, whose conversion to active plasmin promotes the invasion process.
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PMID:Plasmodium ookinetes coopt mammalian plasminogen to invade the mosquito midgut. 2194 3

The most vulnerable stages of Plasmodium development occur in the lumen of the mosquito midgut, a compartment shared with symbiotic bacteria. Here, we describe a strategy that uses symbiotic bacteria to deliver antimalaria effector molecules to the midgut lumen, thus rendering host mosquitoes refractory to malaria infection. The Escherichia coli hemolysin A secretion system was used to promote the secretion of a variety of anti-Plasmodium effector proteins by Pantoea agglomerans, a common mosquito symbiotic bacterium. These engineered P. agglomerans strains inhibited development of the human malaria parasite Plasmodium falciparum and rodent malaria parasite Plasmodium berghei by up to 98%. Significantly, the proportion of mosquitoes carrying parasites (prevalence) decreased by up to 84% for two of the effector molecules, scorpine, a potent antiplasmodial peptide and (EPIP)(4), four copies of Plasmodium enolase-plasminogen interaction peptide that prevents plasminogen binding to the ookinete surface. We demonstrate the use of an engineered symbiotic bacterium to interfere with the development of P. falciparum in the mosquito. These findings provide the foundation for the use of genetically modified symbiotic bacteria as a powerful tool to combat malaria.
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PMID:Fighting malaria with engineered symbiotic bacteria from vector mosquitoes. 2286 63


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