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)

Chloroquine resistance in Plasmodium falciparum malaria results from mutations in PfCRT, a member of a unique family of transporters present in apicomplexan parasites and Dictyostelium discoideum. Mechanisms that have been proposed to explain chloroquine resistance are difficult to evaluate within malaria parasites. Here we report on the targeted expression of wild-type and mutant forms of PfCRT to acidic vesicles in D. discoideum. We show that wild-type PfCRT has minimal effect on the accumulation of chloroquine by D. discoideum, whereas forms of PfCRT carrying a key charge-loss mutation of lysine 76 (e.g. K76T) enable D. discoideum to expel chloroquine. As in P. falciparum, the chloroquine resistance phenotype conferred on transformed D. discoideum can be reversed by the channel-blocking agent verapamil. Although intravesicular pH levels in D. discoideum show small acidic changes with the expression of different forms of PfCRT, these changes would tend to promote intravesicular trapping of chloroquine (a weak base) and do not account for reduced drug accumulation in transformed D. discoideum. Our results instead support outward-directed chloroquine efflux for the mechanism of chloroquine resistance by mutant PfCRT. This mechanism shows structural specificity as D. discoideum transformants that expel chloroquine do not expel piperaquine, a bisquinoline analog of chloroquine used frequently against chloroquine-resistant parasites in Southeast Asia. PfCRT, nevertheless, may have some ability to act on quinine and quinidine. Transformed D. discoideum will be useful for further studies of the chloroquine resistance mechanism and may assist in the development and evaluation of new antimalarial drugs.
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PMID:Dictyostelium discoideum expresses a malaria chloroquine resistance mechanism upon transfection with mutant, but not wild-type, Plasmodium falciparum transporter PfCRT. 1588 56

Haemoglobin C, which carries a glutamate-to-lysine mutation in the beta-globin chain, protects West African children against Plasmodium falciparum malaria. Mechanisms of protection are not established for the heterozygous (haemoglobin AC) or homozygous (haemoglobin CC) states. Here we report a marked effect of haemoglobin C on the cell-surface properties of P. falciparum-infected erythrocytes involved in pathogenesis. Relative to parasite-infected normal erythrocytes (haemoglobin AA), parasitized AC and CC erythrocytes show reduced adhesion to endothelial monolayers expressing CD36 and intercellular adhesion molecule-1 (ICAM-1). They also show impaired rosetting interactions with non-parasitized erythrocytes, and reduced agglutination in the presence of pooled sera from malaria-immune adults. Abnormal cell-surface display of the main variable cytoadherence ligand, PfEMP-1 (P. falciparum erythrocyte membrane protein-1), correlates with these findings. The abnormalities in PfEMP-1 display are associated with markers of erythrocyte senescence, and are greater in CC than in AC erythrocytes. Haemoglobin C might protect against malaria by reducing PfEMP-1-mediated adherence of parasitized erythrocytes, thereby mitigating the effects of their sequestration in the microvasculature.
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PMID:Abnormal display of PfEMP-1 on erythrocytes carrying haemoglobin C may protect against malaria. 1597 12

Histones are the building units of nucleosomes and play essential roles in DNA replication, repair and transcription. A comprehensive analysis of histone genes revealed that the Plasmodium falciparum genome encodes a canonical form of each core histone and four histone variants H2A.Z, H3.3, centromere-specific H3 (CenH3), and H2Bv. Mass spectrometry confirmed the synthesis of all histones except CenH3. Real-time reverse transcriptase-polymerase chain reaction and immunoblotting detected a dramatic increase in core histone gene expression during the late trophozoite stages, consistent with their role in replication-related nucleosome assembly. In contrast, the expression of variant histones decreased in mid- or late trophozoite stages. The N-terminal tails of histones participate in transcription regulation through covalent modifications, especially at the lysine residues. In accordance, mass spectrometry analysis revealed acetylation of lysines and methylation of lysines and arginines in the N-termini of H3, H3.3, and H4. Moreover, we identified a new pattern of lysine modifications of the H2A.Z variant. Using a panel of acetylation-specific antibodies, we found that K5, K8, and K12 of H4 were abundantly acetylated at a relatively steady level throughout the erythrocytic cycle. In comparison, the H3-K9 acetylation increased in late trophozoite and schizont stages, while H4-K16 acetylation peaked in mid-trophozoite stage. We have also shown that despite the sequence divergence in the PfH3 N-terminus from their mammalian homologues, the recombinant PfH3 was still efficiently acetylated by both recombinant and native PfGCN5 at K9 and K14. This study suggests that histone replacement and the dynamic histone modifications play important roles in regulating gene expression during erythrocytic development of the malaria parasite.
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PMID:The malaria parasite Plasmodium falciparum histones: organization, expression, and acetylation. 1641 41

