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)

Radiolabelled methionine incorporation into synchronised Plasmodium berghei gametocytes or ookinete cultures, showed that Pbs21 is not synthesised in bloodstage parasites; synthesis was detected within three hours of induction of gametogenesis; synthesis was triggered at gametogenesis, not by fertilisation. We show native Pbs21 to be a hydrophobic membrane protein that was insensitive to cleavage by phosphatidylinositol phospholipase C (PI-PLC), but sensitive to alkaline hydroxylamine, and partially sensitive to glycosylphosphatidylinositol-dependent phospholipase D (GPI-PLD) and HNO2. 3H-myristic and palmitic acid, 3H-glucosamine and mannose incorporation indicated Pbs21 was acylated and glycosylated. Linkage of the acyl group was sensitive to HNO2, which released an acyl-phosphatidylinositol more hydrophobic than that released from P3 of Trypanosoma brucei. All these properties are consistent with the presence of a malaria-specific glycosylphosphatidylinositol (GPI) anchor. In contrast recombinant Pbs21 (rPbs21), expressed in Spodoptera frugiperda cells, was sensitive to both PI-PLC and GPI-PLD, consistent with the protein being modified by a different (S. frugiperda) GPI anchor. Brefeldin A blocked secretion of rPbs21 within a cytoplasmic reticular compartment. Following deletion of the putative GPI anchor addition site (amino acids 189 213), the protein was transported to the cell surface and secreted directly into the aqueous phase of the culture medium. Deletion of amino acids 205-213 disrupted Pbs21 processing, transport through the ER and distribution onto the cell surface. Deletion of amino acids 1-28 prevented transport of Pbs21 into the ER. This suggests that correct processing of the GPI anchor in the ER-Golgi network is essential for the successful secretion of the recombinant protein, which is additionally dependent upon an N-terminal secretory signal sequence.
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PMID:The biosynthesis and post-translational modification of Pbs21 an ookinete-surface protein of Plasmodium berghei. 1008 Mar 86

There is great need to identify and characterize drug targets and chemotherapeutic strategies against malaria. Here we show that a vacuolar-network induced by the human malaria parasite Plasmodium falciparum, is a major import pathway for artemisinin, a leading, new anti-malarial that is known to be effective against drug resistant strains. We also show that artemisinin-treatment induces aberrant, budding of a vacuolar-network membrane protein and its antimalarial activity is additive with toxic sphingolipid analogues that block the network. The data suggest that artemisinin alters membrane protein export from the vacuolar-network and combinations with anti-network reagents have the potential to provide powerful new chemotherapy for drug resistant malaria.
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PMID:Artemisinin and its derivatives are transported by a vacuolar-network of Plasmodium falciparum and their anti-malarial activities are additive with toxic sphingolipid analogues that block the network. 1041 44

Chloroquine-resistance is associated with higher malaria mortality in children in Africa where the drug is still widely used. In sensitive strains the drug attacks hemoglobin digestion in the lysosome and prevents detoxification of hemin to hemozoin. Reduced drug uptake is responsible for resistance, which is incompletely associated with changes in lysosome membrane protein PGH1. The report discussed here gives evidence for the role of another lysosome membrane protein, PfCRT, where a change from lysine to threonine in a transmembrane domain determines the change to resistance. Other changes in PfCRT, and to some extent change(s) in PGH1, are believed to compensate for loss of fitness of the modified PfCRT.
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PMID:New developments: chloroquine-resistance in Plasmodium falciparum. 1176 27

