Spelling suggestions: "subject:"plasmodium parasites"" "subject:"lasmodium parasites""
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Molecular modeling elucidates parasite-specific features of polyamine pathway enzymes of Plasmodium falciparusWells, Gordon Andreas 11 November 2010 (has links)
Malaria remains a debilitating disease, especially in developing countries of the tropics and sub-tropics. Increasing drug resistance and the rising cost of drug development calls for methods that can cost-effectively identify new drugs. The proteins of the malaria causing Plasmodium parasites often exhibit unique features compared to their mammalian counterparts. Such features invite discovery of parasite-specific drugs. In this study computational methods were applied to understand unique structural features of enzymes from the Plasmodium polyamine biosynthesis pathways. Molecular modeling of P. falciparum arginase was used to explore the structural metal dependency between enzyme activity and trimer formation. This dependency is not observed in the mammalian host. A novel inter-monomer salt-bridge was discovered between Glu 295 and Arg 404 that helps mediate the structural metal dependency. Removal of the active site metal atoms promoted breaking of the Glu 295á::Arg 404b interaction during simulation. The involvement of this salt-bridge was further confirmed by site-directed mutagenesis of the recombinantly expressed enzyme and subsequent simulation of the mutants in silico. Mutations designed to break the salt-bridge resulted in decreased enzyme activity and oligomerisation. Furthermore, simulation of the mutants indicated potential loss of metal co-ordination within the active site. The interface around Glu 295á::Arg 404b could thus serve as a novel therapeutic target. In Plasmodium the usually separate activities S-adenosylmethionine decarboxylase and ornithine decarboxylase occur in a single bifunctional enzyme. Previous studies have established the importance of complex formation and protein-protein interactions for correct enzyme functioning. Disturbing these interactions within the complex may therefore have inhibitory potential. In the second aspect of this study the potential quarternary structure of AdoMetDC/ODC was studied by homology modeling of the domains followed by protein-protein docking. The results from five Plasmodium species suggest that one face of each domain is favoured for complex formation. The predicted faces concur with existing experimental results, suggesting the direct involvement of Plasmodium-specific inserts in maintaining complex formation. Further fine-grained analysis revealed potentially conserved residue pairs between AdoMetDC/ODC that can be targeted during experimental follow-up. In both aspects of this study computational methods yielded useful insights into the parasite-specific features of polyamine biosynthesis enzymes from Plasmodium. Exploitation of these features may lead to novel parasite-specific drugs. Furthermore, this study highlights the importance of simulation and computational methods in the current and future practice of Science. / Thesis (PhD)--University of Pretoria, 2010. / Biochemistry / unrestricted
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Structural Studies By X-ray Diffraction On Two Key Enzymes Of Plasmodium falciparum : Triosephosphate Isomerase And Adenylosuccinate SynthetaseEaazhisai, K 07 1900 (has links) (PDF)
No description available.
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Integrating protein annotations for the in silico prioritization of putative drug target proteins in malariaMpangase, Phelelani Thokozani 15 May 2013 (has links)
Current anti-malarial methods have been effective in reducing the number of malarial cases. However, these methods do not completely block the transmission of the parasite. Research has shown that repeated use of the current anti-malarial drugs, which include artemisinin-based drug combinations, might be toxic to humans. There have also been reports of an emergence of artemisinin-resistant parasites. Finding anti-malarial drugs through the drug discovery process takes a long time and failure results in a great financial loss. The failure of drug discovery projects can be partly attributed to the improper selection of drug targets. There is thus a need for an eff ective way of identifying and validating new potential malaria drug targets for entry into the drug discovery process. The availability of the genome sequences for the Plasmodium parasite, human host and the Anopheles mosquito vector has facilitated post-genomic studies on malaria. Proper utilizationof this data, in combination with computational biology and bioinformatics techniques, could aid in the in silico prioritization of drug targets. This study was aimed at extensively annotating the protein sequences from the Plasmodium parasites, H. sapiens and A. gambiae with data from di fferent online databases in order to create a resource for the prioritization of drug targets in malaria. Essentiality, assay feasibility, resistance, toxicity, structural information and druggability were the main target selection criteria which were used to collect data for protein annotations. The data was used to populate the Discovery resource (http://malport. bi.up.ac.za/) for the in silico prioritization of potential drug targets. A new version of the Discovery system, Discovery 2.0 (http://discovery.bi.up.ac.za/), has been developed using Java. The system contains new and automatically updated data as well as improved functionalities. The new data in Discovery 2.0 includes UniProt accessions, gene ontology annotations from the UniProt-GOA project, pathways from Reactome and Malaria Parasite Metabolic Pathways databases, protein-protein interactions data from. IntAct as well as druggability data from the DrugEBIlity resource hosted by ChEMBL. Users can access the data by searching with a protein identi er, UniProt accession, protein name or through the advanced search which lets users filter protein sequences based on different protein properties. The results are organized in a tabbed environment, with each tab displaying different protein annotation data. A sample investigation using a previously proposed malarial target, S-adenosyl-Lhomocysteine hydrolase, was carried out to demonstrate the diff erent categories of data available in Discovery 2.0 as well as to test if the available data is su fficient for assessment and prioritization of drug targets. The study showed that using the annotation data in Discovery 2.0, a protein can be assessed, in a species comparative manner, on the potential of being a drug target based on the selection criteria mentioned here. However, supporting data from literature is also needed to further validate the findings. / Dissertation (MSc)--University of Pretoria, 2012. / Biochemistry / unrestricted
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