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Artykuły w czasopismach na temat "Plasmodial Enzyme"
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Musyoka, Thommas, i Özlem Tastan Bishop. "South African Abietane Diterpenoids and Their Analogs as Potential Antimalarials: Novel Insights from Hybrid Computational Approaches". Molecules 24, nr 22 (7.11.2019): 4036. http://dx.doi.org/10.3390/molecules24224036.
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The hemoglobin degradation process in Plasmodium parasites is vital for nutrient acquisition required for their growth and proliferation. In P. falciparum, falcipains (FP-2 and FP-3) are the major hemoglobinases, and remain attractive antimalarial drug targets. Other Plasmodium species also possess highly homologous proteins to FP-2 and FP-3. Although several inhibitors have been designed against these proteins, none has been commercialized due to associated toxicity on human cathepsins (Cat-K, Cat-L and Cat-S). Despite the two enzyme groups sharing a common structural fold and catalytic mechanism, distinct active site variations have been identified, and can be exploited for drug development. Here, we utilize in silico approaches to screen 628 compounds from the South African natural sources to identify potential hits that can selectively inhibit the plasmodial proteases. Using docking studies, seven abietane diterpenoids, binding strongly to the plasmodial proteases, and three additional analogs from PubChem were identified. Important residues involved in ligand stabilization were identified for all potential hits through binding pose analysis and their energetic contribution determined by binding free energy calculations. The identified compounds present important scaffolds that could be further developed as plasmodial protease inhibitors. Previous laboratory assays showed the effect of the seven diterpenoids as antimalarials. Here, for the first time, we demonstrate that their possible mechanism of action could be by interacting with falcipains and their plasmodial homologs. Dynamic residue network (DRN) analysis on the plasmodial proteases identified functionally important residues, including a region with high betweenness centrality, which had previously been proposed as a potential allosteric site in FP-2.
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Berger, Louise C., Judith Wilson, Pamela Wood i Bradley J. Berger. "Methionine Regeneration and Aspartate Aminotransferase in Parasitic Protozoa". Journal of Bacteriology 183, nr 15 (1.08.2001): 4421–34. http://dx.doi.org/10.1128/jb.183.15.4421-4434.2001.
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ABSTRACT Aspartate aminotransferases have been cloned and expressed fromCrithidia fasciculata, Trypanosoma brucei brucei, Giardia intestinalis, andPlasmodium falciparum and have been found to play a role in the final step of methionine regeneration from methylthioadenosine. All five enzymes contain sequence motifs consistent with membership in the Ia subfamily of aminotransferases; the crithidial and giardial enzymes and one trypanosomal enzyme were identified as cytoplasmic aspartate aminotransferases, and the second trypanosomal enzyme was identified as a mitochondrial aspartate aminotransferase. The plasmodial enzyme contained unique sequence substitutions and appears to be highly divergent from the existing members of the Ia subfamily. In addition, the P. falciparum enzyme is the first aminotransferase found to lack the invariant residue G197 (P. K. Mehta, T. I. Hale, and P. Christen, Eur. J. Biochem. 214:549–561, 1993), a feature shared by sequences discovered in P. vivax and P. berghei. All five enzymes were able to catalyze aspartate-ketoglutarate, tyrosine-ketoglutarate, and amino acid-ketomethiobutyrate aminotransfer reactions. In the latter, glutamate, phenylalanine, tyrosine, tryptophan, and histidine were all found to be effective amino donors. The crithidial and trypanosomal cytosolic aminotransferases were also able to catalyze alanine-ketoglutarate and glutamine-ketoglutarate aminotransfer reactions and, in common with the giardial aminotransferase, were able to catalyze the leucine-ketomethiobutyrate aminotransfer reaction. In all cases, the kinetic constants were broadly similar, with the exception of that of the plasmodial enzyme, which catalyzed the transamination of ketomethiobutyrate significantly more slowly than aspartate-ketoglutarate aminotransfer. This result obtained with the recombinant P. falciparum aminotransferase parallels the results seen for total ketomethiobutyrate transamination in malarial homogenates; activity in the latter was much lower than that in homogenates from other organisms. Total ketomethiobutyrate transamination in Trichomonas vaginalis and G. intestinalis homogenates was extensive and involved lysine-ketomethiobutyrate enzyme activity in addition to the aspartate aminotransferase activity. The methionine production in these two species could be inhibited by the amino-oxy compounds canaline and carboxymethoxylamine. Canaline was also found to be an uncompetitive inhibitor of the plasmodial aspartate aminotransferase, with aKi of 27 μM.
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Eschbach, Marie-Luise, Ingrid B. Müller, Tim-Wolf Gilberger, Rolf D. Walter i Carsten Wrenger. "The human malaria parasite Plasmodium falciparum expresses an atypical N-terminally extended pyrophosphokinase with specificity for thiamine". Biological Chemistry 387, nr 12 (1.12.2006): 1583–91. http://dx.doi.org/10.1515/bc.2006.197.
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Abstract Vitamin B1 is an essential cofactor for key enzymes such as 2-oxoglutarate dehydrogenase and pyruvate dehydrogenase. Plants, bacteria and fungi, as well as Plasmodium falciparum, are capable of synthesising vitamin B1 de novo, whereas mammals have to take up this cofactor from their diet. Thiamine, a B1 vitamer, has to be pyrophosphorylated by thiamine pyrophosphokinase (TPK) to the active form. The human malaria parasite P. falciparum expresses an N-terminally extended pyrophosphokinase throughout the entire erythrocytic life cycle, which was analysed by Northern and Western blotting. The recombinant enzyme shows a specific activity of 27 nmol min-1 mg-1 protein and specificity for thiamine with a K m value of 73 μM, while thiamine monophosphate is not accepted. Mutational analysis of the N-terminal extension of the plasmodial TPK showed that it influences thiamine binding as well as metal dependence, which suggests N-terminal participation in the conformation of the active site. Protein sequences of various plasmodial TPKs were analysed for their phylogeny, which classified the Plasmodium TPKs to a group distinct from the mammalian TPKs. To verify the location of the parasite TPK within the cell, immunofluorescence analyses were performed. Co-staining of PfTPK with a GFP marker visualised its cytosolic localisation.
