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

Hereditary ovalocytes from a Mauritian subject are extremely rigid, with a shear elastic modulus about three times that of normal cells, and have increased resistance to invasion by the malaria parasite Plasmodium falciparum in vitro. The genetic anomaly resides in band 3; the protein gives rise to chymotryptic fragments with reduced mobility in SDS/polyacrylamide gel electrophoresis, but this is a result of anomalous binding of SDS and not a higher molecular weight. Analysis of the band 3 gene reveals (1) a point mutation (Lys56----Glu), which also occurs in a common asymptomatic band 3 (Memphis) variant and governs the electrophoretic properties, and (2) a deletion of nine amino acid residues, including a proline residue, encompassing the interface between the membrane-associated and the N-terminal cytoplasmic domains. The interaction of the mutant band 3 with ankyrin appears unperturbed. The fraction of band 3 capable of undergoing translation diffusion in the membrane is greatly reduced in the ovalocytes. Cells containing the asymptomatic band 3 variant were normal with respect to all the properties that we have studied. Possible mechanisms by which a structural change in band 3 at the membrane interface could regulate rigidity are examined.
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PMID:Basis of unique red cell membrane properties in hereditary ovalocytosis. 153 5

The effectiveness of synthetic vaccines is dependent upon the chance event that antibodies formed against largely disordered peptides can bind native protein surfaces which are often ordered. To improve on this situation, new methods are being developed for the conformational restriction of synthetic peptides. Cognate peptide sequences often form predictable secondary structures in proteins characterized by distinct hydrogen-bonding patterns. These weak hydrogen bonds have now been replaced with covalent mimics to conformationally restrict selected peptides to the Type 1 reverse turn and alpha helix. Potential uses for this chemistry are discussed in the context of malaria vaccines. The peptide component of a Plasmodium falciparum sporozoite vaccine, acetyl-(ASN-ALA-ASN-PRO)3-NH2 has been conformationally analysed using two-dimensional nuclear magnetic resonance spectroscopy. These studies are consistent with the formation of transiently ordered turnlike structures which provide a guide for the design and synthesis of a conformationally restricted synthetic vaccine. To assess the effects of conformational restriction and chemical modification on the sporozoite vaccine, ASN side-chains were linked around proline with ethylene bridges. Polyclonal antibodies to this shaped peptide show a strong cross-reaction with living sporozoites.
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PMID:The conformational restriction of synthetic vaccines for malaria. 209 82

Malaria continues to cause extensive morbidity and mortality in man. The exact number of individuals affected is not known. Estimates vary from 200 to 400 million, and more than one million die each year. Protective immunity against malaria can be obtained by vaccination with irradiated sporozoites. The protective antigens are polypeptides (circumsporozoite [CS] proteins) which cover the surface membrane of the parasite. CS proteins contain species-specific immunodominant epitopes, formed by tandem repeated sequences of amino acids. The dominant epitope of Plasmodium falciparum is represented in the synthetic peptide asparagine-alanine-asparagine-proline repeated in tandem three times; that is, (NANP)3. Monoclonal antibodies and most or all polyclonal human antibodies to P. falciparum sporozoites react with (NANP)3. Polyclonal antibodies raised against the synthetic peptide (NANP)3 react with the surface of the parasite and neutralize its infectivity. Since (NANP)3 repeats are present worldwide in CS proteins from P. falciparum, this epitope is a logical target for vaccine development.
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PMID:Experimental basis for the development of a synthetic vaccine against Plasmodium falciparum malaria sporozoites. 242 50

A major sporozoite surface antigen, the circumsporozoite protein, has been identified in all four malaria parasites affecting humans and in numerous species causing malaria in rodents and simians. The corresponding genes have been cloned and sequenced, and considerable similarities are apparent. An extensive central region of these proteins consists of tandemly repeated sequences of four to 16 amino acids. The sporozoite protein of Plasmodium falciparum has 37-41 repeats of four amino acids: NANP (asparagine-alanine-asparagine-proline). Most sera from people in endemic areas that react with sporozoites also recognize the dodecamer (NANP)3. Conjugated to a carrier, (NANP)3 is an excellent immunogen for rabbits and mice. NANP has recently served as the basis for two experimental malaria vaccines tested in volunteers. One of these vaccines, (NANP)32 tet32, was genetically engineered in Escherichia coli; the other consisted of the synthetic peptide (NANP)3 conjugated to tetanus toxoid. Most peptide-immunized volunteers developed antipeptide/sporozoite antibodies; however, there was no booster effect, and only one of three individuals was completely protected. For optimal protection, future vaccines must not only contain the B cell epitope but also induce T helper cells and cytotoxic T cells producing interferon-gamma, which has been shown to inhibit the development of liver-stage parasites.
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PMID:Antisporozoite vaccine for malaria: experimental basis and current status. 266 1

A clone of complementary DNA encoding the circumsporozoite (CS) protein of the human malaria parasite Plasmodium falciparum has been isolated by screening an Escherichia coli complementary DNA library with a monoclonal antibody to the CS protein. The DNA sequence of the complementary DNA insert encodes a four-amino acid sequence: proline-asparagine-alanine-asparagine, tandemly repeated 23 times. The CS beta-lactamase fusion protein specifically binds monoclonal antibodies to the CS protein and inhibits the binding of these antibodies to native Plasmodium falciparum CS protein. These findings provide a basis for the development of a vaccine against Plasmodium falciparum malaria.
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PMID:DNA cloning of Plasmodium falciparum circumsporozoite gene: amino acid sequence of repetitive epitope. 620 84

