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)

Malaria-infected red cells and free parasites have limited capabilities for the biosynthesis of amino acids. Therefore, the principal amino acid sources for parasite protein synthesis are the plasma free amino acids and host cell haemoglobin. Infected cells and plasmodia incorporate exogenously supplied amino acids into protein. However, the hypothesis that amino acid utilization (from an external source) is related to availability of that amino acid in haemoglobin is without universal support: it is true for isoleucine and for Plasmodium knowlesi and P. falciparum, but not for methionine, cysteine, and other amino acids, and it does not apply to P. lophurae. More by default than by direct evidence, haemoglobin is believed to be the main amino acid reservoir available to the intraerythrocytic plasmodium. Haemoglobin, ingested via the cytostome, is held in food vacuoles where auto-oxidation takes place. As a consequence, haem is released and accumulates in the vacuole as particulate haemozoin (= malaria pigment). Current evidence favours the view that haemozoin is mainly haematin. Acid and alkaline proteases (identified in crude extracts from mammalian and avian malarias) are presumably secreted directly into the food vacuole. They then digest the denatured globin and the resulting amino acids are incorporated into parasite protein. Cell-free protein synthesizing systems have been developed using P. knowlesi and P. lophurae ribosomes. In the main these systems are typically eukaryotic.Studies of amino acid metabolism are exceedingly limited. Arginine, lysine, methionine, and proline are incorporated into protein, whereas glutamic acid is metabolized via an NADP-specific glutamic dehydrogenase. Glutamate oxidation generates NADPH and auxiliary energy (in the form of alpha-ketoglutarate). The role of red cell glutathione in the economy of the parasite remains obscure. Important goals for future research should be: quantitative assessment of the relative importance of amino acid sources for parasite protein synthesis; purification and characterization of plasmodial proteinases; and in vitro translation of parasite messenger RNA.
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PMID:Amino acid metabolism and protein synthesis in malarial parasites. 33 83

Aflatoxin-albumin adduct levels were measured in serum samples obtained from a group of Gambian children. The relationships between exposure to aflatoxin and the prevalence of malaria, between exposure and humoral and cellular responses in vitro to defined malaria antigens and, amongst children with evidence of exposure to hepatitis B infection, between aflatoxin and carriage of the hepatitis B surface antigen (HBsAg), were assessed. Aflatoxin-albumin adduct was found in nearly all serum samples collected during a survey performed at the end of the dry season and levels of adduct were generally high (up to 720 pg aflatoxin-lysine equivalent/mg albumin). Higher levels of aflatoxin-albumin adduct were detected in Wollof children than in children of other ethnic groups and marked variation in mean adduct levels between villages was observed. Aflatoxin-albumin adduct levels were higher in children who were HbsAg positive and in children with Plasmodium falciparum parasitaemia than in controls. However, levels of adduct had no consistent effect on either malaria-specific antibody responses, lymphoproliferative responses in vitro, or morbidity from malaria during the subsequent rainy season. Much lower levels of aflatoxin-albumin adduct were detected in repeat samples obtained at the end of the rainy season. There was poor correlation between dry and rainy season levels of adduct in individual children. We have shown that Gambian children are exposed to high levels of aflatoxin. The seasonal variation of aflatoxin-albumin adduct and marked fluctuation of adduct with time in individual children need to be considered in the future planning of epidemiological studies using this marker of exposure.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Aflatoxin exposure, malaria and hepatitis B infection in rural Gambian children. 144 Aug 26

Hereditary ovalocytosis is common in some areas of Melanesia and South East Asia where malaria is endemic. These red cells resist invasion by malarial parasites in vitro and ovalocytic individuals are less parasitized than normal. This has been attributed to the greater rigidity of ovalocytic red cells. It has been suggested that South East Asian ovalocytosis results from the heterozygous presence of an altered membrane anion transporter (band 3). We have used the polymerase chain reaction to clone the abnormal band 3 complementary DNA from an ovalocytic of Indian origin and found two changes from the normal protein: a point mutation (Lys 56----Glu) and the deletion of the sequence AFSPQVLAA (residues 400-408), but no evidence for an N-terminal extension. The deletion is also found in the abnormal band 3 of South East Asian ovalocytes and seems to be responsible for the unusual properties of the ovalocytic red cell. We show here that the membrane domain of the abnormal ovalocyte band 3 has a substantially altered structure and that the protein is defective in anion transport activity. The changed transport properties of the red cells may have a role in the reduced parasitaemia of ovalocytic individuals.
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PMID:Defective anion transport activity of the abnormal band 3 in hereditary ovalocytic red blood cells. 153 63