Malaria parasites invade erythrocytes in a process mediated by a series of molecular interactions. Invasion of human erythrocytes by Plasmodium vivax is dependent upon the presence of a single receptor, but P. falciparum, as well as some other species, exhibits the ability to utilize multiple alternative invasion pathways. Conserved cysteine-rich domains play important roles at critical times during this invasion process and at other stages in the life cycle of malaria parasites. Duffy-binding-like (DBL) domains, expressed as a part of the erythrocyte-binding proteins (DBL-EBP), are such essential cysteine-rich ligands that recognize specific host cell surface receptors. DBL-EBP, which are products of the erythrocyte-binding-like (ebl) gene family, act as critical determinants of erythrocyte specificity and are the best-defined ligands from invasive stages of malaria parasites. The ebl genes include the P. falciparum erythrocyte-binding antigen-175 (EBA-175) and P. vivax Duffy-binding protein. DBL domains also mediate cytoadherence as a part of the variant erythrocytic membrane protein-1 (PfEMP-1) antigens expressed from var genes on the surface of P. falciparum-infected erythrocytes. A paralogue of the ebl family is the malarial ligand MAEBL, which has a chimeric structure where the DBL domain is functionally replaced with a distinct cysteine-rich erythrocyte-binding domain with similarity to the apical membrane antigen-1 (AMA-1) ligand domain. The Plasmodium AMA-1 ligand domain, which encompasses the extracellular cysteine domains 1 and 2 and is well conserved in a Toxoplasma gondii AMA-1, has erythrocyte-binding activity distinct from that of MAEBL. These important families of Plasmodium molecules (DBL-EBP, PfEMP-1, MAEBL, AMA-1) are interrelated through the MAEBL. Because MAEBL and the other ebl products have the characteristics expected of homologous ligands involved in equivalent alternative invasion pathways to each other, we sought to better understand their roles during invasion by determining their relative origins in the Plasmodium genome. An analysis of their multiple cysteine-rich domains permitted a unique insight into the evolutionary development of PLASMODIUM: Our data indicate that maebl, ama-1, and ebl genes have ancient origins which predate Plasmodium speciation. The maebl evolved as a single locus, including its unique chimeric structure, in each Plasmodium species, in parallel with the ama-1 and the ebl genes families. The ancient character of maebl, along with its different expression characteristics suggests that MAEBL is unique and does not play an alternative role in invasion to ebl products such as EBA-175. The multiple P. falciparum ebl paralogues that express DBL domains, which have occurred by duplication and diversification, potentially do provide multiple functionally equivalent ligands to EBA-175 for alternative invasion pathways.
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PMID:Evolutionary relationships of conserved cysteine-rich motifs in adhesive molecules of malaria parasites. 1208 32

Mutations in the novel membrane protein Pfcrt were recently found to be essential for chloroquine resistance (CQR) in Plasmodium falciparum, the parasite responsible for most lethal human malaria (Fidock, D. A., Nomura, T., Talley, A. K., Cooper, R. A., Dzekunov, S. M., Ferdig, M. T., Ursos, L. M., Sidhu, A. B., Naude, B., Deitsch, K. W., Su, X. Z., Wootton, J. C., Roepe, P. D., and Wellems, T. E. (2000) Mol. Cell 6, 861-871). Pfcrt is localized to the digestive vacuolar membrane of the intraerythrocytic parasite and may function as a transporter. Study of this putative transport function would be greatly assisted by overexpression in yeast followed by characterization of membrane vesicles. Unfortunately, the very high AT content of malarial genes precludes efficient heterologous expression. Thus, we back-translated Pfcrt to design idealized genes with preferred yeast codons, no long poly(A) sequences, and minimal stem-loop structure. We synthesized a designed gene with a two-step PCR method, fused this to N- and C-terminal sequences to aid membrane insertion and purification, and now report efficient expression of wild type and mutant Pfcrt proteins in the plasma membrane of Saccharomyces cerevisiae and Pichia pastoris yeast. To our knowledge, this is the first successful expression of a full-length malarial parasite integral membrane protein in yeast. Purified membranes and inside-out plasma membrane vesicle preparations were used to analyze wild type versus CQR-conferring mutant Pfcrt function, which may include effects on H(+) transport (Dzekunov, S., Ursos, L. M. B., and Roepe, P. D. (2000) Mol. Biochem. Parasitol. 110, 107-124), and to perfect a rapid purification of biotinylated Pfcrt. These data expand on the role of Pfcrt in conferring CQR and define a productive route for analysis of important P. falciparum transport proteins and membrane associated vaccine candidates.
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PMID:Analysis of the antimalarial drug resistance protein Pfcrt expressed in yeast. 1235 20

Apical membrane antigen-1 (AMA-1) is an integral Plasmodium falciparum malaria parasite membrane protein. Peptides having high activity binding to human red blood cells have been identified in this protein. One of them, peptide 4325, with the amino acid sequence MIKSAFLPTGAFKADRYKSH, for which critical binding residues have already been defined (underlined), is conserved and non-immunogenic. Its critical binding residues were changed for amino acids having similar mass but different charge to change such immunological properties. These changes rendered some peptides immunogenic and protective against experimental challenge in Aotus monkeys. Three-dimensional models of peptide 4325 and its analogues, 20032 and 20034, were calculated from NMR experiments with distance geometry and restrained molecular dynamic methods. Non-immunogenic, non-protective peptide 4325 showed differences in its secondary structure with respect to protective, immunogenic peptides 20032 and 20034. Such data suggest that these modifications could have converted non-immunogenic peptides into immunogenic, protective ones, making them excellent candidates for a multi-component subunit synthetic malaria vaccine.
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PMID:Protection against experimental P falciparum malaria is associated with short AMA-1 peptide analogue alpha-helical structures. 1262 94

