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)

(E)-4-Hydroxy-3-methylbut-2-enyl diphosphate synthase (GcpE), which catalyzes the conversion of 2-C-methyl-D-erythritol cyclodiphosphate (MEcPP) into (E)-4-hydroxy-3-methylbut-2-enyl diphosphate (HMBPP), is an essential enzyme of the non-mevalonate (2-C-methyl-D-erythritol-4-phosphate (MEP)) pathway for isoprenoid biosynthesis. The terminal steps of the MEP pathway are still not fully understood, although this pathway is necessary for survival in various organisms such as cyanobacteria, plastids of algae and higher plants, and the apicoplast of human malaria parasites. To determine the efficient redox partner for thermophilic cyanobacterial GcpE, We have expressed the gcpE and petF genes in Escherichia coli and studied the protein-protein interaction of GcpE protein with ferredoxin I (PetF) from the thermophilic cyanobacterium Thermosynechococcus elongatus BP-1. Recombinant GcpE protein was purified by an N-terminal His(6) tag and reconstituted as a [4Fe-4S](2+) metalloprotein. GcpE was shown to interact strongly with PetF via the bacterial two-hybrid system designed to detect protein-protein interactions. Moreover, a direct protein-protein interaction between PetF and GcpE was confirmed in an in vitro glutathione S-transferase (GST) pull-down assay. To investigate electron transfer activity from PetF to GcpE, we also constructed a NADPH-dependent reducing shuttle system with purified recombinant ferredoxin-NADP(+) oxidoreductase (PetH) and PetF. The result demonstrated that PetF has the ability to transfer electrons to GcpE. Thus, the combined data provide the first evidence that GcpE is a ferredoxin-dependent enzyme in T. elongatus BP-1.
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PMID:Cyanobacterial non-mevalonate pathway: (E)-4-hydroxy-3-methylbut-2-enyl diphosphate synthase interacts with ferredoxin in Thermosynechococcus elongatus BP-1. 1579 53

Glutaredoxin-like proteins form a new subgroup of glutaredoxins with a serine replacing the second cysteine in the CxxC-motif of the active site. Yeast Grx5 is the only glutaredoxin-like protein studied biochemically so far. We identified and cloned three genes encoding glutaredoxin-like proteins from the malaria parasite Plasmodium falciparum (Pf Glp1, Pf Glp2, and Pf Glp3) containing a conserved cysteine in the CGFS-, CKFS-, and CKYS-motif, respectively. Here, we describe biochemical properties of Pf Glp1 and Pf Glp2. Cys 99, the only cysteine residue in Pf Glp1, has a pK(a) value as low as 5.5 and is able to mediate covalent homodimerization. Monomeric and dimeric Pf Glp1 react with GSSG and GSH, respectively. Pf Glp2 is monomeric and both of its cysteine residues can be glutathionylated. Molecular models reveal a thioredoxin fold for the putative C-terminal domain of Pf Glp1, Pf Glp2, and Pf Glp3, as well as conserved residues presumably required for glutathione binding. However, Pf Glp1 and Pf Glp2 neither possess activity in a classical glutaredoxin assay nor display activity as glutathione peroxidase or glutathione S-transferase. Mutation of Ser 102 in the CGFS-motif of Pf Glp1 to cysteine did not generate glutaredoxin activity either. We conclude that, despite their ability to react with glutathione, glutaredoxin-like proteins are a mechanistically and functionally heterogeneous group with only little similarities to canonical glutaredoxins.
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PMID:Plasmodium falciparum glutaredoxin-like proteins. 1584 45

Antibodies that bind to Fc receptors and activate complement are implicated in the efficient control of pathogens, but the processes that regulate their induction are still not well understood. To investigate antigen-dependent factors that regulate class switching, we have developed an in vivo model of class switching to immunoglobulin G2b (IgG2b) using the malaria antigen Plasmodium falciparum merozoite surface protein 2 (MSP2). C57BL/6 mice were immunized with recombinant proteins representing discrete domains of MSP2, and a T-cell epitope (C8) was identified within the conserved C terminus of the protein that preferentially induces IgG2b antibodies. The ability of C8 to induce IgG2b is ablated in both homozygous gamma interferon-negative and interleukin 10-negative mice. The IgG2b-inducing properties of C8 override the IgG1-inducing properties of both the fusion protein partner, glutathione S-transferase, and the adjuvant. Furthermore, when attached to other proteins that normally induce IgG1 responses, C8 induces a switch to IgG2b secretion. This is the first description of a defined T-cell epitope that drives specific IgG2b subclass switching, and our data offer proof of the concept that chimeric vaccines incorporating specific T-cell "switch epitopes" might be used to enhance qualitative aspects of the antibody response.
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PMID:Epitope-specific regulation of immunoglobulin class switching in mice immunized with malarial merozoite surface proteins. 1629 6

