Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A third calcium-dependent protein kinase (CDPK) gene has been isolated from the human malaria parasite Plasmodium falciparum by vectorette technology. The gene consists of five exons and four introns. The open reading frame resulting from removal of the four introns encodes a protein of 562 amino acid residues with a predicted molecular mass of 65.3 kDa. The encoded protein, termed PfCDPK3, consists of four distinct domains characteristic of a member of the CDPK family and displays the highest homology (46% identity and 69% similarity) to PfCDPK2, the second CDPK of P. falciparum. The N-terminal variable domain is rich in serine/threonine and lysine and contains multiple consensus phosphorylation sites for a range of protein kinases. The catalytic domain possesses all conserved motifs of the protein kinase family except for the highly conserved glutamic acid residue in subdomain VIII, which is replaced by a glutamine residue. The sequence of the junction domain comprising 31 amino acid residues is less conserved. The calmodulin-like regulatory domain contains four EF-hand calcium-binding motifs, each consisting of a loop of 12 amino acid residues which is flanked by two alpha-helices. Southern blotting of genomic DNA digests showed that the Pfcdpk3 gene is present as a single copy per haploid genome. A 2900 nucleotide transcript of this gene is expressed specifically in the sexual erythrocytic stage, indicating that PfCDPK3 is involved in sexual stage-specific events. It is proposed that PfCDPK3 may serve as a link between calcium and gametogenesis of P. falciparum.
 ...
PMID:Sexual stage-specific expression of a third calcium-dependent protein kinase from Plasmodium falciparum. 1076 Jun 1

We performed a gene expression screen of the entire transcriptome of the major African malaria vector Anopheles gambiae for immune response genes in adult female mosquitoes, which is the developmental stage infected by malaria parasites. Mosquitoes were immune-stimulated for subtractive cloning by treatment with bacterial lipopolysaccharide, a potent and general elicitor of the innate immune response, and by injury. The screen yielded a highly enriched cDNA library in which more than half of the clones were immune responsive. In this paper, we describe 23 immune-regulated genes, including putative protease inhibitors, serine proteases, regulatory molecules, and a number of genes without known relatives. A molecule related to the protease inhibitor alpha-2-macroglobulin responded strongly to malaria parasite infection, but displayed little or no response to bacteria, whereas other genes exhibited the inverse pattern. These results indicate that the insect immune system discriminates between molecular signals specific to infection with bacteria and malaria parasites.
 ...
PMID:Genes identified by an expression screen of the vector mosquito Anopheles gambiae display differential molecular immune response to malaria parasites and bacteria. 1100 29

In mice infected with the non-lethal malaria parasite Plasmodium chabaudi chabaudi AS, a prominent switch from a Th1 to a Th2 type of response occurs in CD4+ T cells at the time of peak parasitemia or shortly thereafter (9-15 days after infection). This is accompanied by a major increase in IL-4, and a similar decrease in IFN-gamma-producing cells. Non-B-non-T cells have been shown to be the main source of the IL-4 in these mice. The IL-4-producing cells are hyperresponsive to IL-3, indicating mast cell or basophil origin. To further characterize this cell population we have studied various organs at different time points of malarial infection by Northern blot analysis. No significant increase in the expression of any of the classical mouse mast cell serine proteases (MMCP)-1 to 7 or carboxypeptidase A was detected in the spleen during the entire infection. However, a marked increase in the expression of MMCP-8 was observed in the spleen at around day 15 post infection. Isolation of IgE receptor-positive cells from spleen shortly after peak parasitemia led to a prominent enrichment of MMCP-8-expressing cells. Fifty thousand of these cells were, after IL-3 stimulation, found to produce IL-4 to levels comparable with more than one million fully activated T cells. Our results show that basophil-like cells are very potent producers of IL-4 and that IL-4 produced by these cells may be of major importance for the initiation of a Th2 response. In addition, the detection of MMCP-8 in these cells has led to the identification of the first basophil-specific differentiation marker in the mouse.
 ...
PMID:MMCP-8, the first lineage-specific differentiation marker for mouse basophils. Elevated numbers of potent IL-4-producing and MMCP-8-positive cells in spleens of malaria-infected mice. 1100