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Lande, Duc Hoàng, Abed Nasereddin, Arne Alder, Tim W. Gilberger, Ron Dzikowski, Johann Grünefeld i Conrad Kunick. "Synthesis and Antiplasmodial Activity of Bisindolylcyclobutenediones". Molecules 26, nr 16 (5.08.2021): 4739. http://dx.doi.org/10.3390/molecules26164739.
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Malaria is one of the most dangerous infectious diseases. Because the causative Plasmodium parasites have developed resistances against virtually all established antimalarial drugs, novel antiplasmodial agents are required. In order to target plasmodial kinases, novel N-unsubstituted bisindolylcyclobutenediones were designed as analogs to the kinase inhibitory bisindolylmaleimides. Molecular docking experiments produced favorable poses of the unsubstituted bisindolylcyclobutenedione in the ATP binding pocket of various plasmodial protein kinases. The synthesis of the title compounds was accomplished by sequential Friedel-Crafts acylation procedures. In vitro screening of the new compounds against transgenic NF54-luc P. falciparum parasites revealed a set of derivatives with submicromolar activity, of which some displayed a reasonable selectivity profile against a human cell line. Although the molecular docking studies suggested the plasmodial protein kinase PfGSK-3 as the putative biological target, the title compounds failed to inhibit the isolated enzyme in vitro. As selective submicromolar antiplasmodial agents, the N-unsubstituted bisindolylcyclobutenediones are promising starting structures in the search for antimalarial drugs, albeit for a rational development, the biological target addressed by these compounds has yet to be identified.
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Dieckmann, A., i A. Jung. "The mechanism of pyrimethamine resistance in Plasmodium falciparum". Parasitology 93, nr 2 (październik 1986): 275–78. http://dx.doi.org/10.1017/s0031182000051441.
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SUMMARYThe uptake of radioactive pyrimethamine by a sensitive and a resistant strain of Plasmodium falciparum, the metabolic fate of pyrimethamine inside these parasites and the kinetic properties of dihydrofolate reductase (DHFR) from both strains have been studied. Uptake of the drug was identical in both strains and no metabolite of pyrimethamine was found in either strain. DHFR from the resistant strain was 300 times less sensitive to inhibition by pyrimethamine than the enzyme from the sensitive strain, while the Michaelis constant for dihydrofolate remained unchanged and inhibition was competitive in both cases. Altered properties of plasmodial DHFR are apparently the only mechanism responsible for pyrimethamine resistance in the strain of Plasmodium falciparum studied.
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Janoff, A., W. J. Roth, S. Sinha i J. W. Barnwell. "Degradation of plasmodial antigens by human neutrophil elastase." Journal of Immunology 141, nr 4 (15.08.1988): 1332–40. http://dx.doi.org/10.4049/jimmunol.141.4.1332.
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Abstract Human neutrophil elastase (HNE) has been well-studied with respect to its role in pathologic states, but less is known about the physiologic functions of this important granulocyte enzyme. In the present study, we show that HNE can degrade the major circumsporozoite protein of the infective (sporozoite) stage of Plasmodium vivax malaria, and that this enzyme can also interfere with the cytoadherence of human E infected with Plasmodium falciparum (strain K+ FMG-FCR3) (IE). Cytoadherence reactions are not only blocked by treatment of IE with as little as 10 fg HNE/IE, but already adherent IE are also removed by the enzyme. Normal E surface Ag are not extensively destroyed by these doses of HNE. This suggests that the effect of HNE on cytoadherence is selective and probably due to degradation of the malarial Ag exported to the IE surface and responsible for the formation of "recognition knobs" upon which the cytoadherence reaction depends. This conclusion, in turn, was supported by the results of Western blot analysis showing that HNE degrades a high m.w. Ag found exclusively in membrane extracts of IE. Our results suggest that one physiologic role of HNE may be degradation of parasitic antigens during host defense against malaria.
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TASDEMIR, D., N. GUNER, R. PEROZZO, R. BRUN, A. DONMEZ, I. CALIS i P. RUEDI. "Anti-protozoal and plasmodial FabI enzyme inhibiting metabolites of roots". Phytochemistry 66, nr 3 (luty 2005): 355–62. http://dx.doi.org/10.1016/j.phytochem.2004.11.013.
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YEO, Hye-Jeong, Marie-Pierre LARVOR, Marie-Laure ANCELIN i Henri J. VIAL. "Plasmodium falciparum CTP:phosphocholine cytidylyltransferase expressed in Escherichia coli: purification, characterization and lipid regulation". Biochemical Journal 324, nr 3 (15.06.1997): 903–10. http://dx.doi.org/10.1042/bj3240903.
