Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

A strategy to overcome multidrug resistance in cancer cells involves treatment with a combination of the antineoplastic agent and a chemomodulator that inhibits the activity of the resistance-causing protein. The aim of our study was to investigate the effects of antimalarial drugs on human recombinant glutathione S-transferase (GSTs) activity in the context of searching for effective and clinically acceptable inhibitors of these enzymes. Human recombinant GSTs heterologously expressed in Escherichia coli were used for inhibition studies. GST A1-1 activity was inhibited by artemisinin with an IC(50) of 6 microM, whilst GST M1-1 was inhibited by quinidine and its diastereoisomer quinine with IC(50)s of 12 microM and 17 microM, respectively. GST M3-3 was inhibited by tetracycline only with an IC(50) of 47 microM. GST P1-1 was the most susceptible enzyme to inhibition by antimalarials with IC(50) values of 1, 2, 1, 4, and 13 microM for pyrimethamine, artemisinin, quinidine, quinine and tetracycline, respectively. The IC(50) values obtained for artemisinin, quinine, quinidine and tetracycline are below peak plasma concentrations obtained during therapy of malaria with these drugs. It seems likely, therefore, that GSTs may be inhibited in vivo at doses normally used in clinical practice. Using the substrate ethacrynic acid, a diuretic drug also used as a modulator to overcome drug resistance in tumour cells, GST P1-1 activity was inhibited by tetracycline, quinine, pyrimethamine and quinidine with IC(50) values of 18, 27, 45 and 70 microM, respectively. The ubiquitous expression of GSTs in different malignancies suggests that the addition of nontoxic reversing agents such as antimalarials could enhance the efficacy of a variety of alkylating agents.
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PMID:Inhibition of glutathione S-transferases by antimalarial drugs possible implications for circumventing anticancer drug resistance. 1180 1

Using bioinformatics analyses of the unfinished malaria genome sequence, we have identified a novel protein of Plasmodium falciparum that contains two epidermal growth factor (EGF)-like domains near the C-terminus of the protein. The sequence contains a single open reading frame of 1572bp with the potential to encode a protein of 524 residues containing hydrophobic regions at the extreme N- and C-termini which appear to represent signal peptide and glycosylphosphatidylinositol (GPI)-attachment sites, respectively. RT-PCR analysis has confirmed that the novel gene is transcribed in asexual stages of P. falciparum. Antibodies to the EGF-like domains of the novel protein are highly specific and do not cross-react with the EGF-like domains of MSP1, MSP4, MSP5 or MSP8 expressed as GST fusion proteins. Antisera to the C-terminal fragments react with two bands of 80 and 36kDa in P. falciparum parasite lysates whereas antisera to the most N-terminal fusion protein only recognises the 80kDa band, suggesting that the novel protein may undergo processing in a similar way to MSP1 and MSP8, but with fewer cleavage events. Immunoblot analysis of stage-specific parasite samples reveals that the protein is present in trophozoites, schizonts and in isolated merozoites. The protein partitions in the detergent-enriched phase after Triton X-114 fractionation and is localised to the surfaces of trophozoites, schizonts and free merozoites in an apical distribution. Based on the accepted nomenclature in the field we now designate this protein MSP10. We have shown that the MSP10 fusion proteins are in a conformation that can be recognised by human immune sera and that there is very limited sequence diversity in an approximately lkb region of MSP10, encompassing the two EGF-like domains. A sequence similar to MSP10 can be identified in the available P. yoelii genomic sequence, offering the possibility of ascertaining whether this novel protein can induce host protective responses in an in vivo model.
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PMID:Apical location of a novel EGF-like domain-containing protein of Plasmodium falciparum. 1261 36

BACKGROUND: Serological tests to detect antibodies specific to Plasmodium vivax could be a valuable tool for epidemiological studies, for screening blood donors in areas where the malaria is not endemic and for diagnosis of infected individuals. Because P. vivax cannot be easily obtained in vitro, ELISA assays using total or semi-purified antigens are rarely used. Based on this limitation, we tested whether recombinant proteins representing the 19 kDa C-terminal region of the merozoite surface protein-1 of P. vivax (MSP119) could be useful for serological detection of malaria infection. METHODS: Three purified recombinant proteins produced in Escherichia coli (GST-MSP119, His6-MSP119 and His6-MSP119-PADRE) and one in Pichia pastoris (yMSP119-PADRE) were compared for their ability to bind to IgG antibodies of individuals with patent P. vivax infection. The method was tested with 200 serum samples collected from individuals living in the north of Brazil in areas endemic for malaria, 53 serum samples from individuals exposed to Plasmodium falciparum infection and 177 serum samples from individuals never exposed to malaria. RESULTS: Overall, the sensitivity of the ELISA assessed with sera from naturally infected individuals was 95%. The proportion of serum samples that reacted with recombinant proteins GST-MSP119, His6-MSP119, His6-MSP119-PADRE and yMSP119-PADRE was 90%, 93.5%, 93.5% and 93.5%, respectively. The specificity values of the ELISA determined with sera from healthy individuals and from individuals with other infectious diseases were 98.3% (GST-MSP119), 97.7% (His6-MSP119 and His6-MSP119-PADRE) or 100% (yMSP119-PADRE). CONCLUSIONS: Our study demonstrated that for the Brazilian population, an ELISA using a recombinant protein of the MSP119 can be used as the basis for the development of a valuable serological assay for the detection of P. vivax malaria.
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PMID:Serological detection of Plasmodium vivax malaria using recombinant proteins corresponding to the 19-kDa C-terminal region of the merozoite surface protein-1. 1461 78

