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 efficacy of sulfadoxine/pyrimethamine (S/P) in treatment of uncomplicated falciparum malaria in Africa is increasingly compromised by development of resistance. The occurrence of active site mutations in the Plasmodium falciparum gene sequences coding for dihydrofolate reductase (DHFR) and dihydropteroate synthetase (DHPS) is known to confer resistance to pyrimethamine and sulfadoxine. This study investigated the occurrence of these mutations in infected blood samples taken from Ugandan children before treatment with S/P and their relationship to parasite breakthrough by day 7. The results confirm the occurrence of mutations in DHFR and DHPS that were significantly selected under S/P pressure at day 7: a combination of alleles 51-isoleucine and 108-asparagine in DHFR, and 436-serine, 437-alanine, 540-lysine and 581-alanine in DHPS, appears to play a major role in the development of in vivo resistance in P. falciparum strains against S/P. Therefore, earlier results derived from isolates from hyperendemic areas in Tanzania were confirmed by this investigation.
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PMID:Plasmodium falciparum resistance to sulfadoxine/pyrimethamine in Uganda: correlation with polymorphisms in the dihydrofolate reductase and dihydropteroate synthetase genes. 1049 91

Cytidine diphosphate-diacylglycerol (CDP-DAG), an obligatory intermediate compound in the biosynthesis of the major anionic and zwitterionic phospholipids, is synthesized by CDP-DAG synthase (CDS). The gene encoding CDS was isolated from the human malaria parasite Plasmodium falciparum, based on sequence conservation to CDS from other organisms. The P. falciparum gene is located as a single copy on chromosome 14. The open reading frame (ORF) of PfCDS gene encodes a putative protein of 667 amino acids and 78 kDa. Only the C-terminal 422 amino acids share 40% homology with eukaryotic CDSs. The very long and non-conserved N-terminal region of 245 amino acids is hydrophilic and contains asparagine-rich and repetitive sequences. Two mRNA of 3.5 and 4 kb were detected. Transcription is developmentally regulated during the asexual intraerythrocytic cycle, being the weakest in the ring-stage. PfCDS enzyme activities in infected erythrocytes correlates with the transcription pattern, consistent with an increased synthesis of phospholipids in trophozoites and schizonts. Antisera raised against two synthetic peptides from the C-terminal region of PfCDS detected a single protein of 51 kDa in Western blot analysis, specific for parasitized erythrocytes. A protein of 28 kDa was recognized by an antiserum against an N-terminal peptide, indicating that PfCDS is proteolytically processed. Expression of 51- and 28-kDa proteins was developmentally regulated similar to regulation of the transcripts and the enzyme activity. The conserved C-terminal region of PfCDS, cloned into a eukaryote expression vector and transfected in COS-7 cells, showed a two-fold increase CDP-DAG synthase activities, indicating that the isolated gene most likely encoded the P. falciparum CDS enzyme.
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PMID:Characterization of Plasmodium falciparum CDP-diacylglycerol synthase, a proteolytically cleaved enzyme. 1098 48

Samples of three pyrimethamine-sensitive clones of Plasmodium falciparum were grown for periods of 22-46 weeks in media containing stepwise increases in pyrimethamine concentrations and were seen to develop up to 1000-fold increases in resistance to the drug. With clone T9/94RC17, the dihydrofolate reductase (DHFR) gene was sequenced from 10 uncloned populations and 29 pure clones, all having increased resistance to pyrimethamine, and these sequences were compared with the sequence of the original pyrimethamine-sensitive clone. No changes in amino acid sequence were found to have occurred. Some resistant clones obtained by this method were then examined by pulsed-field gel electrophoresis, and the results indicated that there had been an increase in the size of chromosome 4. This was confirmed by hybridization of Southern blots with a chromosome 4-specific probe, the vacuolar ATPase subunit B gene, and a probe to DHFR. Dot-blotting with an oligonucleotide probe to DHFR confirmed that there had been increases up to 44-fold in copy number of the DHFR gene in the resistant strains. Resistant clones obtained by this procedure were then grown in medium lacking pyrimethamine for a period of nearly 2 years, and reversion nearly to the level of pyrimethamine sensitivity of the original clone T9/94RC17 was found to occur after about 16 months. Correspondingly, the chromosome 4 of the reverted population reverted to a size like that of the original sensitive clone T9/94RC17. The procedure of growing parasites in stepwise increases of pyrimethamine concentration was repeated with two other pyrimethamine-sensitive clones: TM4CB8-2.2.3 and G112CB1.1. (The DHFR gene of these clones encodes serine at position 108, in place of threonine as in clone T9/94RC17, and it was thought that this difference might conceivably affect the rate of mutation to asparagine at this position). Clones TM4CB8-2.2.3 and G112CB1.1 also responded by developing gradually increased resistance to pyrimethamine. However, in clone TM4CB8-2.2.3 a single mutation from Ile to Met at position 164 in the DHFR gene sequence was identified, and in clone G112CB1.1 there was a single mutation from Ala to Ser at position 16, but no mutations at position 108 were obtained in any of the clones studied here. In addition, chromosome 4 of clone TM4CB8-2.2.3 increased in size, presumably due to amplification of the DHFR gene. No increase in size was seen in clone G112CB1.1. We conclude that whereas some mutations producing changes in the amino acid sequence of the DHFR molecule may occur occasionally in clones or populations of P. falciparum grown in vitro in the presence of pyrimethamine, amplification of the DHFR gene following adaptation to growth in medium containing pyrimethamine occurs as a regular feature. The bearing of these findings on the development of pyrimethamine-resistant forms of malaria parasites in endemic areas is discussed.
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PMID:Plasmodium falciparum: gene mutations and amplification of dihydrofolate reductase genes in parasites grown in vitro in presence of pyrimethamine. 1146 89