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The Plasmodium falciparum CTP:phosphocholine cytidylyltransferase (PfCCT) has been isolated from an overexpressing strain of Escherichia coli. The plasmid pETPfCCT mediated the overexpression of the full-length polypeptide directly. The recombinant protein corresponded to 6–9% of the total cellular proteins and was found essentially in the insoluble membrane fraction. Urea at 6 M was used to solubilize the recombinant protein from the insoluble fraction. The CCT activity was restored upon the removal of urea, and the protein was subsequently purified to homogeneity on a Q-Sepharose column. Approx. 1.4 mg of pure enzyme was obtained from a 250 ml culture of E. coli. Biochemical properties, including in vitro substrate specificity and enzymic characterization, were assessed. The lipid regulation of the recombinant plasmodial CCT activity was characterized for the first time. The Km values were 0.49±0.03 mM (mean±S.E.M.) for phosphocholine and 10.9±0.5 mM for CTP in the presence of lipid activators (oleic acid/egg phosphatidylcholine vesicles), whereas the Km values were 0.66±0.07 mM for phosphocholine and 28.9±0.8 mM for CTP in the absence of lipid activators. The PfCCT activity was stimulated to the same extent in response to egg phosphatidylcholine vesicles containing anionic lipids, such as oleic acid, cardiolipin and phosphatidylglycerol, and was insensitive or slightly sensitive to PC vesicles containing neutral lipids, such as diacylglycerol and monoacylglycerol. Furthermore, the stimulated enzyme activity by oleic acid was antagonized by the cationic aminolipid sphingosine. These lipid-dependence properties place the parasite enzyme intermediately between the mammalian enzymes and the yeast enzyme.
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Ullah, Najeeb, Hina Andaleeb, Celestin Nzanzu Mudogo, Sven Falke, Christian Betzel i Carsten Wrenger. "Solution Structures and Dynamic Assembly of the 24-Meric Plasmodial Pdx1–Pdx2 Complex". International Journal of Molecular Sciences 21, nr 17 (19.08.2020): 5971. http://dx.doi.org/10.3390/ijms21175971.
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Plasmodium species are protozoan parasites causing the deadly malaria disease. They have developed effective resistance mechanisms against most antimalarial medication, causing an urgent need to identify new antimalarial drug targets. Ideally, new drugs would be generated to specifically target the parasite with minimal or no toxicity to humans, requiring these drug targets to be distinctly different from the host’s metabolic processes or even absent in the host. In this context, the essential presence of vitamin B6 biosynthesis enzymes in Plasmodium, the pyridoxal phosphate (PLP) biosynthesis enzyme complex, and its absence in humans is recognized as a potential drug target. To characterize the PLP enzyme complex in terms of initial drug discovery investigations, we performed structural analysis of the Plasmodium vivax PLP synthase domain (Pdx1), glutaminase domain (Pdx2), and Pdx1–Pdx2 (Pdx) complex (PLP synthase complex) by utilizing complementary bioanalytical techniques, such as dynamic light scattering (DLS), X-ray solution scattering (SAXS), and electron microscopy (EM). Our investigations revealed a dodecameric Pdx1 and a monodispersed Pdx complex. Pdx2 was identified in monomeric and in different oligomeric states in solution. Interestingly, mixing oligomeric and polydisperse Pdx2 with dodecameric monodisperse Pdx1 resulted in a monodispersed Pdx complex. SAXS measurements revealed the low-resolution dodecameric structure of Pdx1, different oligomeric structures for Pdx2, and a ring-shaped dodecameric Pdx1 decorated with Pdx2, forming a heteromeric 24-meric Pdx complex.
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SINGH, Ajay, Bhaskar R. SHENAI, Youngchool CHOE, Jiri GUT, Puran S. SIJWALI, Charles S. CRAIK i Philip J. ROSENTHAL. "Critical role of amino acid 23 in mediating activity and specificity of vinckepain-2, a papain-family cysteine protease of rodent malaria parasites". Biochemical Journal 368, nr 1 (15.11.2002): 273–81. http://dx.doi.org/10.1042/bj20020753.
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Cysteine proteases of Plasmodium falciparum, known as falcipains, have been identified as haemoglobinases and potential drug targets. As anti-malarial drug discovery requires the analysis of non-primate malaria, genes encoding related cysteine proteases of the rodent malaria parasites P. vinckei (vinckepain-2) and P. berghei (berghepain-2) were characterized. These genes encoded fairly typical papain-family proteases, but they contained an unusual substitution of Gly23 with Ala (papain numbering system). Vinckepain-2 was expressed in Escherichia coli, solubilized, refolded and autoprocessed to an active enzyme. The protease shared important features with the falcipains, including an acidic pH optimum, preference for reducing conditions, optimal cleavage of peptide substrates with P2 Leu and ready hydrolysis of haemoglobin. However, key differences between the plasmodial proteases were identified. In particular, vinckepain-2 showed very different kinetics against many substrates and an unusual preference for peptide substrates with P1 Gly. Replacement of Ala23 with Gly remarkably altered vinckepain-2, including loss of the P1 Gly substrate preference, markedly increased catalytic activity (kcat/Km increased approx. 100-fold) and more rapid autohydrolysis. The present study identifies key animal-model parasite targets. It indicates that drug discovery studies must take into account important differences between plasmodial proteases and sheds light on the critical role of amino acid 23 in catalysis by papain-family proteases.
Rozprawy doktorskie na temat "Plasmodial Enzyme"
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Maheshwari, Sweta. "Caractérisation biochimique et cellulaire des enzymes clés du métabolisme des phospholipides chez Plasmodium falciparum". Thesis, Montpellier 2, 2012. http://www.theses.fr/2012MON20004.
