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Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The canonical mitogen-activated protein kinase (MAPK) signal cascade was previously suggested to be atypical in the malaria parasite. This raises queries on the existence of alternative mediators of plasmodial MAPK pathways. This study describes, Pfnek3, a malarial protein kinase belonging to the NIMA (Never in Mitosis, Aspergillus) family. Endogenous Pfnek3 is expressed during late asexual to gametocyte stages and lacks some classical protein kinase sequence motifs. Moreover, Pfnek3 is phylogenetically distant from mammalian NIMA-kinases. Recombinant Pfnek3 was able to phosphorylate and stimulate a malarial MAPK (Pfmap2). Contrastingly, this was not observed with two other kinases, Pfmap1 and human MAPK1, suggesting that the Pfnek3-Pfmap2 interaction may be specific for Pfmap2 regulation. In summary, our data reveal a malarial NIMA-kinase with the potential to regulate a MAPK. Possessing biochemical properties divergent from classical mammalian NIMA-kinases, Pfnek3 could potentially be an attractive target for parasite-selective anti-malarials.
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PMID:Pfnek3: an atypical activator of a MAP kinase in Plasmodium falciparum. 1706 92

Dendritic cells (DCs) have been proposed as mediators of immunity against malaria parasites, as well as a target for inhibition of cellular responses. Here we describe the transcriptomic analysis of spleen DCs in response to Plasmodium infection in a rodent model. We identified a high number of unique transcripts modulated in DCs upon infection. Many cellular functions suffer extensive genomic regulation including the cell cycle, the glycolysis and purine metabolism pathways and also defence responses. Only a small fraction of the regulated genes are coincident with the response induced by other pathogens, suggesting that Plasmodium induces a unique genetic re-programming of DCs. We confirmed regulation of a number of cytokines at the mRNA level including IL-6, IL-10 and IFN-gamma. We further dissected a signalling pathway regulating Plasmodium-induced expression of IL-6 by DCs, which is mediated by release of PGE2, increases in intracellular cAMP and activation of PKA and p38-MAPK.
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PMID:Transcriptome profile of dendritic cells during malaria: cAMP regulation of IL-6. 1732 58

After transmission by infected mosquitoes, malaria sporozoites rapidly travel to the liver. To infect hepatocytes, sporozoites traverse Kupffer cells, but surprisingly, the parasites are not killed by these resident macrophages of the liver. Here we show that Plasmodium sporozoites and recombinant circumsporozoite protein (CSP) suppress the respiratory burst in Kupffer cells. Sporozoites and CSP increased the intracellular concentration of cyclic adenosyl mono-phosphate (cAMP) and inositol 1,4,5-triphosphate in Kupffer cells, but not in hepatocytes or liver endothelia. Preincubation with cAMP analogues or inhibition of phosphodiesterase also inhibited the respiratory burst. By contrast, adenylyl cyclase inhibition abrogated the suppressive effect of sporozoites. Selective protein kinase A (PKA) inhibitors failed to reverse the CSP-mediated blockage and stimulation of the exchange protein directly activated by cAMP (EPAC), but not PKA inhibited the respiratory burst. Both blockage of the low-density lipoprotein receptor-related protein (LRP-1) with receptor-associated protein and elimination of cell surface proteoglycans inhibited the cAMP increase in Kupffer cells. We propose that by binding of CSP to LRP-1 and cell surface proteoglycans, malaria sporozoites induce a cAMP/EPAC-dependent, but PKA-independent signal transduction pathway that suppresses defence mechanisms in Kupffer cells. This allows the sporozoites to safely pass through these professional phagocytes and to develop inside neighbouring hepatocytes.
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PMID:Malaria circumsporozoite protein inhibits the respiratory burst in Kupffer cells. 1757 5

We tested Pfmrk against several naphthalene and isoquinoline sulfonamides previously reported as protein kinase A (PKA) inhibitors. Pfmrk is a Cyclin Dependent protein Kinase (CDK) from Plasmodium falciparum, the causative parasite of the most lethal form of malaria. We find that the isoquinoline sulfonamides are potent inhibitors of Pfmrk and that substitution on the 5 position of the isoquinoline ring greatly influences the degree of potency. Molecular modeling studies suggest that the nitrogen atom in the isoquinoline ring plays a key role in ligand-receptor interactions. Structural analysis suggests that even subtle differences in amino acid composition within the active sites are responsible for conferring specificity of these inhibitors for Pfmrk over PKA.
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PMID:Evaluation of broad spectrum protein kinase inhibitors to probe the architecture of the malarial cyclin dependent protein kinase Pfmrk. 1758 49

Phosphorylation by protein kinases is a very common and crucial process in many signal transduction pathways in eukaryotes. This review describes comparative protein kinase analysis of two apicomplexa Plasmodium falciparum (3D7 strain) and Plasmodium yoelii yoelii (17XNL strain) which are causative agents of malaria in human and African rat respectively. Sensitive bioinformatics techniques enable identification of 82 and 60 putative protein kinases in P. falciparum and P. yoelii yoelii respectively and these sequences could be classified into known subfamilies of protein kinases. The most populated kinase subfamilies in both the plasmodium species correspond to CAMK and CMGC groups. Analysis of domain architectures enables detection of uncommon domain organization in kinases of both the organisms such as kinase domain tethered to EF hands as well as PH domain. Components of MAPK signaling pathway is not well conserved in plasmodium organisms. Such observations suggest that plasmodium protein kinases are highly divergent from other eukaryotes. A transmembrane kinase with 6 membrane spanning segments in P. falciparum seems to have no orthologue in P. yoelii yoelii. 19 P. falciparum kinases have been found to cluster separately from P. yoelii yoelii kinases and hence these kinases are unique to P. falciparum genome. Only 28 orthologous pairs of kinases seem to be present between these two plasmodium organisms. Comparative kinome analysis of two plasmodium species has thus provided clues to the function of many protein kinases based upon their classification and domain organization and also implicate marked differences even between two plasmodium organisms.
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PMID:Comparative kinomics of Plasmodium organisms: unity in diversity. 1762 89