Studying 12 selected individuals from a malaria-endemic area in West Africa, 24 variants of the CD36 gene were found, 21 of them novel ones. These included three single-nucleotide substitutions causing non-conservative amino acid exchanges E123K, T174A, and I271T as well as a three base pair (bp) insertion resulting in the addition of an asparagine residue (N232-233ins). The E123K variant was located within the putative ligand-binding domain for oxidized low density lipoprotein, while the other substitutions resided outside any of the binding sites for reaction partners mapped on CD36 so far. Twelve single-nucleotide polymorphisms (SNPs) were identified in untranslated parts of the exons and in introns. Five additional SNPs were located in the promoter region whereby -144G-->T, -53G-->T, and -2A-->G alter putative binding sites for the transcription factors purine factor (PuF), phorbol ester-responsive element AP-2, and CCAAT/enhancer-binding protein. A G-->T exchange at position -50 appears to introduce a new recognition site for PuF. Calculations of nucleotide diversity revealed extraordinarily high numbers for all parts of the gene, which may, however, to some extent be due to the selection of individuals studied.
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PMID:Variability of the CD36 gene in West Africa. 1166 37

Adhesion molecules on endothelial cells are known to be important ligands for malaria infected red blood cells (PRBC) [Mol Biochem Parasitol, 76, (1996) 1], and may be involved in the pathogenic process of cerebral malaria (CM) which is the most serious complication of falciparum malaria, through enhancing micro embolism or sequestration in the capillaries of the brain. PECAM-1/CD31 is one of these candidate ligands and is coded by a polymorphic gene. Two hundred and ten Thai malaria patients (43 cerebral, 89 severe and 78 uncomplicated) were analyzed for their genetic polymorphism of CD31 to examine the clinical relationship between the disease and specific genotypes. Four alleles were defined 125 valine (V)-563 asparagine (N); 125V-563 serine (S); 125 leucine (L)-563N; and 125L-563S. We found that the frequency of the 125 V/V 563 N/N genotype was significantly high in CM patients as compared with severe cases without CM (P<0.01, OR=2.92), suggesting that this genotype is one of the risk factors for CM.
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PMID:Association of adhesion molecule PECAM-1/CD31 polymorphism with susceptibility to cerebral malaria in Thais. 1171 9

The malaria causing protozoan Plasmodium falciparum contains a vestigal, non-photosynthetic plastid, the apicoplast. Numerous proteins encoded by nuclear genes are targeted to the apicoplast courtesy of N-terminal extensions. With the impending sequence completion of an entire genome of the malaria parasite, it is important to have software tools in place for prediction of subcellular locations for all proteins. Apicoplast targeting signals are bipartite; containing a signal peptide and a transit peptide. Nuclear-encoded apicoplast protein precursors were analyzed for characteristic features by statistical methods, principal component analysis, self-organizing maps, and supervised neural networks. The transit peptide contains a net positive charge and is rich in asparagine, lysine, and isoleucine residues. A novel prediction system (PATS, predict apicoplast-targeted sequences) was developed based on various sequence features, yielding a Matthews correlation coefficient of 0.91 (97% correct predictions) in a 40-fold cross-validation study. This system predicted 22% apicoplast proteins of the 205 potential proteins on P. falciparum chromosome 2, and 21% of 243 chromosome 3 proteins. A combination of the PATS results with a signal peptide prediction yields 15% potentially nuclear-encoded apicoplast proteins on chromosomes 2 and 3. The prediction tool will advance P. falciparum genome analysis, and it might help to identify apicoplast proteins as drug targets for the development of novel anti-malaria agents.
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PMID:Deciphering apicoplast targeting signals--feature extraction from nuclear-encoded precursors of Plasmodium falciparum apicoplast proteins. 1173 14