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Le développement du parasite Plasmodium falciparum, responsable du paludisme, nécessite la synthèse de phospholipides et plus particulièrement de phosphatidylcholine (PC) et phosphaditylethanolamine (PE) qui représentent environ 85% de la totalité des phospholidipes du parasite. Leur synthèse s'effectue principalement par les voies métaboliques de novo, voies de Kennedy, en trois étapes enzymatiques. Les enzymes CTP: phosphoethanolamine cytidylyltransferase (ECT) et CTP: phosphocholine cytidylyltransferase (CCT) catalysent les étapes limitantes des deux voies de biosynthèse de la PE et de la PC, respectivement. Ces deux enzymes sont essentielles à la survie du parasite murin, P. berghei et représentent ainsi des cibles thérapeutiques potentielles. La PfCCT est constituée de deux domaines cytidylyltranférases (CT) répétés alors que l'enzyme homologue chez l'homme est composée d'un seul domaine. En revanche, pour la ECT, la présence de deux domaines CT est retrouvée chez toutes les espèces mais les analyses de séquences et de structures ont montré que des résidus importants du site catalytique liant le substrat n'étaient pas conservés dans le domaine CT C-terminal de la PfECT. Ce travail a eu pour but de déterminer les propriétés enzymatiques et les caractéristiques cellulaires de la PfECT et de la PfCCT. Les paramètres cinétiques de ces enzymes ont été quantifiés in vitro à l'aide protéines recombinantes ainsi que sur les enzymes endogènes à l'aide d'extraits parasitaires. Grâce à l'utilisation de protéines recombinantes ponctuellement mutées, nous avons montré que seul le domaine CT N-terminal de la PfECT est catalytiquement actif. Chez P. falciparum, la PfECT et la PfCCT sont exprimées tout au long du cycle intra-érythrocytaire du parasite. La PfECT est présente dans la fraction soluble du parasite alors que la PfCCT apparait aussi bien dans la fraction soluble qu'insoluble. Des expériences d'immunofluorescence ont montré que la PfECT est cytosolique. L'ensemble des résultats présentés apportent un éclairage important sur les fonctions et les propriétés de ces deux cibles potentielles et constituent les premières étapes indispensables à l'élaboration d'une approche thérapeutiquePhospholipids are essential for the growth and development of Plasmodium falciparum malaria parasite. Phosphatidylcholine (PC) and phosphatidylethanolamine (PE) are its major structural phospholipids. This study focused on CTP: phosphoethanolamine cytidylyltransferase (ECT) and CTP: phosphocholine cytidylyltransferase (CCT) that catalyzes the rate-limiting steps of the de novo Kennedy pathways for PE and PC biosynthesis respectively. Both ECT and CCT are essential in the rodent malaria parasite P. berghei and constitute potential chemotherapeutic targets to fight against malaria. PfCCT consists of two very similar cytidylyltransferase (CT) domains whereas the human enzyme consists of only one CT domain. The presence of two CT domains in ECT seems to be widespread in all the organisms. Sequence and structural analysis showed that the C-terminal CT domain of ECT lacks key residues in the substrate binding motif. This study aimed at unravelling the enzymatic properties and cellular characteristics of PfECT and PfCCT enzymes. In addition, these studies addressed the key question if C-terminal CT domain of PfECT is catalytically active. Kinetic parameters of the enzymes were evaluated in vitro on native proteins as well as on recombinant proteins, the latter being produced in bacterial system. Cellular characterisation studies using polyclonal antisera showed that PfECT and PfCCT are expressed throughout the intra-erythrocytic life cycle of the parasite. PfECT is found mainly in soluble form in the parasite while PfCCT is present in soluble as well as insoluble forms in the parasite. Furthermore, immunofluorescence studies for PfECT revealed that it is mainly cytosolic. To assess the contribution of each CT domain to overall PfECT enzyme activity, recombinant PfECT mutants were generated by site-directed mutagenesis. Kinetic studies on these mutants indicated that the N-terminal CT domain was the only active domain of PfECT. Collectively, these results bring new insights into the kinetic and cellular properties of the enzymes and will pave the way in developing a future pharmacological approach
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Higham, Christopher W. "A study of lactate dehydrogenase from Plasmodium falciparum". Thesis, University of Bristol, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.299529.
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Shoemark, Deborah Karen. "The kinetic characterization of the lactate dehydrogenase enzyme from Plasmodium falciparum". Thesis, University of Bristol, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.326677.
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Birkholtz, Lyn-Marie. "Functional and structural characterization of the unique bifunctional enzyme complex involved in regulation of polyamine metabolism in Plasmodium falciparum". Pretoria : [s.n.], 2005. http://upetd.up.ac.za/thesis/available/etd-06302005-120320/.
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Birkholtz, Lyn-Marie. "Functional and structural charaterization of the unique bifunctional enzyme complex involved in regulation of polyamine metabolism in Plasmodium falciparum". Thesis, University of Pretoria, 2001. http://hdl.handle.net/2263/25944.
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Malaria remains one of the most serious tropical infectious diseases affecting mankind. The prevention of the disease is hampered by the increasing resistance of the parasite to existing chemotherapies. The need for novel therapeutic targets and drugs is therefore of the utmost importance and detailed knowledge of the biochemistry of the parasite is imperative. This study was directed at the biochemical characterisation of the polyamine metabolic pathway of P. falciparum in order to elucidate differences between the parasite and its human host that can be exploited in the design of novel antimalarials. The thesis focussed on the two rate-limiting enzymes in polyamine biosynthesis, S¬adenosylmethionine decarboxylase (AdoMetDC) and ornithine decarboxylase (ODC), which occur as a unique bifunctional complex in P. falciparum. The genomic structure of the bifunctional gene indicated a single, monocistronic transcript with large untranslated regions that were predicted to be involved in unique translational regulatory mechanisms. This gives rise to a bifunctional protein containing both decarboxylase activities on a single polypeptide forming a heterotetrameric complex. Activity of the decarboxylases decreases dramatically if these proteins are expressed in their monofunctional forms as homodimeric ODC and heterotetrameric AdoMetDC. The deduced amino acid sequence indicated that all the essential residues for catalysis are conserved and highlighted the presence of three parasite-specific insertions. The parasite-specific inserts were shown to be essential for the catalytic activity of the respective domains and also to influence the activity of the neighbouring domain, indicating that intramolecular communication exists in the heterotetrameric complex. The most structured and smallest insert was also shown to mediate protein-protein interactions between the two domains and to stabilise the complex. Further structure- functional characterisations of specifically the ODC domain were deduced from a comparative homology model. The model predicted an overall structure corresponding to those of other homologous proteins. The validity of the model is supported by mutagenesis results. However, certain parasite-specific properties were identified in the active site pocket and dimerisation interface. The former was exploited in the rational design of novel putative ODC inhibitors directed only against the P. falciparumprotein by in silico screening of chemical structure libraries. This study therefore describes the identification of certain parasite-specific properties in a unique bifunctional protein involved in regulation of polyamine metabolism of P. falciparum. Such discoveries are invaluable in strategies aimed at elucidating biochemical and metabolic differences between the parasite and its human host that could be exploited in the design of alternative, parasite-specific chemotherapies. Moreover, the thesis also contributed new knowledge on certain less well-understood biological phenomena characteristic of P. falciparum, the nature and origin of bifunctional proteins and the functional properties of parasite-specific inserts found in some proteins of the parasite.Thesis (PhD (Biochemistry))--University of Pretoria, 2002.