In a previous study, human beings were vaccinated with a P. falciparum malaria vaccine candidate consisting of tetanus toxoid coupled to linear (Asn-Ala-Asn-Pro)3 ((NANP)3). The vaccine initiated protection in some people, but some individuals mainly produced anti-peptide antibodies that did not react with the pathogen. A likely contributor to the formation of epitopes that give rise to pathogen-unreactive antibodies is the free terminal proline which is not a terminal residue in the native protein. To avoid the elicitation of antibodies against terminal epitopes, (NANP)3 was cyclized. In contrast to monoclonal antibodies to the linear peptide where 35% were unreactive with the parasite, all monoclonal antibodies to the cyclized peptide were found to react with the parasite.
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PMID:Towards a synthetic malaria vaccine: cyclization of a peptide eliminates the production of parasite-unreactive antibody. 809 45

Sporozoite recognition of host cells is a key step in the life-cycle of malaria parasites. Two sporozoite proteins have so far been characterized in some detail, the circumsporozoite protein (CS) and thrombospondin related adhesive protein (TRAP). We report here the cloning and expression of the TRAP gene homologue from Plasmodium berghei, PbTRAP. The PbTRAP gene encodes a protein of 606 amino acids having a deduced molecular mass of 66 kDa. The overall structure is clearly that of the TRAP family having a signal sequence followed by an integrin A domain, a sulphatide binding motif, followed by a proline based repeat before a transmembrane domain and helical cytoplasmic tail. The observed molecular mass is almost 50% larger than expected, this can be explained almost entirely by the abnormal behaviour in SDS-PAGE of the proline based repeat. As would be expected PbTRAP shows greatest similarity with the P. yoelli TRAP homologue sporozoite surface protein 2 (SSP2) than with PfTRAP, the TRAP gene from P. falciparum. The pattern of expression is similar to that of SSP2.
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PMID:Cloning and expression of the thrombospondin related adhesive protein gene of Plasmodium berghei. 904 16

The immunodominant region on the circumsporozoite surface (CS) protein of the malaria parasite Plasmodium falciparum contains 37 repeated copies of a asparagine-alanine-asparagine-proline (NANP) motif NMR studies of linear synthetic peptides containing one, two or three repeat units provided evidence for nascent type I beta-turns within the NPNA cadence in aqueous solution. The beta-turns could be stabilised upon substituting proline for alpha-methylproline (p(Me)) in the dodecamer (NP(Me)NA)3, without loss of the ability to elicit antibodies cross-reactive with P. falciparum sporozoites. In this work, four 4 ns MD simulations of the dodecapeptide Acetyl-(NP(Me)NA)3, in water, using NOE distance restraints, using 3J-coupling constant restraints, using both these restraints and without restraints, were carried out to determine the conformations of this peptide in aqueous solution. An unrestrained MD simulation of the unmethylated Ac-(NPNA)3 peptide in water was also carried out to investigate the effect of the additional methyl groups on the structure and dynamics of the peptide. The application of NOE distance restraints and 3J-coupling constant restraints leads to contradictory results, probably due to different averaging time scales inherent to the measurement of these data, which exceed the 100 ps averaging applied in the simulations. The additional methyl groups lead to more compact structures, which display enhanced local fluctuations. The central tetrapeptide adopts a type I beta-turn, while the outer motifs display more conformational variability. The three motifs in the methylated dodecamer peptide, however, adopt frequently in the distance restrained MD simulation a compact structure such that the outer motifs appear to form a hydrophobic core by stacking of their two proline rings. This arrangement also suggests how a peptide containing multiple tandemly linked copies of a stable beta-turn NPNA motif might adopt a folded stem-like structure, which conceivably may be of biological relevance in the native CS protein.
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PMID:Dynamical studies of peptide motifs in the Plasmodium falciparum circumsporozoite surface protein by restrained and unrestrained MD simulations. 913 27

To compare the compliance with and tolerance of mefloquine (MQ) and chloroquine + proguanil (CQ-PRO) chemoprophylaxis, we conducted a study using a self-reported questionnaire in 2 groups of native French adult visitors to Senegal or Kenya. CQ (100 mg daily) + PRO (200 mg daily) prophylaxis was prescribed for all patients travelling to Senegal and for those going to Kenya when MQ was contraindicated; MQ (250 mg weekly) was prescribed for the other subjects. There were no significant differences in age, sex, exposition and measures of protection against mosquito bites, concomitant drug use or mean duration of chemoprophylaxis between the 2 groups, and compliance during travel was excellent in both. Chemoprophylaxis was more frequently interrupted prematurely in the MQ group. The rates of overall side-effects attributed to malaria chemoprophylaxis were 16% for MQ against 12% CQ-PRO (not significant). However, nonserious neuropsychiatric adverse events are more frequent with MQ: 11.5% compared to 2% with CQ-PRO. MQ should be used with caution.
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PMID:Compliance with and tolerance of mefloquine and chloroquine + proguanil malaria chemoprophylaxis in French short-term travellers to sub-Saharan Africa. 935 84


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