Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.3 (phospholipase C)
 18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In patients with malaria, the clinical manifestations of the disease are associated with the presence of high concentrations of tumour necrosis factor (TNF) in the serum. Blood-stage parasites of human and rodent malarial parasites release serologically related exoantigens which induce the production of TNF in vitro and in vivo and which can kill mice made hypersensitive to TNF by pretreatment with D-galactosamine. They also elicit the production of T-independent antibody, which blocks these effects. The capacity of the exoantigens to stimulate macrophages to secrete TNF does not require the presence of protein or carbohydrate, but is associated with a lipid whose activity can be abolished by treatment with phospholipase C. Treatments of the exoantigens which destroyed their activity in vitro also abrogated their immunogenicity and their toxicity for mice. No TNF-inducing activity could be detected in preparations of parasitized erythrocytes that was not associated with phospholipid, and the TNF-inducing properties of the malarial phospholipids are quite distinct from those of bacterial lipopolysaccharide. We conclude that release of potentially toxic phospholipids by parasites may be responsible for some of the pathology of malaria.
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PMID:Tumour necrosis factor induction by malaria exoantigens depends upon phospholipid. 153 89

Quantification of human peripheral blood NK subsets has been made in a group of Kenyan adults and children with acute P. falciparum malaria. Results were compared with data obtained from three age- and sex-matched control cohorts: parasitaemic but asymptomatic children; aparasitaemic children and adults; and adult Caucasians with no previous history of malaria. Separated NK subsets were tested in vitro for cytotoxicity to erythrocytic schizonts of P. falciparum in the presence and absence of cytokines. There was a statistically significant quantitative and qualitative depression of the CD3-CD56+ subset in patients with acute malaria and this was accompanied by an expansion of the 'non-functional' CD3-CD57+CD16-CD56- subset. Both CD3-CD16+ and CD3-CD56+ NK cells from all patients and donors lysed schizonts, and this cytotoxicity was enhanced by the addition of recombinant interferon-alpha and/or IL-2, notably with the CD3-CD56+ subset. Interestingly, asymptomatic donors had the highest levels of CD3-CD56+ NK cells, which also demonstrated an enhanced response to cytokine stimulation. Cytotoxicity to schizonts was accompanied by the release of soluble NK cell lytic factors. Neomycin suppressed cytotoxicity in a dose-dependent manner, indicating that the lysis of schizonts by NK cells involves phospholipase C-mediated phosphoinositide metabolism. Our findings define a role for NK cells in immunity to malaria through the lysis of infected erythrocytes as a first-line defence against the parasite.
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PMID:Cytotoxicity of human natural killer (NK) cell subsets for Plasmodium falciparum erythrocytic schizonts: stimulation by cytokines and inhibition by neomycin. 183

Three enzymes have been described in malaria merozoites: a serine-protease and two phospholipases. The parasite serine-protease is necessary for parasite entry into the red blood cell. This enzyme is synthesized by intraerythrocytic schizonts as a glycolipid-anchored membrane precursor, harbouring a preformed serine-protease active site but no detectable proteolytic activity. Detection of the enzymatic activity correlates with the solubilisation of the enzyme by a parasite glycolipid-specific phospholipase C in merozoites. A third enzyme has been detected with glycolipid-degrading activity, presumably a lipase A. These activities participate in a biochemical cascade originating with the attachment of the merozoite to the red blood cell, including the translocation of the phospholipase C to the membrane-bound protease, the solubilisation/activation of the protease and its secretion at the erythrocyte/parasite junction and ending with the entry of the parasite into the host cell. Both the phospholipase C and the lipase A might generate secondary messages in the merozoite. Our current knowledge concerning these enzymes is presented.
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PMID:Malaria parasites: enzymes involved in red blood cell invasion. 808 Dec 50

The kinetics of phosphoinositol 4,5 bisphosphate hydrolysis products in activated Plasmodium falciparum gametocytes suggests a role for inositol trisphosphate [Ins(1,4,5)P3] and diacylglycerol (DAG) in the signal transduction pathway of malaria gametocytes. To investigate further this role, compounds that have an effect on the metabolism and biologic functions of these second messengers were tested in an in vitro system. Gentamycin, 2,3 diphosphoglycerate (2,3 DPG) and magnesium ion (Mg2+), inhibitors of Ins(1,4,5)P3 5' phosphatase, all stimulated gametocytes to exflagellate in suspended animation buffer, pH 7.4, at room temperature. In addition, methylxanthines, caffeine and theobromine, calcium ionophore (A-23187), and external calcium also stimulated exflagellation. In contrast, neomycin, an aminoglycoside that inhibits phospholipase C activity, and heparin, an antagonist of Ins(1,4,5)P3 binding to its receptor, inhibited microgamete formation. Quinine and chloroquine which can inhibit both phospholipase A and C activity also inhibited gametocyte exflagellation. The consistent manner in which these various compounds affect gametocyte activation further implicates phosphoinositol turnover in the signal transduction pathway of falciparum gametocytes.
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PMID:Use of pharmacological agents to implicate a role for phosphoinositide hydrolysis products in malaria gamete formation. 824 Apr 17