Biochemistry
unrestricted
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Turgut, Dilek. "Overproduction of the active lactate dehydrogenase from Plasmodium falciparum opens a route to obtain new antimalarials". Thesis, University of Bristol, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.389088.
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Ko, Reamonn, i 高耀駿. "X-ray crystallographic studies of Plasmodium falciparum adenylate kinases". Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2014. http://hdl.handle.net/10722/208020.
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Malaria is a global health concern accounting for approximately 219 million cases and an estimated 660 000 deaths in 2010. The most fatal strain of malarial parasite, Plasmodium falciparum is found to contain 3 Adenylate Kinases (PfAK1, PfAK2 and PfGAK). Adenylate Kinases are important enzymes that essentially catalyze and regulate energy metabolism processes. PfAK1 and PfAK2 catalyze the reversible MG2+ reaction ATP + AMP ←→ 2ADP whereas, the PfGAK catalyzes the Mg2+ dependent reaction GTP+AMP ←→ ADP+GDP. Of all malarial strains, only the Plasmodium falciparum Adenylate Kinase 2 (PfAK2) was found to contain a N-myristoylation sequence and subsequently formed a stable heterodimer with Plasmodium falciparum N-myristoyl transferase (PfNMT). The myristoylation of PfAK2 by PfNMT is believed to help transport PfAK2 to the parasitophorous vacuole membrane (PVM) so that the enzyme can perform its essential functions. With these enzymes being key components in the parasite’s survival, the structural study of these enzymes would provide a lot of insight into targeting these proteins for drug design that would effectively kill the parasite without affecting the human host. In this study, PfAK1 was able to be expressed, purified and crystallized with a dataset collected at 4.3Å. PfGAK was expressed and purified. A GTP analogue called GP5A was used to soak the purified PfGAKand the PfGAK bound to GP5A was crystallized and diffracted. Moreover, PfAK2 and PfNMT was successfully expressed and co-purified. The purified PfAK2-PfNMT heterodimer are undergoing crystal screening for possible crystallization conditions.published_or_final_version
Physiology
Master
Master of Philosophy
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Yao, Jia. "Synthesis of silver nanoparticles and their role against a thiazolekinase enzyme from Plasmodium falciparum". Thesis, Rhodes University, 2014. http://hdl.handle.net/10962/d1020894.
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Malaria, a mosquito-borne infectious disease, caused by the protozoan Plasmodium genus, is the greatest health challenges worldwide. The plasmodial vitamin B1 biosynthetic enzyme PfThzK diverges significantly, both structurally and functionally from its counterpart in higher eukaryotes, thereby making it particularly attractive as a biomedical target. In the present study, PfThzK was recombinantly produced as 6×His fusion protein in E. coli BL21, purified using nickel affinity chromatography and size exclusion chromatography resulting in 1.03% yield and specific activity 0.28 U/mg. The enzyme was found to be a monomer with a molecular mass of 34 kDa. Characterization of the PfThzK showed an optimum temperature and pH of 37°C and 7.5 respectively, and it is relatively stable (t₁/₂=2.66 h). Ag nanoparticles were synthesized by NaBH₄/tannic acid, and characterized by UV-vis spectroscopy and transmission electron microscopy. The morphologies of these Ag nanoparticles (in terms of size) synthesized by tannic acid appeared to be more controlled with the size of 7.06±2.41 nm, compared with those synthesized by NaBH₄, with the sized of 12.9±4.21 nm. The purified PfThzK was challenged with Ag NPs synthesized by tannic acid, and the results suggested that they competitively inhibited PfThzK (89 %) at low concentrations (5-10 μM) with a Ki = 6.45 μM.
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Khairallah, Afrah. "The identification of natural inhibitory compounds against the plasmodium GTP Cyclohydrolase I (GCH1) enzyme". Thesis, Rhodes University, 2019. http://hdl.handle.net/10962/72284.
