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)

The capacity of macrophages activated in vivo and in vitro to kill Plasmodium yoelii was investigated. Macrophages activated by BCG-, Con A-, or malaria-induced lymphokines (LK) were cultured with P. yoelii-parasitized erythrocytes (PE). In some experiments, effector and target cells were separated by a 0.45-micron filter. Parasite viability was assessed a) in vivo by injection of mice and quantitative detection of parasites by RIA or b) in vitro by the incorporation of 3H amino acids into parasite proteins. Activated macrophages killed target PE in a dose-dependent manner by elaborating a membrane-permeable soluble factor(s). The addition of small amounts of immune serum augmented the killing of the parasites. LK-activated macrophages underwent an oxidative burst upon the phagocytosis of PE as evidenced by the accumulation of reduced formazan in the NBT assay. The magnitude of the oxidative response corresponded to the number of parasites that were ingested. The phagocytosis-induced oxidative burst was necessary for subsequent killing of Plasmodium. Parasites incubated in microchambers separated from macrophages by a 0.45-micron filter were susceptible to H2O2 released by LK-activated macrophages incubated with PMA, opsonized zymosan, or P. yoelii antigen. Inhibition of protein synthesis by parasites exposed to products of activated macrophages was abrogated by preincubating macrophages with catalase but not with SOD, mannitol, or histidine. These results suggest that phagocytosis-associated oxidative mechanisms mediate the destruction of the malaria parasite. Hence, cell-mediated as well as antibody-dependent mechanisms cooperate in the immune response against malaria.
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PMID:Oxidative killing of the intraerythrocytic malaria parasite Plasmodium yoelii by activated macrophages. 669 Jun 6

Riboflavin deficiency interferes with the growth and multiplication of malaria parasites as well as the host response to malaria. The objective of the present work was to determine the effects of riboflavin deficiency on erythrocyte glutathione peroxidase (EC 1.11.1.9; GPx) and superoxide dismutase (EC 1.15.1.1; SOD) in rats infected with Plasmodium berghei malaria. Riboflavin in its co-enzyme form, FAD, is required by glutathione reductase (EC 1.6.4.1) to regenerate GSH and GSH is an important cellular antioxidant both in its own right and also as a substrate for the enzyme GPx. Weanling rats were deprived of riboflavin for 8 weeks before intraperitoneal injection of 1 x 10(6) P. berghei parasites. Control animals were weight-matched to the respective riboflavin-deficient group. At 10 d post-infection, parasite counts were higher in the weight-matched control group than the riboflavin-deficient group (P = 0.004). GPx activity was higher in erythrocytes of rats parasitized with P. berghei than comparable non-infected rats regardless of riboflavin status (P < 0.05). As mature erythrocytes do not synthesize new protein, the higher GPx activities were probably due to the presence of the parasite protein. In erythrocytes from riboflavin-deficient rats, GPx activity tended to be lower than in those rats fed on diets adequate in riboflavin (weight-matched controls) whether parasitized or not, but the difference was not significant. Neither riboflavin deficiency nor malaria had any effect on erythrocyte SOD activity. It was concluded that riboflavin deficiency has no marked effect on erythrocyte GPx or SOD activity in the rat.
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PMID:Glutathione peroxidase (EC 1.11.1.9) and superoxide dismutase (EC 1.15.1.1) activities in riboflavin-deficient rats infected with Plasmodium berghei malaria. 957 9

Oxidant stress is associated with the generation of reactive oxygen species that are responsible for the damage of a variety of cellular components. The prevention of such biological damage can be achieved by dismutation of superoxide to H2O2 which in turn is removed by catalase and GSH peroxidase. However, redox-active iron released during the development of plasmodia in the erythrocyte can mediate the conversion of H2O2 to hydroxyl radical which is more reactive. The roles of SOD and the nitroxide SOD mimic 4-OH,2,2,6,6,tetramethyl piperidine-N-oxyl (Tempol) were examined in P. falciparum grown in vitro. Both compounds did not prevent the interference with growth inflicted by various inducers of oxidant stress. Moreover, Tempol inhibited parasite growth, in agreement with previous experiments depicting accelerated mortality in SOD overexpressing mouse model of malaria. Probably, effective defense against ROS requires balanced increments in antioxidant enzymes and is not necessarily improved by an increase in the activity of one enzyme.
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PMID:The role of superoxide dismutation in malaria parasites. 1044 98