Plasmodium falciparum is the causative agent of malaria tropica in man. Biochemical studies were focused on the asexual, intraerythrocytic stages of P. falciparum, because of their role in the clinical phase of the disease and the possibility of propagation in a cell culture system. In this report, we describe the in-culture labeling of malarial glycolipids and the analysis of their hydrophilic moieties. They were identified as glycosylphosphatidylinositols (GPIs) by: 1) labeling with [3H]mannose, [3H]glucosamine, and [3H]ethanolamine and 2) sensitivity toward glycosylphosphatidylinositol-specific phospholipase D, phospholipase A2, and nitrous acid. Malarial GPIs are shown to be unaffected by treatment with phosphatidylinositol-specific phospholipase C, regardless of prior treatment with mild base commonly used for inositol deacylation. Two candidates for putative GPI-anchor precursors to malarial membrane proteins with the structures ethanolamine-phosphate-6(Man alpha 1-2)Man alpha 1-2Man alpha 1-6Man alpha 1-4 GlcN-PI (Pfg1 alpha) and ethanolamine-phosphate-6Man alpha 1-2Man alpha 1-6Man-alpha 1-4-GlcN-PI (Pfg1 beta) were identified.
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PMID:Glycosylphosphatidylinositols synthesized by asexual erythrocytic stages of the malarial parasite, Plasmodium falciparum. Candidates for plasmodial glycosylphosphatidylinositol membrane anchor precursors and pathogenicity factors. 830 May 89

Previous studies have shown that 'toxic malarial antigens' released by Plasmodium yoelii can induce hypoglycaemia in mice and act synergistically with insulin in stimulating lipogenesis in rat adipocytes in vitro. In this study, it was shown that similar bioactivity could be detected in Plasmodium falciparum culture supernatant, and the molecular basis of this activity was further investigated. Boiled spent culture medium from P. falciparum cultures ('BS-Pf') (exclusively released into the culture supernatant when schizonts rupture) acts in synergy with insulin to increase lipogenesis in a rat adipocyte assay by more than 250% (P < 0.001). Control preparations prepared from non-parasitized erythrocytes grown under similar conditions had no effect (P < 0.001). While contamination with mycoplasma has previously been shown to interfere with the interpretation of data obtained with other molecules thought to be released from P. falciparum in culture, including those inducing TNF-alpha and NO production by macrophages, such contamination was unequivocally ruled out here. BS-Pf alone did not stimulate the lipogenesis in short-term assays (less than 4 h), while long-term exposure of rat adipocytes to BS-Pf alone (12-24 h) caused a stimulation of lipogenesis at a level comparable to that observed with insulin. Furthermore, lipogenesis-inducing activity was also detected in the serum of squirrel monkeys infected with different species of malaria parasites (P. vivax, P. falciparum and P. brasilianum). Preliminary biochemical characterization showed that the biological activity was found in the solvent-extracted polar lipid fraction of boiled supernatant of P. falciparum cultures. All the different polar lipid fractions, collected from silica gel column chromatography, showed a comparable lipogenesis-inducing activity. Enzymatic treatment by phospholipase C of the lipid fraction, which co-migrated with the phosphatidylcholine standard, showed that the activity of the fraction was associated with the 1,2-diacylglycerol (1,2-DAG) moieties released from polar lipids. When this exogenous 1,2-DAG was added to the adipocyte cultures (short- and long-term cultures), it induced stimulation of lipogenesis in rat adipocytes, while no lipogenic activity was obtained from bacterial polar lipids and 1,2-DAG isolated from unparasitized erythrocytes. The importance of these findings is discussed with reference to other toxic malarial antigens and also to the potential role of these molecules in the induction of hypoglycaemia in the severe forms of malaria.
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PMID:Polar Plasmodium falciparum lipids induce lipogenesis in rat adipocytes in vitro. 1116 22