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Malaria is a disease caused by protozoan parasites that invade red blood cells causing an infection. Malaria remains a global health problem. The genus Plasmodium infects about a quarter of a billion people annually, resulting in over a million death cases. This can severely affect the public health and socioeconomic development especially in countries with limited resources. Malaria is transmitted by the female Anopheles mosquito. Five species within the Plasmodium genus are known to cause infection in humans; namely Plasmodium falciparum, Plasmodium Ovale, Plasmodium knowlesi, Plasmodium vivax and Plasmodium malariae. The increased resistance by the parasite to the majority of available anti-malarial drugs has raised a great challenge in anti-malarial drug discovery. With the problem of drug resistance on the rise, the need to develop new anti-malarial treatment strategies and identification of alternative metabolic targets for the treatment of malaria is crucial. This study is focused on the Guanosine triphosphate CycloHydrolase I (GCH1) enzyme as a potential drug target. GCH1 is important for the survival of malaria parasites as shown by failed attempts to generate knockout lines in plasmodium falciparum. In this study, sequence and evolutionary analysis were carried out in both the human host and parasite GCH1 enzyme. Accurate 3D models of the parasite GCH1 were built and validated. The resulting models were used for high throughput screening against 623 compounds from the South African Natural Compounds Database (SANCDB; https://sancdb.rubi.ru.ac.za/). The high throughput screening was done to identify possible binding sites as well as hit compounds with high selectivity and binding affinity towards the parasite enzyme, this is followed by molecular dynamics simulations to identify protein-ligand complexes and analyze their stability. In this study, a total of five SANCDB compounds were identified as potential inhibitors: SANC00317, SANC00335, SANC00368, SANC00106, SANC00103 and SANC00286. It was found that GCH1 protein can be a potential anti-malarial drug target as it showed selective binding with the inhibitor compounds. The identified inhibitors showed good selectivity and lower free energy of binding towards the parasite GCH1. Force field parameters of GCH1 active site metal were derived and validated. The development of these force field parameters was important for accurate MD simulations of the protein active site; which will allow for future investigation of interactions and stability of the GCH1 protein-ligand complexes.
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Goolab, Shivani. "Optimization of the heterologous expression of folate metabolic enzymes of Plasmodium falciparum". Diss., University of Pretoria, 2010. http://hdl.handle.net/2263/23647.
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Malaria is a fatal tropical disease affecting billions of people in impoverished countries world-wide. An alarming fact is that a child in Africa dies of malaria every 30 seconds that amounts to 2500 children per day (www.who.int/features/factfiles). Malaria is caused by the intraerythrocytic forms of Plasmodium species, notably P. falciparum, P. vivax, P. ovale and P. malariae (Hyde 2007). The spread of drug-resistant strains, failure of vector control programs, rapid growth rate of the parasite, and lack of a vaccine have further exacerbated the effects of malaria on economic development and human health. It is therefore imperative that novel drug targets are developed or current antimalarial drugs optimized (Foley and Tilley 1998). One such target is folate biosynthesis, given that folates and their derivatives are required for the survival of organisms (Muller et al. 2009). DHFR and DHPS are currently the only folate targets exploited however, their antifolate drugs are almost useless against parasite resistant strains. As such, guanosine-5’triphosphate cyclohydrolase I (GTPCHl) among other antifolate candidates are considered for intervention (Lee et al. 2001). Knock-out studies (of P. falciparum gtpchI) resulted in the suppression of DHPS activity (Nzila et al. 2005). Additionally, gtpchI amplified 11-fold in P. falciparum strains resistant to antifolates due to mutations in dhps and dhfr and this may be a mechanism for the compensation of reduced flux of folate intermediates (Kidgell et al. 2006; Nair et al. 2008). Over-expression of P. falciparum proteins in E. coli remains a challenge mainly due to the A+T rich Plasmodium genome resulting in a codon bias. This results in the expression of recombinant proteins as insoluble proteins sequestered in inclusion bodies (Carrio and Villaverde 2002; Mehlin et al. 2006; Birkholtz et al. 2008a). Comparative expression studies were conducted of native GTPCHI (nGTPCHI), codon optimized GTPCHI (oGTPCHI) and codon harmonized (hGTPCHI) in various E. coli cell lines, using alternative media compositions and co-expression with Pfhsp70. The nGTPCHI protein did not express because the gene consisted of codons rarely used by E. coli (codon bias). The expression levels of purified hGTPCHI were a greater in comparison to oGTPCHI using the different expression conditions. This is because codon-harmonization involves substituting codons to replicate the codon frequency preference of the target gene in P. falciparum, as such the translation machinery matches that of Plasmodium (Angov et al. 2008). Furthermore, greater expression levels of GTPCHI were achieved in the absence of Pfhsp70 due to expression of a possible Nterminal deletion product or E. coli protein. Purification conditions could be improved to obtain homogenous GTPCHI and further analysis (mass spectrometry and enzyme activity assays) would be required to determine the nature of soluble GTPCHI obtained. To improve the expression of soluble proteins the wheat germ expression system was used as an alternate host. However, GTPCHI expression was not effective, possibly due to degradation of mRNA template or the absence of translation enhancer elements.Dissertation (MSc)--University of Pretoria, 2011.
Biochemistry
unrestricted
Książki na temat "Plasmodial Enzyme"
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Costanzo, Marna Schutte. Constraints and trade-offs in enzyme evolution of Plasmodium falciparum. Cambridge, Mass: Harvard University, 2010.
Znajdź pełny tekst źródłaCzęści książek na temat "Plasmodial Enzyme"
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Ancelin, Marie L., Henri J. Vial i Jean R. Philippot. "Characterization of Choline and Ethanolamine Kinase Activities in Plasmodium — Infected Erythrocytes". W Enzymes of Lipid Metabolism II, 59–64. Boston, MA: Springer US, 1986. http://dx.doi.org/10.1007/978-1-4684-5212-9_8.
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Gardiner, Donald, John Dalton i Sheena McGowan. "Chapter 7. Plasmodium falciparum Neutral Aminopeptidases: Development of Novel Anti-Malarials by Understanding Enzyme Structure". W Drug Discovery, 169–85. Cambridge: Royal Society of Chemistry, 2011. http://dx.doi.org/10.1039/9781849733151-00169.
