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)

To investigate the rosette formation properties of Plasmodium vivax, blood was sampled from 26 adult Thai patients admitted with acute P. vivax malaria and a predominance of trophozoite and schizont stages in their peripheral blood smears. In each case, P. vivax-infected cells formed spontaneous rosettes with two or more uninfected red blood cells. Rosette formation of P. vivax was dependent on the divalent cations (Ca2+/Mg2+) and was highly sensitive to trypsin and heparin, but, unlike P. falciparum, rosettes of P. vivax did not reform after removal of heparin. Plasma taken from patients with either acute uncomplicated P. falciparum or P. vivax malaria reversed rosette formation of all P. vivax isolates whereas plasma from uninfected controls had no effect. There was a small but significant increase in rosette-reversing activity in plasma taken during the convalescent period (P < 0.001). The increment in reversal activity was significantly greater in plasma taken following recovery from P. vivax malaria compared with P. falciparum malaria. This suggests that P. vivax rosette reversal activity is antibody mediated and has both species-specific and cross-species components.
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PMID:Characteristics of Plasmodium vivax-infected erythrocyte rosettes. 968 31

The asexual development of the malaria parasite takes place inside the host's erythrocyte, an environment that is different from that of most other eukaryotic organisms. The intense and rapid development of the parasite, as well as the homeostatic regulation of its cellular composition, require an extensive exchange of material between the parasite and its immediate surroundings. Studies on free murine parasite species suggest that a plasma membrane H+ pump is responsible for the maintenance of membrane potential and pH gradient, which are used as driving forces for the uptake of glucose and extrusion of Ca2+ by means of a symporter and an antiporter, respectively. In Plasmodium falciparum, a similar transport of Ca2+ may prevail. Several other transporters have been assigned to the plasma membrane of this parasite, either by direct measurements or by inference: D-glucose, nucleosides, L-amino acids, L-lactate and pantothenic acid. A Na+/H+ antiporter has been demonstrated, and implicated in the regulation of pH, and an ATP/ADP antiporter, whose function remains controversial, has been characterized. The presence of Mg2+ and Na+/K+ pumps and an active extrusion of oxidized glutathione can be inferred from the composition of the parasite cytosol vs. that of the host cell. Several genes coding for cation pumps have been cloned and their functions await characterization.
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PMID:The permeability properties of the parasite cell membrane. 1064 41

The YgbP protein of Escherichia coli encodes the enzyme 4-diphosphocytidyl-2-C-methylerythritol (CDP-ME) synthetase, a member of the cytidyltransferase family of enzymes. CDP-ME is an intermediate in the mevalonate-independent pathway for isoprenoid biosynthesis in a number of prokaryotic organisms, algae, the plant plastids and the malaria parasite. Because vertebrates synthesize isoprenoid precursors using a mevalonate pathway, CDP-ME synthetase and other enzymes of the mevalonate-independent pathway for isoprenoid production represent attractive targets for the structure-based design of selective antibacterial, herbicidal and antimalarial drugs. The high-resolution structures of E. coli CDP-ME synthetase in the apo form and complexed with both CTP-Mg2+ and CDP-ME-Mg2+ reveal the stereochemical principles underlying both substrate and product recognition as well as catalysis in CDP-ME synthetase. Moreover, these complexes represent the first experimental structures for any cytidyltransferase with both substrates and products bound.
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PMID:Structure of 4-diphosphocytidyl-2-C- methylerythritol synthetase involved in mevalonate- independent isoprenoid biosynthesis. 1142 97

The enzyme delta-aminolevulinic acid dehydratase (ALAD) catalyses the second reaction in the heme biosynthetic pathway. It has been suggested previously that the malaria parasite Plasmodium falciparum imports this enzyme from the host cell for de novo heme biosynthesis. However, the parasite's genome encodes an orthologue for ALAD. Here we report molecular cloning of a complete cDNA for the parasite's intrinsic ALAD and show it rescues an ALAD-null mutant of Escherichia coli, indicating that the malarial gene encodes a functional ALAD. The malarial ALAD has a long bipartite extension at its N-terminus, which may function as a plastid targeting signal. The amino acid sequence of the enzyme is related most closely to those of plant/algal chloroplast ALADs, though the malarial version may lack the allosteric Mg2+-binding site, which is conserved among chloroplast ALADs.
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PMID:The genome of Plasmodium falciparum encodes an active delta-aminolevulinic acid dehydratase. 1191 78