Intracellular cell signaling cascades of protozoan parasite Plasmodium falciparum are not clearly understood. We have reported previously (Kumar, A., Vaid, A., Syin, C., and Sharma, P. (2004) J. Biol. Chem. 279, 24255-24264) the identification and characterization of a protein kinase B-like enzyme in P. falciparum (PfPKB). PfPKB lacks the phosphoinositide-interacting pleckstrin homology domain present in mammalian protein kinase B. Therefore, the mechanism of PfPKB regulation was expected to be different from that of the host and had remained unknown. We have identified calmodulin (CaM) as the regulator of PfPKB activity. A CaM binding domain was mapped in the N-terminal region of PfPKB. CaM, in a calcium-dependent manner, interacts with this domain and activates PfPKB. CaM associates with PfPKB in the parasite and regulates its activity. Furthermore phospholipase C acts as an upstream regulator of this cascade as it facilitates the release of calcium from intracellular stores. This is one of the first multicomponent signaling pathways to be dissected in the malaria parasite.
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PMID:PfPKB, a protein kinase B-like enzyme from Plasmodium falciparum: II. Identification of calcium/calmodulin as its upstream activator and dissection of a novel signaling pathway. 1680 43

Recombinant homologues of the Plasmodium merozoite surface protein 1 C-terminus are leading blood stage malaria vaccine candidates. MSP1 is anchored to the merozoite plasma membrane in vivo by a glycosyl-phosphatidyl-inositol (GPI) moiety, implicated in malaria pathology. Two types of recombinant Plasmodium falciparum MSP1p19 (PfMSP1p19) expressed in baculovirus/insect cells are described here: (1) a soluble, secreted form (PfMSP1p19S) and (2) detergent soluble cellular form(s) (PfMSP1p19+A), released from the infected cell surface by treatment with GPI specific phosphatidyl-inositol phospholipase C (PI-PLC). Soluble and cellular PfMSP1p19 were purified and characterized using SDS-PAGE, mass spectrometry (MS), N-terminal amino acid sequencing, gel filtration and glycan analyses. Quantitative inositol dosage suggested that surface GPI processed entities constituted only 14% of the purified cellular PfMSP1p19+A, with GPI unprocessed forms likely recovered in the endoplasmic reticulum. Nevertheless, this preparation has dramatic immuno-stimulatory activity to be described elsewhere. The interest of these results for both malaria specific and generic vaccine development are discussed.
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PMID:Soluble and glyco-lipid modified baculovirus Plasmodium falciparum C-terminal merozoite surface protein 1, two forms of a leading malaria vaccine candidate. 1681 34

Molecular mechanisms by which signaling pathways operate in the malaria parasite and control its development are promiscuous. Recently, we reported the identification of a signaling pathway in Plasmodium falciparum, which involves activation of protein kinase B-like enzyme (PfPKB) by calcium/calmodulin (Vaid, A., and Sharma, P. (2006) J. Biol. Chem. 281, 27126-27133). Studies carried out to elucidate the function of this pathway suggested that it may be important for erythrocyte invasion. Blocking the function of the upstream activators of this pathway, calmodulin and phospholipase C, resulted in impaired invasion. To evaluate if this signaling cascade controls invasion by regulating PfPKB, inhibitors against this kinase were developed. PfPKB inhibitors dramatically reduced the ability of the parasite to invade erythrocytes. Furthermore, we demonstrate that PfPKB associates with actin-myosin motor and phosphorylates PfGAP45 (glideosome-associated protein 45), one of the important components of the motor complex, which may help explain its role in erythrocyte invasion.
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PMID:Role of Ca2+/calmodulin-PfPKB signaling pathway in erythrocyte invasion by Plasmodium falciparum. 1816 40

Recent studies have demonstrated that calcium-dependent protein kinases (CDPKs) are used by calcium to regulate a variety of biological processes in the malaria parasite Plasmodium. CDPK4 has emerged as an important enzyme for parasite development, because its gene disruption in rodent parasite Plasmodium berghei causes major defects in sexual differentiation of the parasite ( Billker, O., Dechamps, S., Tewari, R., Wenig, G., Franke-Fayard, B., and Brinkmann, V. (2004) Cell 117, 503-514 ). Despite these findings, it is not very clear how PfCDPK4 or any other PfCDPK is regulated by calcium at the molecular level. We report the biochemical characterization and elucidation of molecular mechanisms involved in the regulation of PfCDPK4. PfCDPK4 was detected on gametocyte periphery, and its activity in the parasite was regulated by phospholipase C. Even though the Junction Domain (JD) of PfCDPK4 shares moderate sequence homology with that of the plant CDPKs, it plays a pivotal role in PfCDPK4 regulation as previously reported for some plant CDPKs. The regions of the J-domain involved in interaction with both the kinase domain and the calmodulin-like domain were mapped. We propose a model for PfCDPK regulation by calcium, which may also prove useful for design of inhibitors against PfCDPK4 and other members of the PfCDPK family.
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PMID:Dissection of mechanisms involved in the regulation of Plasmodium falciparum calcium-dependent protein kinase 4. 1930 75


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