The KEK (Lysine-Glutamic acid-Lysine) motif is frequently found in the primary structure of certain malaria proteins involved in invasion, and plays an important role in the interaction of these proteins with the erythrocyte. This motif is contained in a peptide which forms part of the polymeric synthetic malaria vaccine SPf 66, currently undergoing extensive human trials. Analysis of the antibody titres against the subunit peptides that comprise this vaccine has shown that protection is associated with high titres to the KEK-containing peptide. In this paper we examine the fine recognition of this motif by polyclonal sera from protected vaccinated individuals, demonstrating the critical role played by the interacting ion pair formed between the amino terminal lysine (K) and glutamic acid (E), which act as contact residues for an important proportion of the antibody population directed against this vaccine. This ion pair in the KEK motif constitutes perhaps one of the most important malaria epitopes involved in protection, and could explain the mechanism through which protective immunity is acquired.
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PMID:In human malaria protective antibodies are directed mainly against the Lys-Glu ion pair within the Lys-Glu-Lys motif of the synthetic vaccine SPf 66. 155 26

The C-terminal domain (CTD) of RNA polymerase II (RNAP) has an essential function in the regulation of transcription. The CTD of the human malaria parasite, Plasmodium falciparum, differs dramatically from that of higher eukaryotes. To determine whether this is a general feature of malarial parasites, we have analysed the CTD of the distantly related rodent malaria parasite P.berghei. The CTDs of the two parasites enzymes are very similar in amino acid composition and contain the basic structure of most eukaryotic CTDs, which is a tandem repeat of a heptapeptide (SPTSPSY). The CTD of P.berghei differs, however, in three aspects from the CTD of P.falciparum and other eukaryotes. First, both domains show a divergence from the consensus sequence at position 6 of the heptapeptide repeat. The Ser6 is always substituted, with a bias for lysine. The latter substitution might increase the binding efficiency to the DNA template. Second, the rodent and human malarial CTDs contain a 3' extension of, respectively, 66 or 67 amino acid residues. This tail-piece is unique among eukaryotes. Third, the enlargement of the CTD of the human parasite by six heptapeptide repeats is most likely generated by a recent amplification of a specific repeat unit.
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PMID:The C-terminal domain of RNA polymerase II of the malaria parasite Plasmodium berghei. 184 Apr 89

The major repetitive epitopes of the surface circumsporozoite (CS) protein of malaria sporozoites represent candidates for the development of subunit vaccines against malaria. However, previous experimental work has shown that repetitive peptides from the CS proteins of Plasmodium falciparum, P. vivax, P. yoelii and P. berghei are immunogenic only in mice with the H-2b or H-2k haplotype. This led to the conclusion that strong T helper epitopes from the non-repetitive CS sequences were required in the design of sporozoite vaccines. In the present study, we investigated the immunogenicity in mice of a octa-branched multiple antigen peptide (MAP) containing repeats of the CS protein of the human malaria parasite, P. malariae, [MAP8(NAAG)6], and found that mice with an H-2b, H-2d, H-2k, H-2f, H-2q, and H-2s haplotype produced anti-peptide antibodies after immunization and that only H-2r mice were nonresponsive. This antibody response, not induced in athymic H-2b nu/nu mice, was directed against the (NAAG) sequence, but not against the lysine core of the MAP construct. Finally, when covalently linked to a synthetic polymer of the repetitive (NANP) sequence of the P. falciparum CS protein, [MAP8(NAAG)6] behaved as a carrier molecule for the production of anti-(NANP)n antibodies in H-2d and H-2k mice, genetically nonresponder to the (NANP)n sequence. Should this wide immunogenicity of the P. malariae CS (NAAG) repetitive sequence also apply to humans, it might be considered for the design of multivalent subunit malaria vaccines.
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PMID:A multiple antigen peptide from the repetitive sequence of the Plasmodium malariae circumsporozoite protein induces a specific antibody response in mice of various H-2 haplotypes. 220 49