Desferal, N-acetyl penicillamine (metal chelators) and propylgallate, catechin, and reduced glutathione (antioxidants) suppressed the erythrocytic oxidative damage generated during Plasmodium berghei infection in Mastomys coucha. Superoxide anion and lipid peroxide levels were increased and on the contrary, superoxide dismutase activity was noticeably decreased in the infected erythrocytes. Metal chelators/antioxidant treatment to infected animals resulted in restoration of O(2)(-), LPO and SOD to near normal levels. Furthermore, treatment of the above mentioned agents displayed a controlled mortality/survival time and parasitaemia. In conclusion, metal chelators/antioxidants were found to be effective against oxidative stress injury and parasite growth resulting in prolonged survival time of the host during experimental malaria.
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PMID:Metal chelators/antioxidants: approaches to protect erythrocytic oxidative stress injury during Plasmodium berghei infection in Mastomys coucha. 1047 67

In Plasmodium falciparum, dihydrofolate reductase and thymidylate synthase activities are conferred by a single 70-kDa bifunctional polypeptide (DHFR-TS, dihydrofolate reductase-thymidylate synthase) which assembles into a functional 140-kDa homodimer. In mammals, the two enzymes are smaller distinct molecules encoded on different genes. A 27-kDa amino domain of malarial DHFR-TS is sufficient to provide DHFR activity, but the structural requirements for TS function have not been established. Although the 3'-end of DHFR-TS has high homology to TS sequences from other species, expression of this protein fragment failed to yield active TS enzyme, and it failed to complement TS(-) Escherichia coli. Unexpectedly, even partial 5'-deletion of full-length DHFR-TS gene abolished TS function on the 3'-end. Thus, it was hypothesized that the amino end of the bifunctional parasite protein plays an important role in TS function. When the 27-kDa amino domain (DHFR) was provided in trans, a previously inactive 40-kDa carboxyl-domain from malarial DHFR-TS regained its TS function. Physical characterization of the "split enzymes" revealed that the 27- and the 40-kDa fragments of DHFR-TS had reassembled into a 140-kDa hybrid complex. Thus, in malarial DHFR-TS, there are physical interactions between the DHFR domain and the TS domain, and these interactions are necessary to obtain a catalytically active TS. Interference with these essential protein-protein interactions could lead to new selective strategies to treat malaria resistant to traditional DHFR-TS inhibitors.
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PMID:Essential protein-protein interactions between Plasmodium falciparum thymidylate synthase and dihydrofolate reductase domains. 1060 39

Protozoan of the phylum Apicomplexa are of high medical and veterinary importance, causing diseases such as malaria, toxoplasmosis and cryptosporidiosis. Invasive stages of apicomplexans possess organelles named micronemes, which are involved in the invasion process. We have recently characterized a protein in micronemes of Toxoplasma gondii, TgMIC3, which possess adhesive properties to host cell surface. Immunofluorescence analysis of T. gondii tachyzoite invasion showed that TgMIC3 is exocytosed and re-localised on the surface of the parasite during invasion. By being able to bind both the putative host cells and the parasites, TgMIC3 could be involved in invasion by acting as a bridge between the parasite and the host cell. Gene sequence analysis of TgMIC3 has revealed 5 partially overlapping EGF-like domains and a lectin binding-like domain, which can be involved in protein-protein or protein-carbohydrate interactions respectively. TgMIC3 is a homodimer synthetized with a N-terminal propeptide that is cleaved during trafficking to the organelle, presumably in the trans-Golgi network. The processing involves a serine protease and is required for correct binding function of TgMIC3. The exact role of this propeptide remains unexplained. It may be involved in the targetting of the protein to the micronemes by masking the region involved in interaction with membranes to avoid binding of the protein in the trafficking pathway.
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PMID:[Identification and molecular characterization of a Toxoplasma gondii microneme]. 1178 21

The ornithine decarboxylase (ODC) component of the bifunctional S-adenosylmethionine decarboxylase/ornithine decarboxylase enzyme (PfAdoMetDC-ODC) of Plasmodium falciparum was modeled on the crystal structure of the Trypanosoma brucei enzyme. The homology model predicts a doughnut-shaped active homodimer that associates in a head-to-tail manner. The monomers contain two distinct domains, an N-terminal alpha/beta-barrel and a C-terminal modified Greek-key domain. These domains are structurally conserved between eukaryotic ODC enzymes and are preserved in distant analogs such as alanine racemase and triosephosphate isomerase-like proteins. Superimposition of the PfODC model on the crystal structure of the human enzyme indicates a significant degree of deviation in the carbon alpha-backbone of the solvent accessible loops. The surface locality of the ab initio modeled 38 amino acid parasite-specific insert suggests a role in the stabilization of the large bifunctional protein complex. The active site pockets of PfODC at the interface between the monomers appear to be conserved regarding the binding sites of the cofactor and substrate, but each contains five additional malaria-specific residues. The predicted PfODC homology model is consistent with mutagenesis results and biochemical studies concerning the active site residues and areas involved in stabilizing the dimeric form of the protein. Two competitive inhibitors of PfODC could be shown to interact with several parasite-specific residues in comparison with their interaction with the human ODC. The PfODC homology model contributes toward a structure-based approach for the design of novel malaria-specific inhibitors.
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PMID:Comparative properties of a three-dimensional model of Plasmodium falciparum ornithine decarboxylase. 1255 88