Infected erythrocytes containing the more mature stages of the human malaria Plasmodium falciparum may adhere to endothelial cells and uninfected red cells. These phenomena, called sequestration and rosetting, respectively, are involved in both host pathogenesis and parasite survival. This review provides a critical summary of recent advances in the characterization of the molecules of the infected red blood cell involved in adhesion, i.e. parasite-encoded molecules (PfEMP1, MESA, rifins, stevor, clag 9, histidine-rich protein), a modified host membrane protein (band 3) and exofacial exposure of phosphatidylserine, as well as receptors on the endothelium, i.e. thrombospondin, CD36, ICAM-1 (intercellular adhesion molecule), and chondroitin sulfate.
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PMID:Cytoadherence and sequestration in Plasmodium falciparum: defining the ties that bind. 1291 58

MAEBL is a type 1 membrane protein that is implicated in the merozoite invasion of erythrocytes and sporozoite invasion of mosquito salivary glands. This apical organelle protein is structurally similar to the ebl erythrocyte binding proteins, such as EBA-175, except that the tandem ligand domains of MAEBL are similar to part of the extracellular domain of apical membrane antigen 1 and not the Duffy binding-like domain. Although midgut and salivary gland sporozoites are morphologically similar, salivary gland sporozoites undergo a period of new gene expression after infecting the salivary glands, display distinct phenotypic differences, and are more infectious for the mammalian host. The objectives of this project were to determine the molecular form of MAEBL in the infectious salivary gland sporozoites and whether the ligand has a role in the sporozoite development to exoerythrocytic stages in hepatocytes. We determined that MAEBL is newly expressed in salivary gland sporozoites and in a form distinct from what is present in the midgut sporozoites or present in erythrocytic stages. Both ligand domains (M1 and M2) were expressed as part of a full-length membrane form of MAEBL in the salivary gland sporozoites in contrast to the other stages that retain only the M2 ligand domain as part of the membrane form of the protein. Antisera developed against the cysteine-rich regions of the extracellular portion of MAEBL inhibited sporozoite development to exoerythrocytic forms in vitro. Together these data indicate that MAEBL has a role in this third developmental stage in the life cycle of the malaria parasite. Thus, MAEBL is another target for pre-erythrocytic-stage vaccine development against malaria parasites.
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PMID:Antibodies against MAEBL ligand domains M1 and M2 inhibit sporozoite development in vitro. 1515 70

Rickettsia africae was identified in seven (6%) of 118 patients with acute fevers of unknown etiology proven not to be malaria or typhoid fever from clinics along the coastal region of Cameroon by polymerase chain reaction (PCR) amplification and sequencing of the citrate synthase (gltA) and outer membrane protein A (ompA) genes of Rickettsia. The majority (71%) of the patients were female. Clinical manifestations included fever (100%), headache (71%), myalgia (71%), arthralgia (43%), pulmonary involvement (29%), and diffuse rash (14%). Moreover, R. africae was detected by PCR amplification and sequence analysis of the gltA and ompA genes in 62 (75%) of 83 adult Amblyomma variegatum ticks collected from cattle in the same region. These results confirm the presence of a previously unrecognized infectious disease in the indigenous Cameroonian population, as well as extend the established range of R. africae.
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PMID:Detection of Rickettsia africae in patients and ticks along the coastal region of Cameroon. 1538 20

The merozoite surface of the pathogenic malaria parasite Plasmodium falciparum is comprised of proteins that are important for the identification and invasion of human red cells. Merozoite surface protein (MSP)3 is a polymorphic protein associated with the surface of merozoites and is also a vaccine candidate. A distinct feature of the MSP3 sequence is three blocks of alanine-rich heptad repeats that are predicted to form an intramolecular coiled-coil. Three orthologues of MSP3 that also contain alanine-rich heptad repeats have been described in P. vivax and we therefore searched the P. falciparum genome database for MSP3 paralogues. We have identified two genes, H101 and H103 related to MSP3, however like another MSP3 paralogue, MSP6, H101 and H103 do not contain heptad repeats. H101 and H103 are expressed during the asexual cycle and immunofluorescence indicates H103 localises to the merozoite surface as a peripheral membrane protein. Transfected parasite lines that express truncated forms of H101 or H103 were viable and grew at the same rate as the parental parasite line. This result may reflect redundancy in function among members of the MSP3/MSP6 gene family as has been described for other families of paralogue genes in P. falciparum.
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PMID:Characterisation of two novel proteins from the asexual stage of Plasmodium falciparum, H101 and H103. 1566 49


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