Malaria represents an emerging disease because of increasing parasite resistance against available drugs and because of increasing geographical distribution of the causative agent, Plasmodium falciparum. The complete genome of Plasmodium was sequenced recently, revealing that the parasite harbors only one glutathione S-transferase (PfGST). This observation was of particular interest: First, certain antimalarial drugs such as chloroquine and methylene blue presumably influence the glutathione metabolism in which PfGST is involved. Second, PfGST might play a significant role in drug resistance. PfGST was studied in parasite extracts and as recombinant protein, and its x-ray structure has been solved. The available data indicate that the homodimeric PfGST cannot be assigned to any of the previously known GST classes. PfGST exhibits significant structural differences to human GSTs, particularly at the so-called hydrophobic binding pocket (H-site) where the second substrate binds. Inhibition of PfGST is expected to act at different vulnerable metabolic sites of the parasite in parallel; it is likely to disturb GSH-dependent detoxification processes, to increase the levels of cytotoxic peroxides, and possibly to increase the concentration of toxic hemin. In this chapter, we summarize the current knowledge on PfGST, including aspects of structure, function, and future drug development.
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PMID:Glutathione S-transferase from malarial parasites: structural and functional aspects. 1639 90

A large scale microarray (20k MMC1) from the African malaria vector Anopheles gambiae was used to monitor gene expression in insecticide resistant and susceptible strains of the Asian mosquito Anopheles stephensi. Heterologous hybridization at slightly reduced stringency yielded approximately 7000 significant signals. Thirty-six putative genes were differentially transcribed between the pyrethroid-resistant (DUB-R) and the susceptible (BEECH) strains. The expression profiles of selected transcripts were verified by real-time PCR. A gene putatively involved in the thickening of the adult cuticle showed the most striking up-regulation in DUB-R. A more specialized microarray containing 231 An. gambiae genes putatively involved in insecticide detoxification was used to further analyse classical insecticide resistance genes. Three glutathione S-transferase (GST) transcripts, one esterase and a cytochrome P450 were up-regulated in the resistant strain, while two peroxidases were down-regulated.
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PMID:Transcriptional analysis of insecticide resistance in Anopheles stephensi using cross-species microarray hybridization. 1743 71

Malaria parasite glutathione S-transferases (GSTs) are postulated to be essential for parasite survival by protecting the parasite against oxidative stress and buffering the detoxification of heme-binding compounds; therefore, GSTs are considered potential targets for drug development. In this study, we identified a Plasmodium vivax gene encoding GST (PvGST) and characterized the biochemical properties of the recombinant enzyme. The PvGST contained 618 bp that encoded 205 amino acids and shared a significant degree of sequence identity with GSTs from other Plasmodium species. The recombinant homodimeric enzyme had an approximate molecular mass of 50kDa and exhibited GSH-conjugating and GSH-peroxidase activities towards various model substrates. The optimal pH for recombinant PvGST (rPvGST) activity was pH 8.0, and the enzyme was moderately unstable at 37 degrees C. The K(m) values of rPvGST with respect to GSH and CDNB were 0.17+/-0.09 and 2.1+/-0.4mM, respectively. The significant sequence homology and similar biochemical properties of PvGST and Plasmodium falciparum GST (PfGST) indicate that they may have similar molecular structures. This information may be useful for the design of specific inhibitors for plasmodial GSTs as potential antimalarial drugs.
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PMID:Plasmodium vivax: molecular cloning, expression and characterization of glutathione S-transferase. 1745 79

Cellular redox metabolism is considered to be involved in the pathophysiology of diseases caused by protozoal parasites such as Toxoplasma, Trypanosoma, Leishmania, and Plasmodia. Redox reactions furthermore are thought to play a major role in the action of and the resistance to some clinically used antiparasitic drugs. Interestingly, in malarial parasites, the antioxidant enzymes catalase and glutathione peroxidase are absent which indicates a crucial role of the thioredoxin system in redox control. Besides a glutathione peroxidase-like thioredoxin peroxidase and a glutathione S-transferase with slight peroxidase activity, Plasmodium falciparum (the causative agent of tropical malaria) possesses four classical peroxiredoxins: Two peroxiredoxins of the typical 2-Cys Prx class, one 1-Cys peroxiredoxin with homology to the atypical 2-Cys Prx class, and a peroxiredoxin of the 1-Cys Prx class have been identified and partially characterized In our article we give an introduction to redox-based drug development strategies against protozoal parasites and summarize the present knowledge on peroxiredoxin systems in Plasmodium.
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PMID:Peroxiredoxin systems of protozoal parasites. 1808 96