Malaria infection is initiated when Anopheles mosquitoes inject Plasmodium sporozoites into the skin. Sporozoites subsequently reach the liver, invading and developing within hepatocytes. Sporozoites contact and traverse many cell types as they migrate from skin to liver; however, the mechanism by which they switch from a migratory mode to an invasive mode is unclear. Here, we show that sporozoites of the rodent malaria parasite Plasmodium berghei use the sulfation level of host heparan sulfate proteoglycans (HSPGs) to navigate within the mammalian host. Sporozoites migrate through cells expressing low-sulfated HSPGs, such as those in skin and endothelium, while highly sulfated HSPGs of hepatocytes activate sporozoites for invasion. A calcium-dependent protein kinase is critical for the switch to an invasive phenotype, a process accompanied by proteolytic cleavage of the sporozoite's major surface protein. These findings explain how sporozoites retain their infectivity for an organ that is far from their site of entry.
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PMID:Heparan sulfate proteoglycans provide a signal to Plasmodium sporozoites to stop migrating and productively invade host cells. 1800 48

Malaria symptoms occur during Plasmodium falciparum development into red blood cells. During this process, the parasites make substantial modifications to the host cell in order to facilitate nutrient uptake and aid in parasite metabolism. One significant alteration that is required for parasite development is the establishment of an anion channel, as part of the establishment of New Permeation Pathways (NPPs) in the red blood cell plasma membrane, and we have shown previously that one channel can be activated in uninfected cells by exogenous protein kinase A. Here, we present evidence that in P. falciparum-infected red blood cells, a cAMP pathway modulates anion conductance of the erythrocyte membrane. In patch-clamp experiments on infected erythrocytes, addition of recombinant PfPKA-R to the pipette in vitro, or overexpression of PfPKA-R in transgenic parasites lead to down-regulation of anion conductance. Moreover, this overexpressing PfPKA-R strain has a growth defect that can be restored by increasing the levels of intracellular cAMP. Our data demonstrate that the anion channel is indeed regulated by a cAMP-dependent pathway in P. falciparum-infected red blood cells. The discovery of a parasite regulatory pathway responsible for modulating anion channel activity in the membranes of P. falciparum-infected red blood cells represents an important insight into how parasites modify host cell permeation pathways. These findings may also provide an avenue for the development of new intervention strategies targeting this important anion channel and its regulation.
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PMID:Plasmodium falciparum regulatory subunit of cAMP-dependent PKA and anion channel conductance. 1824 92

Malaria is a major threat to world health. The identification of parasite targets for drug development is a priority and parasitic protein kinases suggest themselves as suitable targets as many display profound structural and functional divergences from their host counterparts. In this paper, we describe the structure of the orphan protein kinase, Plasmodium falciparum protein kinase 7 (PFPK7). Several Plasmodium protein kinases contain extensive insertions, and the structure of PFPK7 reveals how these may be accommodated as excursions from the canonical eukaryotic protein kinase fold. The constitutively active conformation of PFPK7 is stabilized by a structural motif in which the role of the conserved phosphorylated residue that assists in structuring the activation loop of many protein kinases is played by an arginine residue. We identify two series of PFPK7 ATP-competitive inhibitors and suggest further developments for the design of selective and potent PFPK7 lead compounds as potential antimalarials.
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PMID:Structures of P. falciparum protein kinase 7 identify an activation motif and leads for inhibitor design. 1827 14

Malaria remains a major killer in many parts of the world. Recently, the development of nonprofit organisations aimed at fighting this deadly scourge incited academic and industrial scientists to merge their expertise in drug-target validation and lead discovery. Expectations are clear: identification and characterisation of new molecules showing high efficacy, low toxicity and little propensity to induce resistance in the parasite. In this context, protein kinase inhibitors represent an attractive possibility. Here, we compare traditional target-based drug-discovery approaches with innovative exploratory paths (parallel screening, cell-based assays, integrated systems biology and allosteric inhibition) and discuss the benefits of acadaemia-industry cooperation. Early characterisation of distribution, metabolism, pharmacokinetic (DMPK) and toxicology parameters are considered as well.
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PMID:Drugging the Plasmodium kinome: the benefits of academia-industry synergy. 1839 21

Cyclic AMP-dependent protein kinase (protein kinase A, PKA) is a key element in many cell signaling pathways. An essential role of Plasmodium falciparum PKA (PfPKA) activity was reported in the intraerythrocytic growth of the malaria parasite. However, molecular characterization of PfPKA using purified recombinant proteins has not yet been performed. Here, we report the first successful purification of the enzymatically active PKA catalytic subunit of P. falciparum (PfPKA-C) using a wheat germ cell-free expression system. Interestingly, parasite enzymatic activity was weakly inhibited as compared with the inhibition of mammalian PKA catalytic subunit (PKA-C) by the specific PKA inhibitor, H89. Furthermore, PfPKA-C was only slightly inhibited by protein kinase inhibitor (PKI). These results suggest that substrate sites of PfPKA-C may be different from those of mammalian PKA-Cs. In addition, potential PKI corresponding to malarial PKA-C would also be different from those of mammalian cells.
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PMID:Susceptibility of Plasmodium falciparum cyclic AMP-dependent protein kinase and its mammalian homologue to the inhibitors. 1850 80


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