The insect GST (glutathione transferase) supergene family encodes a varied group of proteins belonging to at least six individual classes. Interest in insect GSTs has focused on their role in conferring insecticide resistance. Previously from the mosquito malaria vector Anopheles dirus, two genes encoding five Delta class GSTs have been characterized for structural as well as enzyme activities. We have obtained a new Delta class GST gene and isoenzyme from A. dirus, which we name adGSTD5-5. The adGSTD5-5 isoenzyme was identified and was only detectably expressed in A. dirus adult females. A putative promoter analysis suggests that this GST has an involvement in oogenesis. The enzyme displayed little activity for classical GST substrates, although it possessed the greatest activity for DDT [1,1,1-trichloro-2,2-bis-(p-chlorophenyl)ethane] observed for Delta GSTs. However, GST activity was inhibited or enhanced in the presence of various fatty acids, suggesting that the enzyme may be modulated by fatty acids. We obtained a crystal structure for adGSTD5-5 and compared it with other Delta GSTs, which showed that adGSTD5-5 possesses an elongated and more polar active-site topology.
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PMID:Identification, characterization and structure of a new Delta class glutathione transferase isoenzyme. 1571 64

Metabolic pathways play an important role in insecticide resistance, but the full spectra of the genes involved in resistance has not been established. We constructed a microarray containing unique fragments from 230 Anopheles gambiae genes putatively involved in insecticide metabolism [cytochrome P450s (P450s), GSTs, and carboxylesterases and redox genes, partners of the P450 oxidative metabolic complex, and various controls]. We used this detox chip to monitor the expression of the detoxifying genes in insecticide resistant and susceptible An. gambiae laboratory strains. Five genes were strongly up-regulated in the dichlorodiphenyltrichloroethane-resistant strain ZAN/U. These genes included the GST GSTE2, which has previously been implicated in dichlorodiphenyltrichloroethane resistance, two P450s, and two peroxidase genes. GSTE2 was also elevated in the pyrethroid-resistant RSP strain. In addition, the P450 CYP325A3, belonging to a class not previously associated with insecticide resistance, was expressed at statistically higher levels in this strain. The applications of this detox chip and its potential contribution to malaria vector insecticide resistance management programs are discussed.
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PMID:The Anopheles gambiae detoxification chip: a highly specific microarray to study metabolic-based insecticide resistance in malaria vectors. 1575 17

RNA polymerase II promoters in Plasmodium spp., like in most eukaryotes, have a bipartite structure. However, the identification of a functional TATA box located within the Plasmodium spp. core promoters has been difficult, mainly because of its high A+T content. Only few putative trans-acting elements have been identified in the malaria parasite genome such as a gene orthologous to the TATA box binding protein (PfTBP). In this study, we demonstrate that PfTBP is part of the DNA-protein complexes formed in the kahrp and gbp-130 gene promoter regions. Supershift and footprinting assays performed with a GST-PfTBP fusion protein showed that PfTBP associates with a consensus TATA box sequence located 81 base pairs upstream of the transcription start site in the kahrp promoter region and with a TATA box-like (TGTAA) sequence at position -186 of the gbp-130 gene promoter region. Chromatin immunoprecipitation assays confirmed that native PfTBP is able to associate in vivo with both TATA box elements. This is the first study that reports the identification of cis-acting sequences (TATAA and TGTAA) and their corresponding trans-acting (PfTBP) factor in P. falciparum.
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PMID:Recombinant and native Plasmodium falciparum TATA-binding-protein binds to a specific TATA box element in promoter regions. 1576 Jun 58