Antigenic polymorphism and HLA restriction may limit the immunogenicity of a subunit vaccine against liver-stage Plasmodium falciparum. We examined 59 clinical isolates and five laboratory clones of P. falciparum for polymorphism in the N- and C-terminal regions of LSA-1, evaluated binding of the corresponding peptides to selected HLA class I alleles, and measured IFN-gamma responses in residents of a malaria-endemic area of Papua New Guinea where HLA-A*1101, -24, -B13, and -B40 are the most common class I alleles. LSA-1 polymorphism was limited to a single non-synonymous mutation encoding serine (S), proline (P), or threonine (T) at amino acid 85. Nine-mer 84-92 peptides with S, T, or P at the primary anchor position bound differentially to HLA-A11, -A2, and -B7. IFN-gamma ELISPOT responses increased with age in malaria-exposed subjects: 14-16% and 30-36% of 2-5- and 6-54-year-olds, respectively, had > or =10 IFN-gamma-secreting cells/106 peripheral blood mononuclear cells when stimulated with at least one peptide variant (P<0.05). IFN-gamma responses to all three peptides were also greater for older than younger individuals. No children < 3 years old had lymphocytes that responded to all three 84-92 peptides, whereas 45% of adults (mean age 48 years) had aggregated IFN-gamma responses. These data support the notion that age-related cumulative exposure to P. falciparum increases the frequency of IFN-gamma responses to polymorphic epitopes of liver-stage antigens such as LSA-1.
 ...
PMID:Influence of age and HLA type on interferon-gamma (IFN-gamma) responses to a naturally occurring polymorphic epitope of Plasmodium falciparum liver stage antigen-1 (LSA-1). 1101 24

Innate immunity directs the adaptive immune response by identifying antigens that are associated with infectious agents. Although some microbial antigens can be recognized by innate immune receptors, most cannot, and these require identification by some other means. The introduction of aldehydes into antigens by glycolaldehyde, which can be produced by activated neutrophils reacting with serine, or by the oxidation of an N-linked oligosaccharide with NaIO4, enhances by several orders of magnitude their immunogenicity in mice. The augmented immunogenicity requires the presence of an aldehyde on the antigen, and is not dependent on protein aggregation. An in vitro correlate of augmented immunogenicity is the enhanced presentation of glycolaldehyde-modified antigen to T cells by macrophages and bone marrow-derived dendritic cells. The potential clinical importance of this form of antigen modification is twofold: glycolaldehyde renders a model self antigen immunogenic, and it converts a relatively non-immunogenic malaria antigen, merozoite surface protein-1, into an effective immunogen. Thus, the tagging of antigens by the addition of aldehydes, which may be an innate immune mechanism to facilitate their recognition by the adaptive immune system, may have a role in the genesis of autoimmunity and the development of vaccines.
 ...
PMID:Enhanced immunogenicity of aldehyde-bearing antigens: a possible link between innate and adaptive immunity. 1106 70

The malaria parasite Plasmodium falciparum undergoes distinct morphologic changes during its 48-h life cycle inside human red blood cells. Parasite proteinases appear to play important roles at all stages of the erythrocytic cycle of human malaria. Proteases involved in erythrocyte rupture and invasion are possibly required to breakdown erythrocyte membrane skeleton. To identify such proteases, soluble cytosolic extract of isolated trophozoites/schizonts was incubated with erythrocyte membrane ghosts or spectrin-actin depleted inside-out vesicles, which were then analyzed by SDS-PAGE. In both cases, a new protein band of 155 kDa was detected. The N-terminal peptide sequencing established that the 155 kDa band represents truncated ankyrin. Immunoblot analysis using defined monoclonal antibodies confirmed that ankyrin was cleaved at the C-terminus. While the enzyme preferentially cleaved ankyrin, degradation of protein 4.1 was also observed at high concentrations of the enzyme. The optimal activity of the purified enzyme, using ankyrin as substrate, was observed at pH 7.0-7.5, and the activity was strongly inhibited by standard inhibitors of cysteine proteinases (cystatin, NEM, leupeptin, E-64 and MDL 28 170), but not by inhibitors of aspartic (pepstatin) or serine (PMSF, DFP) proteinases. Furthermore, we demonstrate that protease digestion of ankyrin substantially reduces its interaction with ankyrin-depleted membrane vesicles. Ektacytometric measurements showed a dramatic increase in the rate of fragmentation of ghosts after treatment with the protease. Although the role of ankyrin cleavage in vivo remains to be determined, based on our findings we postulate that the parasite-derived cysteine protease activity cleaves host ankyrin thus weakening the ankyrin-band 3 binding interactions and destabilizing the erythrocyte membrane skeleton, which, in turn, facilitates parasite release. Further characterization of the enzyme may lead to the development of novel antimalarial drugs.
 ...
PMID:A cysteine protease activity from Plasmodium falciparum cleaves human erythrocyte ankyrin. 1107 Dec 81

Glycolipids are important components of cellular membranes involved in various biological functions. In this report we describe the identification of the de-novo synthesis of glycosphingolipids by intraerythrocytic, asexual stages of the malaria parasite, Plasmodium falciparum. Parasite-specific glycolipids were identified in organic solvent extracts of parasites metabolically labeled with tritiated serine and glucosamine and characterised as sphingolipids based on their insensitivity towards alkaline treatment. While the de-novo synthesis of parasite glycosphingolipids was affected by fumonisin B1, threo-PPMP, cyclo-serine and myriocin, these well established inhibitors of de-novo ceramide biosynthesis were unable to arrest the intraerythrocytic development of the parasites in culture.
 ...
PMID:Biosynthesis of glycosphingolipids de-novo by the human malaria parasite Plasmodium falciparum. 1116 84