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Larsen, Mads Delbo, Rafael Bayarri-Olmos, Peter Garred i Lars Hviid. "Enzyme-Linked Immunosorbent Assay for Activation of the Classical Complement Pathway by Plasmodium falciparum-Infected Erythrocyte Surface Antigen-Specific Antibodies". W Methods in Molecular Biology, 673–78. New York, NY: Springer US, 2022. http://dx.doi.org/10.1007/978-1-0716-2189-9_50.
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Silmon de Monerri, Natalie C., Andrea Ruecker i Michael J. Blackman. "Plasmodium Subtilisins". W Handbook of Proteolytic Enzymes, 3260–65. Elsevier, 2013. http://dx.doi.org/10.1016/b978-0-12-382219-2.00720-1.
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Maurya, Radheshyam, i Madhulika Namdeo. "Superoxide Dismutase: A Key Enzyme for the Survival of Intracellular Pathogens in Host". W Reactive Oxygen Species [Working Title]. IntechOpen, 2021. http://dx.doi.org/10.5772/intechopen.100322.
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Superoxide dismutase (SOD) is a crucial enzyme required to maintain the redox potential of the cells. It plays a vital role in protecting normal cells from reactive oxygen species (ROS) produced during many intracellular pathogens infections. SOD removes excess superoxide radicals (O2−) by converting them to hydrogen peroxide (H2O2) and molecular oxygen (O2). Several superoxide dismutase enzymes have been identified based on the metal ion as a cofactor. Human SOD differs from the intracellular pathogens in having Cu/Zn and Mn as metal cofactors. However, SOD of intracellular pathogens such as Trypanosoma, Leishmania, Plasmodium, and Mycobacterium have iron (Fe) as metal cofactors. Iron Superoxide Dismutase (FeSOD) is an essential enzyme in these pathogens that neutralizes the free radical of oxygen (O−) and prevents the formation of Peroxynitrite anion (ONOO−), helping the pathogens escape from redox-based cytotoxic killing. Moreover, most intracellular bacteria hold MnSOD or FeSOD in their cytoplasm such as Salmonella and Staphylococcus, whereas periplasm of some pathogenic bacteria and fungi are also cofactors with Cu/Zn and identified as CuZnSOD. This chapter will review the various types SOD present in intracellular pathogens and their role in the survival of these pathogens inside their host niche.
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Klemba, Michael. "PfA-M1 Aminopeptidase (Plasmodium falciparum)". W Handbook of Proteolytic Enzymes, 445–48. Elsevier, 2013. http://dx.doi.org/10.1016/b978-0-12-382219-2.00090-9.
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Nsangou, Desire M. M., Rency T. Mathew, Karine Thivierge, Donald L. Gardiner i John P. Dalton. "Leucyl Aminopeptidase of Plasmodium falciparum". W Handbook of Proteolytic Enzymes, 1481–84. Elsevier, 2013. http://dx.doi.org/10.1016/b978-0-12-382219-2.00333-1.
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V.T. Minnow, Yacoba, i Vern L. Schramm. "Purine and Pyrimidine Pathways as Antimalarial Targets". W Malaria - Recent Advances, and New Perspectives [Working Title]. IntechOpen, 2022. http://dx.doi.org/10.5772/intechopen.106468.
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Malaria continues to plague the endemic regions of sub-Saharan Africa and Southeast Asia. With the current development of artemisinin resistance and a risk of failure of the current first line therapies, there is a growing need for novel antimalarials. Purine and pyrimidine metabolism in Plasmodium is distinctly different from the human host, making these pathways valid targets for the development of novel antimalarials. Targeting key enzymes in these pathways with transition state analogs has provided high affinity inhibitors. Transition state mimicry can also provide selectivity for the parasite enzymes over the homologous enzymes of the human host. Resistance of Plasmodium parasites to current antimalarials will be compared to resistance development induced by transition state analogs inhibitors, a feature that may contribute to decreased resistance development. Tight binding and specificity of transition state analog inhibitors provide important features for novel antimalaria therapy with low toxicity and prevention of antibiotic resistance.
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Luzzatto, Lucio. "Glucose-6-phosphate dehydrogenase deficiency". W Oxford Textbook of Medicine, redaktorzy Chris Hatton i Deborah Hay, 5472–79. Oxford University Press, 2020. http://dx.doi.org/10.1093/med/9780198746690.003.0541.
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Deficiency of the enzyme glucose-6-phosphate dehydrogenase (G6PD) in red blood cells is an inherited abnormality due to mutations of the G6PD gene on the X chromosome that renders the cells vulnerable to oxidative damage. The condition is widespread in many populations living in or originating from tropical and subtropical areas of the world because it confers a selective advantage against Plasmodium falciparum malaria. Clinical features—G6PD deficiency is mostly an asymptomatic trait, but it predisposes to acute haemolytic anaemia in response to exogenous triggers, including (1) ingestion of fava beans—favism; (2) certain bacterial and viral infections; and (3) some drugs—notably some antimalarials (e.g. primaquine), some antibiotics (e.g. sulphanilamide, dapsone, nitrofurantoin), and even aspirin in high doses. Other manifestations include (1) severe neonatal jaundice; and (2) chronic nonspherocytic haemolytic anaemia—the latter is only seen with rare specific genetic variants. The acute haemolytic attack typically starts with malaise, weakness, and abdominal or lumbar pain, followed by the development of jaundice and passage of dark urine (haemoglobinuria). Most episodes resolve spontaneously. Diagnosis relies on the direct demonstration of decreased activity of G6PD in red cells: a variety of screening tests are available, with (ideally) subsequent confirmation by quantitative assay. Prevention is by avoiding exposure to triggering factors of previously screened subjects. Prompt blood transfusion is indicated in severe acute haemolytic anaemia and may be life-saving.