The transbilayer distribution of glycerophospholipids in the plasma membrane of Plasmodium knowlesi infected erythrocytes was studied by using lysine-116-epsilon-N-palmitoyl amidinated pancreatic phospholipase A2. As a consequence of its superior membrane penetrating capacities, this modified enzyme rapidly degrades its substrates in the outer membrane leaflet of intact erythrocytes, a property that makes the enzyme an excellent tool to study the malaria parasitized red cell. The modified phospholipase A2 caused a nonlytic hydrolysis of up to 12-15% of the phosphatidylethanolamine and none of the phosphatidylserine in the red cell membrane, irrespective of whether the cells harboured trophozoite and schizont stages of parasites or no parasites at all. The absence of phosphatidylserine at the exterior surface of Plasmodium infected erythrocytes was confirmed by applying the prothrombinase assay on Plasmodium falciparum infected human erythrocytes. Consequently, the results from these and previous studies indicate that the plasma membrane of Plasmodium infected erythrocytes exhibit a normal transbilayer phospholipid asymmetry.
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PMID:Phospholipid asymmetry in the plasma membrane of malaria infected erythrocytes. 234 3

A clone encoding a recombinant protein which reacted strongly with human antibodies from a donor clinically immune to malaria, was isolated from a genomic Plasmodium falciparum library. Mice injected with this protein, designated 10b, produced antibodies which reacted with all developmental stages of erythrocytic asexual parasites in indirect immunofluorescence. In immunoblotting, the same antibodies recognized two P. falciparum polypeptides of 36 kDa and 33 kDa. Of three monoclonal antibodies raised against the 10b recombinant protein, two inhibited parasite reinvasion of erythrocytes in an isolate specific manner. Surprisingly, however, the third was found to significantly enhance reinvasion of erythrocytes and also to induce a more rapid maturation of intraerythrocytic parasites in all isolates tested. Nucleotide sequence analysis of the 1124 bp insert revealed that it encodes a protein which consists of 30% asparagine and contains three asparagine rich, imperfect tandem repeats: Lys-Lys-Asn-Asn (3x), Met-Asn-His/Gln-Pro-Asn-Asn (14x), and Lys-Asn-Asn-Asn-Asn (7x).
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PMID:Enhancement or inhibition of Plasmodium falciparum erythrocyte reinvasion in vitro by antibodies to an asparagine rich protein. 246 5

To investigate the genetic basis of drug resistance in human malaria parasites, we have sequenced the entire dihydrofolate reductase thymidylate synthetase DHFR-TS bifunctional gene from the highly pyrimethamine-resistant K1 isolate of Plasmodium falciparum. The protein is predicted to consist of 607 amino acids (aa), (71,685 Da), with an N-terminal methionine encoded by the second start codon of the open reading frame. Compared to the sequence from drug-sensitive parasites, there are two nucleotide changes in the coding region which bring about a substitution of Arg for Cys at aa position 59 and Asn for Thr at aa position 108. Both changes occur in regions of the DHFR domain involved in inhibitor and cofactor binding and are hence strongly implicated in drug resistance. The gene is present as a single copy in both K1 and drug-sensitive FCR3 isolates, and is assigned to chromosome 4. Codon usage follows the pattern observed in that of malarial surface antigen genes, with the exception fo codons corresponding to Val and Pro. The Asn and Lys contents of the predicted protein are exceptionally high, these residues being particularly concentrated in the DHFR and junction domains.
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PMID:Characterisation of the dihydrofolate reductase-thymidylate synthetase gene from human malaria parasites highly resistant to pyrimethamine. 266 50

We have statistically analysed the distribution of nucleotides and dinucleotides in 21 genes of the 81% A + T-rich human malaria parasite Plasmodium falciparum. The mRNA-synonymous strands of this protozoan show in general a marked excess of purines over pyrimidines, correlated with abnormally high levels of Lys and Glu. We have used the large differences in base composition between coding and non-coding regions to estimate that the parasite possesses in the range of 2700-5400 genes. The dinucleotide preference patterns are compared with consensus patterns derived from other organisms [Nussinov, Nucl. Acids Res. 12 (1984) 1749-1763]. Patterns in the coding regions surprisingly resemble those of higher, rather than lower eukaryotes, particularly with respect to TG elevation and CG suppression. The latter is correlated with an abnormally low level of Arg in these parasites. In the non-coding regions, the four dinucleotides made up of C and/or G are found with significantly higher frequencies than expected (approx. 50-150%), specifically to the 5' side of the coding regions. The possible role of these dinucleotides in control sequences is discussed.
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PMID:Anomalous dinucleotide frequencies in both coding and non-coding regions from the genome of the human malaria parasite Plasmodium falciparum. 332 56


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