A neural network approach for the prediction of mitochondrial transit peptides (mTPs) from the malaria-causing parasite Plasmodium falciparum is presented. Nuclear-encoded mitochondrial protein precursors of P. falciparum were analyzed by statistical methods, principal component analysis and supervised neural networks, and were compared to those of other eukaryotes. A distinct amino acid usage pattern has been found in protein encoding regions of P. falciparum: glycine, alanine, tryptophan and arginine are under-represented, whereas isoleucine, tyrosine, asparagine and lysine are over-represented compared to the SwissProt average. Similar patterns were observed in mTPs of P. falciparum. Using principal component analysis (PCA), mTPs from P. falciparum were shown to differ considerably from those of other organisms. A neural network system (PlasMit) for prediction of mTPs in P. falciparum sequences was developed, based on the relative amino acid frequency in the first 24 N-terminal amino acids, yielding a Matthews correlation coefficient of 0.74 (90% correct prediction) in a 20-fold cross-validation study. This system predicted 1177 (22%) mitochondrial genes, based on 5334 annotated genes in the P. falciparum genome. A second network with the same topology was trained to give more conservative estimate. This more stringent network yielded a Matthews correlation coefficient of 0.51 (84% correct prediction) in a 10-fold cross-validation study. It predicted 381 (7.1%) mitochondrial genes, based on 5334 annotated genes in the P. falciparum genome.
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PMID:Properties and prediction of mitochondrial transit peptides from Plasmodium falciparum. 1459 65

The 19 kDa C-terminal fragment of the malaria parasite merozoite surface protein 1 (MSP1(19)) is a leading malaria vaccine candidate. In rodents, high antibody levels to this protein confer protective immunity, and can be generated by immunization with the antigen in adjuvants. In natural human infections, however, MSP1(19)-specific antibody responses can be short-lived and comparatively low, despite repeated exposure to infection. The tightly folded structure of MSP1(19) is stabilized by five or six disulfide bonds. These bonds impede antigen processing and, thereby, may affect the generation of CD4+ T cells providing help for B cells. Asparagine endopeptidase could digest unfolded, but not native MSP1(19) in vitro. Immunization with unfolded MSP1(19) resulted in a faster antibody response, and a combination of unfolded and native MSP1(19) increased antibody responses to the native form. Immunization with either form of the antigen activated similar numbers of CD4+ T cells, but, unlike the antibody response, CD4+ T cells immunized with one form of MSP119 were able to respond in vitro to the other form of the protein. Although the reduced form of MSP1(19) does not induce protective antibodies, our data suggest that inclusion of unfolded protein may improve the efficacy of MSP1(19) as a vaccine.
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PMID:Disulfide bonds in merozoite surface protein 1 of the malaria parasite impede efficient antigen processing and affect the in vivo antibody response. 1499 93

Protective devices against vectors are used by travelers in malaria-endemic areas but their efficacy for protection against mosquitoes has rarely been evaluated. The level of exposure to malaria transmission of 205 soldiers deployed in Africa and the efficacy of their anti-vector prophylaxis was evaluated by comparison of their IgM and IgG responses against five pre-erythrocytic Plasmodium falciparum antigens (circumsporozoite protein, sporozoite threonine- and asparagine-rich protein, sporozoite- and liver-stage antigen, liver stage antigen 1, and SR11.1) before and at the end of their deployment, and three months after returning to France for 106 of these soldiers. The immune responses increased significantly during the mission in 35% (95% confidence interval = 28-42%) of the individuals. The permanent use of insecticide-treated bed nets and long-sleeve battle dress at night were associated with protective efficacy. The analysis of these antibody responses was sensitive enough to evaluate exposure to malaria transmission and the efficacy of anti-vector devices in travelers using antimalarial chemoprophylaxis.
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PMID:Antibody responses to several malaria pre-erythrocytic antigens as a marker of malaria exposure among travelers. 1676 May 7

Pyrimethamine analogs were examined as potential agents against vivax malaria using a bacterial surrogate system carrying Plasmodium vivax dihydrofolate reductase-thymidylate synthase (PvDHFR-TS), in which the PvDHFR complemented chemically knocked out host dihydrofolate reductase. The system was initially tested with P. falciparum dihydrofolate reductase-thymidylate synthase and was found to have good correlation with the parasite-based system. The 50% inhibitory concentrations derived from PvDHFR-TS-dependent bacteria were correlated with their corresponding inhibition constants (Ki) from an enzyme inhibition assay, pointing to the likelihood that the potent enzyme inhibitors will also have potent antimalarial activities. Active compounds against both wild-type and S58R S117N (SP21) double-mutant P. vivax include analogs with structures which can avert a steric clash with the asparagine (S117N) side chain of the mutant, similar to those found for homologous Plasmodium falciparum mutants, raising the possibility that the same compounds can be developed against both types of antifolate-resistant malaria. This rapid and convenient drug screening system should be useful for development of new antifolates against P. vivax, for which a continuous culture system is not yet available.
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PMID:Evaluation of the activities of pyrimethamine analogs against Plasmodium vivax and Plasmodium falciparum dihydrofolate reductase-thymidylate synthase using in vitro enzyme inhibition and bacterial complementation assays. 1695 16


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