Spraying of agricultural crops with insecticides can select for resistance in nontarget insects and this may compromise the use of insecticides for the control of vector-borne diseases. The tolerance of the malaria vector, Anopheles arabiensis to deltamethrin was determined in a field population from a cotton-growing region of Northern Cameroon both prior to and midway through the 4-month period of insecticide application to the cotton crop. A 1.6-fold increase in the median knockdown time was observed. To determine whether this increased tolerance was associated with constitutively elevated levels of genes commonly associated with insecticide resistance, RNA was extracted from F1 progeny from family lines of field-caught mosquitoes and hybridized to the Anopheles gambiae detox chip. The experimental design avoided the confounding effects of colonization, and this study is the first to measure gene expression in the progeny of gravid, wild-caught mosquitoes. Several genes with antioxidant roles, including superoxide dismutases, a glutathione S-transferase and a thioredoxin-dependent peroxidase, and a cytochrome P450 showed elevated expression in mosquito families collected during the insecticide-spraying programme. These genes may constitute an important general defence mechanism against insecticides. Intriguingly, the levels of expression of these genes were strongly correlated suggesting a common regulatory mechanism.
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PMID:Pyrethroid tolerance is associated with elevated expression of antioxidants and agricultural practice in Anopheles arabiensis sampled from an area of cotton fields in Northern Cameroon. 1817 25

Artemether, artemether-lumefantrine, or coartem and halofantrine are alternative antimalarial drugs to chloroquine. Their efficacy and potential to delay drug resistance in falciparum malaria had led to their increased use. Although these drugs have proven to be well tolerated, there are adverse effects associated with them. This study was designed to examine the toxic potential of acute administration of these drugs in rats. Twenty-four rats were divided into four groups: group I (control) received distilled water; group II received artemether for 5 days with an initial dose of 3.2 g/kg body weight on day 1 and 1.6 mg/kg body weight on days 2-5; group III received coartem (27 mg/kg body weight/day) for 3 days, which was divided into two equal portions per day; and group IV received halofantrine (24 mg/kg body weight/day) in three equal portions. Administration of artemether, coartem and halofantrine caused significant decrease (P < 0.05) in reduced glutathione levels in the liver by 29%, 21% and 26%, respectively. In contrast, there were no significant differences (P > 0.05) in the kidney glutathione levels. Furthermore, artemether, coartem and halofantrine decreased the liver- and kidney-enzymatic antioxidant status of the animals. Precisely, artemether, coartem and halofantrine decreased liver superoxide dismutase and catalase activities by 45%, 50% and 57%; and 20%, 29% and 23%, respectively. While the kidney catalase activities were decreased by 41%, 28% and 30%, respectively, the drugs however did not produce significant effect (P > 0.05) on the kidney superoxide dismutase activities. In addition, artemether, coartem and halofantrine decreased the hepatic levels of glutathione S-transferase by 64%, 51% and 53%, respectively. Administration of artemether, coartem and halofantrine significantly increased (P < 0.05) liver and kidney lipid peroxidation levels by 67%, 50% and 81%; and 58%, 43% and 31%, respectively. This indicates that the liver is considerably more affected than the kidneys. Similarly, halofantrine treatment caused significant elevation (P < 0.05) in the levels of serum creatinine, aspartate and alanine aminotransferases and blood urea nitrogen by 73%, 66%, 61% and 63%, respectively. These data indicate that oral administration of artemether, coartem and halofantrine has adverse effects on both enzymic and non-enzymatic antioxidant status of the animals.
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PMID:Changes in antioxidant status and biochemical indices after acute administration of artemether, artemether-lumefantrine and halofantrine in rats. 1828 95

A glutathione S-transferase (GST) from the mosquito Aedes aegypti (aagste2), selected in the field as a major metabolic resistance enzyme for this parasite vector, was employed to produce a highly specific assay for the determination of DDT [1,1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene]. Detection is based on the pH change occurring in an appropriate buffer system by the concomitant release of H(+) during the aagste2-catalyzed dehydrochlorination reaction and is monitored potentiometrically or colorimetrically in the presence of a pH marker. The theoretical limit of detection (LOD) of the assay is 3.8 microg/ml, and the linear range of quantification is 12 to 250 microg/ml. The method does not recognize biologically inactive DDT analogues or major DDT photodegradants and breakdown molecules, and it is highly specific for the insecticidal p.p'DDT [1,1,1-trichloro-2,2-bis(p-chlorophenyl) ethane]. The biosensor was validated with a number of insecticide swabs from DDT-sprayed surfaces and found to be reproducible and reliable as compared with high-performance liquid chromatography (HPLC) (correlation coefficient R(2)=0.98). Given the current expansion of DDT residual sprayings in many regions of Africa as a key strategic intervention for malaria vector control, this simple assay to monitor DDT levels for vector control spraying programs could have an important impact on malaria control.
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PMID:A dehydrochlorinase-based pH change assay for determination of DDT in sprayed surfaces. 1842 89


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