Erythrocytic stages of the malaria parasite Plasmodium falciparum rely on glycolysis for their energy supply and it is unclear whether they obtain energy via mitochondrial respiration albeit enzymes of the tricarboxylic acid (TCA) cycle appear to be expressed in these parasite stages. Isocitrate dehydrogenase (ICDH) is either an integral part of the mitochondrial TCA cycle or is involved in providing NADPH for reductive reactions in the cell. The gene encoding P. falciparum ICDH was cloned and analysis of the deduced amino-acid sequence revealed that it possesses a putative mitochondrial targeting sequence. The protein is very similar to NADP+-dependent mitochondrial counterparts of higher eukaryotes but not Escherichia coli. Expression of full-length ICDH generated recombinant protein exclusively expressed in inclusion bodies but the removal of 27 N-terminal amino acids yielded appreciable amounts of soluble ICDH consistent with the prediction that these residues confer targeting of the native protein to the parasites' mitochondrion. Recombinant ICDH forms homodimers of 90 kDa and its activity is dependent on the bivalent metal ions Mg2+ or Mn2+ with apparent Km values of 13 micro m and 22 micro m, respectively. Plasmodium ICDH requires NADP+ as cofactor and no activity with NAD+ was detectable; the for NADP+ was found to be 90 micro m and that of d-isocitrate was determined to be 40 micro m. Incubation of P. falciparum under exogenous oxidative stress resulted in an up-regulation of ICDH mRNA and protein levels indicating that the enzyme is involved in mitochondrial redox control rather than energy metabolism of the parasites.
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PMID:Isocitrate dehydrogenase of Plasmodium falciparum. 1269 90

The heme biosynthetic pathway of the malaria parasite is a drug target and the import of host delta-aminolevulinate dehydratase (ALAD), the second enzyme of the pathway, from the red cell cytoplasm by the intra erythrocytic malaria parasite has been demonstrated earlier in this laboratory. In this study, ALAD encoded by the Plasmodium falciparum genome (PfALAD) has been cloned, the protein overexpressed in Escherichia coli, and then characterized. The mature recombinant enzyme (rPfALAD) is enzymatically active and behaves as an octamer with a subunit Mr of 46,000. The enzyme has an alkaline pH optimum of 8.0 to 9.0. rPfALAD does not require any metal ion for activity, although it is stimulated by 20-30% upon addition of Mg2+. The enzyme is inhibited by Zn2+ and succinylacetone. The presence of PfALAD in P. falciparum can be demonstrated by Western blot analysis and immunoelectron microscopy. The enzyme has been localized to the apicoplast of the malaria parasite. Homology modeling studies reveal that PfALAD is very similar to the enzyme species from Pseudomonas aeruginosa, but manifests features that are unique and different from plant ALADs as well as from those of the bacterium. It is concluded that PfALAD, while resembling plant ALADs in terms of its alkaline pH optimum and apicoplast localization, differs in its Mg2+ independence for catalytic activity or octamer stabilization. Expression levels of PfALAD in P. falciparum, based on Western blot analysis, immunoelectron microscopy, and EDTA-resistant enzyme activity assay reveals that it may account for about 10% of the total ALAD activity in the parasite, the rest being accounted for by the host enzyme imported by the parasite. It is proposed that the role of PfALAD may be confined to heme synthesis in the apicoplast that may not account for the total de novo heme biosynthesis in the parasite.
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PMID:Delta-aminolevulinic acid dehydratase from Plasmodium falciparum: indigenous versus imported. 1463 82

In the absence of the de novo purine nucleotide biosynthetic pathway in parasitic protozoa, purine salvage is of primary importance for parasite survival. Enzymes of the salvage pathway are, therefore, good targets for anti-parasitic drugs. Adenylosuccinate synthetase (AdSS), catalysing the first committed step in the synthesis of AMP from IMP, is a potential target for anti-protozoal chemotherapy. We report here the crystal structure of adenylosuccinate synthetase from the malaria parasite, Plasmodium falciparum, complexed to 6-phosphoryl IMP, GDP, Mg2+ and the aspartate analogue, hadacidin at 2 A resolution. The overall architecture of P. falciparum AdSS (PfAdSS) is similar to the known structures from Escherichia coli, mouse and plants. Differences in substrate interactions seen in this structure provide a plausible explanation for the kinetic differences between PfAdSS and the enzyme from other species. Additional hydrogen bonding interactions of the protein with GDP may account for the ordered binding of substrates to the enzyme. The dimer interface of PfAdSS is also different, with a pronounced excess of positively charged residues. Differences highlighted here provide a basis for the design of species-specific inhibitors of the enzyme.
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PMID:Crystal structure of fully ligated adenylosuccinate synthetase from Plasmodium falciparum. 1472 41