Type I signal peptidases are important membrane-bound serine proteases responsible for the cleavage of the signal peptide of the proteins. These enzymes are unique serine proteases that carry out catalysis using a serine/lysine catalytic dyad. In the present study, we report the isolation of type I signal peptidase from the malaria parasites Plasmodium falciparum, Plasmodium knowlesi, and Plasmodium yoelii and some characterization of type I signal peptidase of Plasmodium falciparum. We show that these enzymes are homologous to signal peptidases from various sources and also contain the conserved boxes present in other type I signal peptidases. The type I signal peptidase from P falciparum is an intron-less and a single-copy gene. The results also show that the enzyme from Plasmodium falciparum is subject to self-cleavage and it has been demonstrated to possess type I signal peptidase activity in E coli preprotein processing in vivo by complementation assay. This study will be helpful in understanding one of the important metabolic pathways "the secretory pathway" in the parasite and should make an important contribution in understanding the complex process of protein targeting in the parasite.
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PMID:Isolation and characterization of type I signal peptidase of different malaria parasites. 1648 63

The increasing resistance of the malaria parasites has enforced new strategies of finding new drug targets. We have isolated two genes involved in spermidine metabolism, encoding deoxyhypusine synthase (DHS) and eukaryotic initiation factor 5A (eIF-5A) in the malaria parasites. eIF-5A is activated by the formation of the unusual amino acid hypusine. This process occurs in two steps. DHS transfers an aminobutyl moiety from the triamine spermidine to a specific lysine residue in the eIF-5A precursor protein to form deoxyhypusine. In a second step, deoxyhypusine hydroxylase (DHH), completes hypusine biosynthesis. We used DHH inhibitors, being effective in mammalian cells, to study an antiplasmodicidal effect in Plasmodium falciparum. Experiments with the antifungal drug ciclopiroxolamine, an alpha-hydroxypyridone, and the plant amino acid L: -mimosine, a 4-pyridone, resulted in an antiplasmodial effect in vitro. Using mimosine as a lead structure, alkyl 4-oxo-piperidine 3-carboxylates were found to have the most efficient antiplasmodial effects in vitro and in vivo.
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PMID:Piperidones with activity against Plasmodium falciparum. 1655 Apr 32

During its red blood cell stage, the malaria parasite Plasmodium falciparum can switch its variant surface proteins (P. falciparum erythrocyte membrane protein 1) to evade the host immune response. The var gene family encodes P. falciparum erythrocyte membrane protein 1, different versions of which have unique binding specificities to various human endothelial surface molecules. Individual parasites each contain approximately 60 var genes at various locations within their chromosomes; however, parasite isolates contain different complements of var genes, thus, the gene family is enormous with a virtually unlimited number of members. A single var gene is expressed by each parasite in a mutually exclusive manner. We report that control of var gene transcription and antigenic variation is associated with a chromatin memory that includes methylation of histone H3 at lysine K9 as an epigenetic mark. We also discuss how gene transcription memory may affect the mechanism of pathogenesis and immune evasion.
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PMID:Epigenetic memory at malaria virulence genes. 1720 11

Sulfosuccinimidyl-6-(biotinamido) hexanoate and derivatives thereof covalently bind to the epsilon-amino group of lysine residues. Our observation that access of the biotin derivative to specific lysine residues depends on conformational properties of the entire polypeptide chain prompted us to investigate whether differential biotinylation patterns of a protein can be used as indicators for conformational changes. Bovine serum albumin is a soluble protein with characteristic unfolding kinetics upon exposure to high temperature. First, we show that biotinylation patterns of proteins are highly reproducible. Second, we demonstrate by mass spectrometry and tandem mass spectrometry that unfolding of the protein correlates with the accessibility of the biotin derivative to specific lysine residues. We have applied this experimental strategy to the analysis of a cell-surface protein, viz. the human band 3 anion exchanger of erythrocytes infected with the malaria parasite Plasmodium falciparum. We found that Lys(826) in a highly flexible loop can be biotinylated in non-infected (but not infected) erythrocytes, confirming earlier observations (Winograd, E., and Sherman, I. W. (2004) Mol. Biochem. Parasitol. 138, 83-87) based on epitope-specific monoclonal antibodies suggesting that this region undergoes a conformational change upon infection.
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PMID:Use of biotin derivatives to probe conformational changes in proteins. 1754 62