Serine proteases regulate several invertebrate defense responses, including hemolymph coagulation, antimicrobial peptide synthesis, and melanization of pathogen surfaces. These processes require the presence of serine proteases in the hemolymph where they can rapidly activate immune pathways in response to pathogen detection. Hemolymph coagulation in the horseshoe crab is controlled by several serine proteases, including two that are pathogen recognition molecules and two in the clip domain family of serine proteases. The antimicrobial peptide synthesis and melanization pathways include clip domain proteases as well as other, uncharacterized serine proteases. We have identified five serine proteases from the hemolymph of the mosquito, Anopheles gambiae. One, Sp22D, is a large protease with potential pathogen binding domains. Sp22D is expressed in three tissues that have immune functions (midgut epithelium, fat body, and hemocytes), and its transcript abundance increases after immune challenge. Sp14A, Sp14D1, and Sp14D2 are clip domain serine proteases that are similar to enzymes with presumed roles in melanization or antimicrobial peptide synthesis. They undergo changes in transcript abundance in response to infection with bacteria or malaria parasites, and they reside in a chromosomal region that has been associated with melanization of parasites. Sp18D, also a clip domain protease, is similar to a Manduca protease with a likely role in immunity, but immune challenge does not affect its mRNA abundance.
 ...
PMID:Serine proteases as mediators of mosquito immune responses. 1116 95

The elongation step of protein synthesis involves binding of aminoacyl-tRNA to the ribosomal A site, formation of a peptide bond and translocation of the newly formed peptidyl-tRNA to the P site. The nucleotide exchange factor EF-1beta plays a major role in the regulation of this process by regenerating a GTP-bound EF-1alpha necessary for each elongation cycle. EF-1beta has been shown to be phosphorylated and its phosphorylation is critical for optimal activity. We have previously identified a serine/threonine protein phosphatase 2C (PP2C) from the human malaria parasite Plasmodium falciparum. In the current work, we performed Far-Western analysis to identify PfPP2C substrates. Several components of the translation and transcription machinery were identified, including translation elongation factor 1-beta (PfEF-1beta). PfEF-1beta is efficiently phosphorylated by protein kinase C and this phosphorylation results in a 400% increase in its nucleotide exchange activity. PKC-phosphorylated PfEF-1beta is readily and selectively dephosphorylated by recombinant and native PfPP2C, which downregulates the nucleotide exchange activity to its basal level. The identification of a translation elongation component as substrate for PP2C suggests an important regulatory function for this enzyme and suggests that it may be a good target for drug design in the fight against malaria.
 ...
PMID:Plasmodium protein phosphatase 2C dephosphorylates translation elongation factor 1beta and inhibits its PKC-mediated nucleotide exchange activity in vitro. 1125 17

We have cloned Pfnek-1, a gene encoding a novel protein kinase from the human malaria parasite Plasmodium falciparum. This enzyme displays maximal homology to the never-in-mitosis/Aspergillus (NIMA)/NIMA-like kinase (Nek) family of protein kinases, whose members are involved in eukaryotic cell division processes. Similar to other P. falciparum protein kinases and many enzymes of the NIMA/Nek family, Pfnek-1 possesses a large C-terminal extension in addition to the catalytic domain. Bacterially expressed recombinant Pfnek-1 protein is able to autophosphorylate and phosphorylate a panel of protein substrates with a specificity that is similar to that displayed by other members of the NIMA/Nek family. However, the FXXT motif usually found in NIMA/Nek protein kinases is substituted in Pfnek-1 by a SMAHS motif, which is reminiscent of a MAP/ERK kinase (MEK) activation site. Mutational analysis indicates that only one of the serine residues in this motif is essential for Pfnek-1 kinase activity in vitro. We show (a) that recombinant Pfnek-1 is able to specifically phosphorylate Pfmap-2, an atypical P. falciparum MAPK homologue, in vitro, and (b) that coincubation of Pfnek-1 and Pfmap-2 results in a synergistic increase in exogenous substrate labelling. This suggests that Pfnek-1 may be involved in the modulation of MAPK pathway output in malaria parasites. Finally, we demonstrate that recombinant Pfnek-1 can be used in inhibition assays to monitor the effect of kinase inhibitors, which opens the way to the screening of chemical libraries aimed at identifying potential new antimalarials.
 ...
PMID:Pfnek-1, a NIMA-related kinase from the human malaria parasite Plasmodium falciparum Biochemical properties and possible involvement in MAPK regulation. 1132 79


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>