Streszczenia konferencji na temat "Plasmodial Enzyme"
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Vargas, Ana Elisa Assad Teixeira, i Arthur Zambon Piumbini. "RELAÇÃO ENTRE PORTADORES DA HEMOGLOBINA S E A RESISTÊNCIA À MALÁRIA". W II Congresso Brasileiro de Hematologia Clínico-laboratorial On-line. Revista Multidisciplinar em Saúde, 2022. http://dx.doi.org/10.51161/hematoclil/90.
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Introdução: A infecção causada por protozoários do gênero Plasmodium, conhecida como malária, é responsável por uma grande taxa de morbidade e mortalidade em países de clima tropical. Do mesmo modo, o eritrócito é fundamental no ciclo de vida do parasita, portanto qualquer distúrbio nas hemácias pode causar um ambiente desfavorável a esse. Por sua vez, a anemia falciforme é uma doença hemolítica de caráter genético e hereditária, caracterizada pela presença de eritrócitos com formato de foice. Neste caso, o padrão de herança genética é autossômico recessivo e o gene da globina beta S está em homozigose. Quando em heterozigose, em associação do gene beta S com outras variantes, é denominado traço falciforme. Objetivos: Descrever a contribuição do alelo HbS, como fator de proteção contra o P. falciparum. Material e métodos: O estudo foi construído a partir de revisão da literatura, utilizando-se os descritores malária, anemia falciforme, hemoglobina S e resistência. Os artigos foram pesquisados na base de dados SciELO e PubMed. Resultados: Tanto a homozigose quanto a heterozigose da HbS oferecem resistência ao parasita da malária, devido a dificuldade que este protozoário tem de invadir e crescer dentro dos eritrócitos falciformes, uma vez que, nessas células o nível de potássio intracelular está diminuído em decorrência da afinidade reduzida da hemoglobina S pelo oxigênio, causando a morte do parasito. Além disso, outro mecanismo que confere efeito protetor da hemoglobina falciforme contra a malária é mediado pela enzima heme oxigenase-1, cuja expressão é induzida pelas hemácias falciformes, que induz a produção de monóxido de carbono, impedindo que o parasita cause uma reação que leva à morte do hospedeiro. Outros fatores auxiliam na resistência, como a inibição da citoaderência às células endoteliais, o que reduz a chance de malária cerebral. Ademais, a fagocitose esplênica das células parasitadas também é responsável pela baixa densidade do Plasmodium. Conclusão: A Hemoglobina S protege, mesmo que parcialmente, os eritrócitos contra o processo hemolítico causado por infecções do Plasmodium.
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Camilo, Tiara Lange Felipe Oliveira, Renan Rodrigo Corrêa Gomes, Lorena Karla Da Silva i Rafaela Vieira De Souza. "A IMPORTÂNCIA DA TRIAGEM PARA DETECÇÃO DA DEFICIENCIA DE GLICOSE-6-FOSFATO-DESIDROGENASE EM ÁREAS ENDÊMICAS DE MALÁRIA NO BRASIL". W II Congresso Brasileiro de Hematologia Clínico-laboratorial On-line. Revista Multidisciplinar em Saúde, 2022. http://dx.doi.org/10.51161/hematoclil/142.
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INTRODUÇÃO: A deficiência de glicose-6-fosfato-desidrogenase (G6PD) enzima citoplasmática dos eritrócitos, responsável pela proteção das hemácias contra ações oxidantes, é uma anormalidade predominante na população negra, tendo padrão de herança recessivo ligado ao cromossomo X, acometendo homens hemizigóticos, podendo ocorrer também em mulheres homozigóticas. É geralmente assintomática, podendo ser desencadeada por fatores que levam ao estresse oxidante, como os antimaláricos. OBJETIVOS: Elencar a importância da realização prévia de exames que possam indicar a deficiência de g6pd em pacientes com diagnóstico de malária. MATERIAL E MÉTODOS: Trata-se de uma revisão integrativa da literatura. Foram encontrados quinze artigos, sendo selecionados oito artigos para compor a revisão, para a inclusão considerou-se os artigos publicados eletronicamente nos últimos cinco anos, em concordância com os Descritores em Ciência em Saúde (DeCS), através da consulta de artigos científicos publicados no período de 2018 à 2021, com auxílio da Biblioteca Virtual em Saúde (BVS), vinculados a base de dados PubMed e Scielo. RESULTADOS: No Brasil cerca de 90% dos casos diagnosticados segundo o boletim Epidemiológico do Ministério da Saúde, possui Plasmodium vivax como o mais comum. Devido aos agravos que pode trazer ao portador da deficiência de G6PD, tornando-se um problema para a saúde pública. O Programa Nacional de Prevenção e Controle da Malária (PNCM) é responsável pelo tratamento e diagnóstico da doença e o exame para a detecção da G6PD não consta na solicitação padrão para diagnóstico. O uso da primaquina, medicamento antimalárico tem elevado risco de promover o quadro de hemólise no portador da deficiência, assim o diagnóstico da g6pd ainda na triagem poderia levar a uma conduta diferente que não pudesse causar danos ao indivíduo. A intensidade da hemólise apresentada varia de acordo com o grau de deficiência de G6PD, o tempo de uso do medicamento, a ação no organismo e a dosagem utilizada. Além do quadro de hemólise os pacientes tendem a apresentar falência renal aguda, podendo ir a óbito. CONCLUSÃO: É preciso que o diagnóstico da deficiência de G6PDd em populações multiétnicas seja realizado antes da administração de medicamentos antimaláricas, que acarretam alto potencial hemolítico, visando assim um tratamento adequado e seguro para estes indivíduos.