All eight enzymes required for de novo heme biosynthesis have been predicted from the nuclear genome of the human malaria parasite Plasmodium falciparum. We have studied the subcellular localization of three of these using a GFP reporter in live transfected parasites. The first enzyme in the pathway delta-aminolevulinic acid synthase (ALAS) is targeted to the mitochondrion, but the next two enzymes porphobilinogen synthase (PBGS) and hydroxymethylbilane synthase (HMBS) are targeted to the plastid. An enzymatically active recombinant version of PBGS from P. falciparum was over-expressed and its activity found to be stimulated by Mg2+ (and enhanced by Mn2+) but not by Zn2+. A hypothetical scheme for the exchange of intermediates in heme biosynthesis between the mitochondrion and plastid organelle, as well as organelle attachment is discussed.
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PMID:Enzymes for heme biosynthesis are found in both the mitochondrion and plastid of the malaria parasite Plasmodium falciparum. 1514 63

Malaria, with 300-500 million clinical cases resulting in 1-3 million fatalities a year, is one of the most deadly tropical diseases. As current antimalarial therapeutics become increasingly ineffective due to parasitic resistance, there exists an urgent need to develop and pursue new therapeutic strategies. Recent genome sequencing and molecular cloning projects have identified several enzymes from Plasmodium (P.) falciparum that may represent novel drug targets, including a family of proteins that are homologous to the mammalian cyclin-dependent kinases (CDKs). CDKs are essential for the control of the mammalian cell cycle and, based on the conservation of the CDKs across species, the plasmodial CDKs are expected to play a crucial role in parasitic growth. Here we present a 3D structural model of Pfmrk, a putative human CDK activating kinase (CAK) homolog in P. falciparum. Notable features of the present structural model include: (1) parameterization of the Mg2+ hexacoordination system using ab initio quantum chemical calculations to accurately represent the ATP-kinase interaction; and (2) comparison between the docking scores and measured binding affinities for a series of oxindole-based Pfmrk inhibitors of known activity. Detailed analysis of inhibitor-Pfmrk binding interactions enabled us to identify specific residues (viz. Met66, Met75, Met91, Met94 and Phe143) within the Pfmrk binding pocket that may play an important role in inhibitor binding affinity and selectivity. The availability of this Pfmrk structural model, together with insights gained from analysis of ligand-receptor interactions, should promote the rational design of potent and selective Pfmrk inhibitors as antimalarial therapeutics.
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PMID:Structural model of the Plasmodium CDK, Pfmrk, a novel target for malaria therapeutics. 1604 58

Aspartic proteases of human malarial parasites are thought to play key roles in essential pathways of merozoite release, invasion and host cell hemoglobin degradation during the intraerythrocytic stages of their life cycle. Therefore, we have purified and characterized Plasmodium vivax aspartic protease, to determine if this enzyme can be used as potential drug target/immunogen, and its inhibitors as potential antimalarial drug. The P. vivax aspartic protease has been purified by a combination of ion exchange and size exclusion chromatographies and HPLC. Its properties were examined in order to define a role in the hemoglobin degradation process. The purified enzyme migrated as a single band on native PAGE and SDS/PAGE with a molecular mass of 40 kDa. Gelatin zymogram analyses revealed a clear zone of proteolytic activity corresponding to the band obtained on native PAGE and SDS/PAGE. The enzyme has an optimal pH of 4.0 and exhibits its highest activity at 37 degrees C. The enzyme is inhibited by pepstatin, but not by other inhibitors including o-phenanthroline, EDTA, PMSF or E-64, supporting its designation as an aspartic protease; its IC50 value was found to be 3.0 microM. A Lineweaver Burk double reciprocal plot with pepstatin shows that the inhibition is competitive with respect to the substrate. Ca2+ and Mg2+ ions enhance the protease activity, whereas Cu2+ and Hg2+ ions were found to be inhibitory. The pivotal role of aspartic protease in initiating hemoglobin degradation in P. vivax malaria parasite is also demonstrated.
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PMID:Purification and characterization of a hemoglobin degrading aspartic protease from the malarial parasite Plasmodium vivax. 1604 50


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