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)

Hsp90 is important for normal growth and development in eukaryotes. Together with Hsp70 and other accessory proteins, Hsp90 not only helps newly synthesized proteins to fold but also regulates activities of transcription factors and protein kinases. Although the gene coding for heat shock protein 90 from Plasmodium falciparum (PfHsp90) has been characterized previously, there is very little known regarding its function in the parasite. We have analyzed PfHsp90 complexes and addressed its role in parasite life cycle using Geldanamycin (GA), a drug known to interfere with Hsp90 function. Sedimentation analysis and size exclusion chromatography showed PfHsp90 to be in 11 s(20,(w)) complexes of approximately 300 kDa in size. Similar to the hetero-oligomeric complexes of Hsp90 in mammals, PfHsp70 was found to be present in PfHsp90 complexes. Homology modeling revealed a putative GA-binding pocket at the amino terminus of PfHsp90. The addition of GA inhibited parasite growth with LD(50) of 0.2 microm. GA inhibited parasite growth by arresting transition from Ring to trophozoite. Transition from trophozoite to schizonts and reinvasion of new erythrocytes were less significantly affected. While inducing the synthesis of PfHsp70 and PfHsp90, GA did not significantly alter the pattern of newly synthesized proteins. Pre-exposure to heat shock attenuated GA-mediated growth inhibition, suggesting the involvement of heat shock proteins. Specificity of GA action on PfHsp90 was evident from selective inhibition of PfHsp90 phosphorylation in GA-treated cultures. In addition to suggesting an essential role for PfHsp90 during parasite growth, our results highlight PfHsp90 as a potential drug target to control malaria.
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PMID:Heat shock protein 90 function is essential for Plasmodium falciparum growth in human erythrocytes. 1258 93

The human malarial parasite Plasmodium falciparum (Pf) is exposed to wide temperature fluctuations during its life cycle, ranging from 25 degrees C in the mosquito vector and 37 degrees C in humans to 41 degrees C during febrile episodes in the patient. The repeated occurrence of fever at regular intervals is a characteristic of human malaria. We have examined the influence of repeated exposure to elevated temperatures encountered during fever on the intraerythrocytic development of the parasite. Using flow cytometry, we show that repeated exposure to temperatures mimicking febrile episodes promotes parasite development in human erythrocytes. Heat shock-mediated cytoprotection and growth promotion is dependent on the heat shock protein 90 (PfHsp90) multi-chaperone complex. Inhibition of PfHsp90 function using geldanamycin attenuates temperature-dependent progression from the ring to the trophozoite stage. Geldanamycin inhibits parasite development by disrupting the PfHsp90 complex consisting of PfHsp70, PfPP5, and tubulin, among other proteins. While explaining the contribution of febrile episodes to the pathogenesis of malaria, our results implicate temperature as an important environmental cue used by the parasite to coordinate its development in humans.
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PMID:Recurrent fever promotes Plasmodium falciparum development in human erythrocytes. 1533 15

Geldanamycin (GA), an antibiotic of the ansamycin family and an inhibitor of heat shock protein 90 (Hsp90), was previously shown to inhibit the malarial parasite, Plasmodium falciparum. Here we report that cyclosporin A (CsA), an inhibitor of parasitic cyclophilin (Cyp) and protein phosphatase 2B (calcineurin, CN), acted synergistically with GA to inhibit the erythrocytic growth of the parasite. Parasitic calcineurin associated with Hsp90 in vivo, and GA inhibited the association, but CsA had no effect. In a number of CsA-resistant (CsA(R)) P. falciparum clones mutations were detected in functionally significant amino acid residues of the catalytic and regulatory subunits of calcineurin (CnA and CnB, respectively) and in two out of three parasitic cyclophilins, namely Cyp19A and Cyp19B. No mutation was detected in the third cyclophilin, Cyp24. Further analysis of the mutant CnA revealed that its protein phosphatase activity was highly CsA-resistant in vitro. Similarly, one of the mutant Cyp19A proteins was purified and found to be unable to inhibit parasitic CN in the presence of CsA. Together, these results underscore the importance of the proper assembly and function of CN in plasmodial biology and suggest that the inhibition of CN can be a potential mechanism behind the CsA-sensitivity of the malaria parasite.
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PMID:Plasmodium falciparum calcineurin and its association with heat shock protein 90: mechanisms for the antimalarial activity of cyclosporin A and synergism with geldanamycin. 1581 24

Mitochondrial heat shock protein 60 (Hsp60) is a nuclear encoded gene product that gets post-translationally translocated into the mitochondria. Using multiple approaches such as immunofluorescence experiments, isoelectric point analysis with two-dimensional gel electrophoresis, and mass spectrometric identification of the signal peptide, we show that Hsp60 from Plasmodium falciparum (PfHsp60) accumulates in the parasite cytoplasm during the ring, trophozoite, and schizont stages of parasite development before being imported into the parasite mitochondria. Using co-immunoprecipitation experiments with antibodies specific to cytoplasmic PfHsp90, PfHsp70-1, and PfHsp60, we show association of precursor PfHsp60 with cytoplasmic chaperone machinery. Metabolic labeling involving pulse and chase indicates translocation of the precursor pool into the parasite mitochondrion during chase. Analysis of results obtained with Geldanamycin treatment confirmed precursor PfHsp60 to be one of the clients for PfHsp90. Cytosolic chaperones bind precursor PfHsp60 prior to its import into the mitochondrion of the parasite. Our data suggests an inefficient co-ordination in the synthesis and translocation of mitochondrial PfHsp60 during asexual growth of malaria parasite in human erythrocytes.
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PMID:Characterization of Precursor PfHsp60 in Plasmodium falciparum Cytosol during Its Asexual Development in Human Erythrocytes. 2631 63