In the human malaria parasite Plasmodium falciparum antigenic variation facilitates long-term chronic infection of the host. This is achieved by sequential expression of a single member of the 60-member var family. Here we show that the 5' flanking region nucleates epigenetic events strongly linked to the maintenance of mono-allelic var gene expression pattern during parasite proliferation. Tri- and dimethylation of histone H3 lysine 4 peak in the 5' upstream region of transcribed var and during the poised state (non-transcribed phase of var genes during the 48 h asexual life cycle), 'bookmarking' this member for re-activation at the onset of the next cycle. Histone H3 lysine 9 trimethylation acts as an antagonist to lysine 4 methylation to establish stably silent var gene states along the 5' flanking and coding region. Furthermore, we show that competition exists between H3K9 methylation and H3K9 acetylation in the 5' flanking region and that these marks contribute epigenetically to repressing or activating var gene expression. Our work points to a pivotal role of the histone methyl mark writing and reading machinery in the phenotypic inheritance of virulence traits in the malaria parasite.
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PMID:5' flanking region of var genes nucleate histone modification patterns linked to phenotypic inheritance of virulence traits in malaria parasites. 1802 16

Dynamic histone lysine methylation, regulated by methyltransferases and demethylases, plays fundamental roles in chromatin structure and gene expression in a wide range of eukaryotic organisms. A large number of SET-domain-containing proteins make up the histone lysine methyltransferase (HKMT) family, which catalyses the methylation of different lysine residues with relatively high substrate specificities. Another large family of Jumonji C (JmjC)-domain-containing histone lysine demethylases (JHDMs) reverses histone lysine methylation with both lysine site and methyl-state specificities. Through bioinformatic analysis, at least nine SET-domain-containing genes were found in the malaria parasite Plasmodium falciparum and its sibling species. Phylogenetic analysis separated these putative HKMTs into five subfamilies with different putative substrate specificities. Consistent with the phylogenetic subdivision, methyl marks were found on K4, K9 and K36 of histone H3 and K20 of histone H4 by site-specific methyl-lysine antibodies. In addition, most SET-domain genes and histone methyl-lysine marks displayed dynamic changes during the parasite asexual erythrocytic cycle, suggesting that they constitute an important epigenetic mechanism of gene regulation in malaria parasites. Furthermore, the malaria parasite and other apicomplexan genomes also encode JmjC-domain-containing proteins that may serve as histone lysine demethylases. Whereas prokaryotic expression of putative active domains of four P. falciparum SET proteins did not yield detectable HKMT activity towards recombinant P. falciparum histones, two protein domains expressed in vitro in a eukaryotic system showed HKMT activities towards H3 and H4, respectively. With the discovery of these Plasmodium SET- and JmjC-domain genes in the malaria parasite genomes, future efforts will be directed towards elucidation of their substrate specificities and functions in various cellular processes of the parasites.
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PMID:Histone lysine methyltransferases and demethylases in Plasmodium falciparum. 1829 33

Malaria is one of the foremost public health problems in developing countries affecting nearly 40% of the global population. Apart from this, the past two decade's emergence of drug resistance has severely limited the choice of available antimalarial drugs. Furthermore, the general trend emerging from the SAR-studies is that chloroquine resistance does not involve any change to the target of this class of drugs but involves compound specific efflux mechanism. Based on this premise a number of groups have developed short chain analogues of 4-aminoquinoline, which are active against CQ-resistant strains of P. falciparum in in vitro studies. However, these derivatives undergo biotransformation (de-alklyation) significantly affecting lipid solubility of the drug. In view of this background information, we thought that it would be interesting to study the effect of additional lipophilicity and cationic charge at the lateral side chain of 4-aminoquinoline. This prompted us to explore the cationic amino acid conjugates namely, lysine and ornithine of 4-aminoquinoline with a view to achieve improved antimalarial activity and to the best of our knowledge such amino acid conjugates have not been hitherto reported in the literature in the case of 4-aminoquinolines. In the present study, a new series of side-chain modified 4-aminoquinolines have been synthesized and found active against both susceptible and multidrug resistant strains of P. falciparum in vitro and P. yoelli in vivo. The seminal finding of the present study is that a new series of compounds having significantly more activity against CQ resistant parasites has been identified.
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PMID:Synthesis and antimalarial activity of novel side chain modified antimalarial agents derived from 4-aminoquinoline. 1878 41


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