Structural investigations of a GST (glutathione transferase), adGSTD4-4, from the malaria vector Anopheles dirus show a novel lock-and-key 'Clasp' motif in the dimer interface of the Delta class enzyme. This motif also appears to be highly conserved across several insect GST classes, but differs from a previously reported mammalian lock-and-key motif. The aromatic 'key' residue not only inserts into a hydrophobic pocket, the 'lock', of the neighbouring subunit, but also acts as part of the 'lock' for the other subunit 'key'. The 'key' residues from both subunits show aromatic ring stacking with each other in a pi-pi interaction, generating a 'Clasp' in the middle of the subunit interface. Enzyme catalytic and structural characterizations revealed that single amino acid replacements in this 'Clasp' motif impacted on catalytic efficiencies, substrate selectivity and stability. Substitutions to the 'key' residue create strong positive co-operativity for glutathione binding, with a Hill coefficient approaching 2. The lock-and-key motif in general and especially the 'Clasp' motif with the pi-pi interaction appear to play a pivotal role in subunit communication between active sites, as well as in stabilizing the quaternary structure. Evidence of allosteric effects suggests an important role for this particular intersubunit architecture in regulating catalytic activity through conformational transitions of subunits. The observation of co-operativity in the mutants also implies that glutathione ligand binding and dimerization are linked. Quaternary structural changes of all mutants suggest that subunit assembly or dimerization basically manipulates subunit communication.
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PMID:An intersubunit lock-and-key 'clasp' motif in the dimer interface of Delta class glutathione transferase. 1622 58

Malaria represents an emerging disease because of increasing parasite resistance against available drugs and because of increasing geographical distribution of the causative agent, Plasmodium falciparum. The complete genome of Plasmodium was sequenced recently, revealing that the parasite harbors only one glutathione S-transferase (PfGST). This observation was of particular interest: First, certain antimalarial drugs such as chloroquine and methylene blue presumably influence the glutathione metabolism in which PfGST is involved. Second, PfGST might play a significant role in drug resistance. PfGST was studied in parasite extracts and as recombinant protein, and its x-ray structure has been solved. The available data indicate that the homodimeric PfGST cannot be assigned to any of the previously known GST classes. PfGST exhibits significant structural differences to human GSTs, particularly at the so-called hydrophobic binding pocket (H-site) where the second substrate binds. Inhibition of PfGST is expected to act at different vulnerable metabolic sites of the parasite in parallel; it is likely to disturb GSH-dependent detoxification processes, to increase the levels of cytotoxic peroxides, and possibly to increase the concentration of toxic hemin. In this chapter, we summarize the current knowledge on PfGST, including aspects of structure, function, and future drug development.
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PMID:Glutathione S-transferase from malarial parasites: structural and functional aspects. 1639 90

The rapidly developing resistance to drugs used for prophylaxis and treatment of malaria makes the identification of novel drug targets necessary. Glutathione-S-transferase (GST, E.C. 2.5.1.18), an important enzyme of the glutathione (GSH) cycle, is considered to be an essential detoxification enzyme in malarial parasites. Selective inhibition of this enzyme from malarial parasites by various classes of inhibitors may be viewed as a potential chemotherapeutic strategy to combat malaria. Purified GST from Plasmodium yoelii was inhibited by compounds like protoporphyrin IX, cibacron blue, as well as by the GSH depletor menadione. Cytosolic GST was inhibited to varying degrees by each compound. A characteristic inhibitor constant (Ki) was obtained for each inhibitor. The possible consequences of selective inhibition of parasitic GST to that of the host are discussed in relation to the chemotherapy of malaria.
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PMID:Inhibition of glutathione-S-transferase from Plasmodium yoelii by protoporphyrin IX, cibacron blue and menadione: implications and therapeutic benefits. 1818 Sep 58

The bisquinoline drug dequalinium (DQ) has demonstrated remarkable activity against some infection diseases, including malaria. Oxidative stress represents a biochemical target for potential antimalarials. In this work, we have tested the ability of this compound to modify the oxidative status in Plasmodium berghei-infected erythrocytes. After hemolysis, activities of superoxide dismutase (SOD), catalase (CAT), glutathione cycle, and dehydrogenase enzymes were investigated. The activity of glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (6PGLD) in infected cells were diminished by this drug compared to controls (300% and 80% approximately, respectively), while glutathione peroxidase (GPx), glutathione transferase (GST), and glutathione levels were also lowered. As a compensatory response, we could appreciate an increase of SOD activity (20% approximately) in infected cells treated with DQ; however, catalase was not affected by the compound. Lipid peroxidation was also decreased by this drug, protecting the cells from the hemolysis caused by the infection. In conclusion, oxidative stress represents a biochemical event which is modulated by DQ, interfering with the antioxidant regular activities in P. berghei infection.
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PMID:Effect of dequalinium on the oxidative stress in Plasmodium berghei-infected erythrocytes. 1920 39


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