The malaria parasite proliferates in the bloodstream of its vertebrate host by invading and replicating within erythrocytes. To achieve successful invasion, a number of discrete and essential events need to take place at the parasite-host cell interface. Erythrocyte-binding antigen 175 (EBA-175) is a member of a family of Plasmodium falciparum erythrocyte-binding proteins involved in the formation of a tight junction, a necessary step in invasion. Here we present the crystal structure of EBA-175 region VI (rVI), a cysteine-rich domain that is highly conserved within the protein family and is essential for EBA-175 trafficking. The structure was solved by selenomethionine single-wavelength anomalous dispersion at 1.8 A resolution. It reveals a homodimer, containing in each subunit a compact five-alpha-helix core that is stabilized by four conserved disulfide bridges. rVI adopts a novel fold that is likely conserved across the protein family, indicating a conserved function. It shows no similarity to the Duffy-binding-like domains of EBA-175 involved in erythrocyte binding, indicating a distinct role. Remarkably, rVI possesses structural features related to the KIX-binding domain of the coactivator CREB-binding protein, supporting the binding and trafficking roles that have been ascribed to it and providing a rational basis for further experimental investigation of its function.
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PMID:Malarial EBA-175 region VI crystallographic structure reveals a KIX-like binding interface. 1803 13

Molecular mechanisms underlying the interaction between malarial sporozoites and putative receptor(s) on the salivary glands of Anopheles gambiae remain largely unknown. In previous studies, a salivary gland protein of ~100 kDa was identified as a putative target based on recognition of the protein by a monoclonal antibody (mAb) 2A3 that caused a >/= 70% reduction in the average number of sporozoites per infected salivary gland when fed to mosquitoes. Using affinity purification we purified the target of this mAb from extracts of female A. gambiae salivary glands and it was found to be a novel protein by tandem mass spectrometric analysis. Biochemical and molecular characterization of the 100 kDa protein showed that this molecule, designated Saglin, exists as a disulphide-bonded homodimer of 50 kDa subunits. The ability to form homodimers was retained even in the recombinant Saglin expressed in mammalian cells (HEK293). The amino acid sequence of Saglin contains a signal peptide suggesting that Saglin is a secreted protein. If Saglin is indeed involved in the process of invasion of A. gambiae salivary glands by sporozoites of Plasmodium, it could provide a novel target for future investigations aimed at interruption of malaria transmission.
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PMID:Identification and molecular characterization of a novel protein Saglin as a target of monoclonal antibodies affecting salivary gland infectivity of Plasmodium sporozoites. 1809

Thioredoxin reductase (TrxR) catalyzes the reduction of thioredoxin (Trx) by NADPH. Like other members of the pyridine nucleotide-disulfide oxidoreductase enzyme family, the enzyme from Drosophila melanogaster is a homodimer, and each catalytically active unit consists of three redox centers: FAD and an N-terminal Cys-57/Cys-62 redox-active disulfide from one monomer and a Cys-489'/Cys-490' C-terminal redox-active disulfide from the second monomer. Because dipteran insects such as D. melanogaster lack glutathione reductase, thioredoxin reductase (DmTrxR) is particularly important; in addition to its normal functions, it also reduces GSSG for antioxidant protection. DmTrxR, used as a model for the enzyme from the malaria vector, Anopheles gambiae, has been shown to cycle in catalysis between the two-electron and four-electron reduced states, EH2 and EH4 [Bauer, H. et al. (2003) J. Biol. Chem. 278, 33020-33028]. His-464' acts as an acid-base catalyst of the dithiol-disulfide interchange reactions required in catalysis. The H464'Q enzyme has only 2% of the wild-type activity, emphasizing the importance of this residue. The pH dependence of Vmax for wild-type DmTrxR has pKa values of 6.4 and 9.3 on the DmTrxR-DmTrx-2 complex, whereas H464'Q DmTrxR only has an observable pKa at 6.4, indicating that the pKa at pH 9.3 is contributed mainly by His-464'. The pKa at pH 6.4 has been assigned to Cys-57 and Cys-490'; the thiolate on Cys-490' is the nucleophile in the reduction of Trx. In contrast to wild-type DmTrxR, H464'Q DmTrxR does not stabilize a thiolate-FAD charge-transfer complex in the presence of excess NADPH. The rates of steps in both the reductive and the oxidative half-reactions are markedly diminished in H464'Q DmTrxR as compared to those of wild-type enzyme, indicating that His-464' is involved in both half-reactions.
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PMID:Acid-base catalysis in the mechanism of thioredoxin reductase from Drosophila melanogaster. 1821 Nov 1


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