Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activation of the enzyme phospholipase (PLA 2) has been proposed to be part of the molecular mechanism involved in the alteration of 2-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) glutamate receptor responsiveness during long term changes in synaptic plasticity (long term potentiation). This study assesses the effect of the caveolin-1 scaffolding domain (CSD) on the activity of the regulatory enzyme PLA2. Caveolin-1 is a 22-kDa cholesterol-binding membrane protein known to inhibit the activity of most of its interacting partners. Our results show that the calcium-dependent cytosolic form of PLA2 (cPLA2) and caveolin-1 co-localized in mouse primary hippocampal neuron cultures and that they were co-immunoprecipitated from mouse hippocampal homogenates. A peptide corresponding to the scaffolding domain of caveolin-1 (Cav-(82-101)) dramatically inhibited cPLA2 activity in purified hippocampal synaptoneurosomes. Activation of endogenous PLA2 activity with KCl or melittin increased the binding of [3H]AMPA to its receptor. This effect was almost completely abolished by the addition of the CSD peptide to these preparations. Moreover, we demonstrated that the inhibitory action of the CSD peptide on AMPA receptor binding properties is specific (because a scrambled version of this peptide failed to have any effect) and that it is mediated by an inhibition of PLA2 enzymatic activity (because the CSD peptide failed to have an effect in membrane preparations lacking endogenous PLA2 activity). These results raised the possibility that caveolin-1, via the inhibition of cPLA2 enzymatic activity, may interfere with synaptic facilitation and long term potentiation formation in the hippocampus.
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PMID:The caveolin scaffolding domain modifies 2-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor binding properties by inhibiting phospholipase A2 activity. 1456 56

Platelet membrane glycoprotein IIb/IIIa plays an important role in platelet aggregation. A polymorphism of the gene encoding the IIIa subunit, with the two allele forms PLA1 and PLA2, has been identified. Some, but not all, studies suggest that the PLA2 allele confers an increased risk of suffering a myocardial infarction. Conversely, a recent study suggests that the PLA1 allele may contribute to early atherosclerosis and more rapid progression of stable coronary artery disease. To test whether these associations could be reproduced in a well-characterized sample of survivors of premature myocardial infarction, we examined 369 patients admitted to coronary care units in the Stockholm area who suffered a first myocardial infarction before the age of 60 years. There were no significant differences in extent of coronary artery disease according to PLA genotype group (based on quantitative coronary angiography). In addition, the frequencies of PLA1 and PLA2 alleles did not differ from those of 388 well-matched control subjects without coronary artery disease. These results suggest that the PLA1/PLA2 polymorphism of the platelet glycoprotein IIIa gene does not substantially contribute to the development of coronary atherosclerosis or the genetic susceptibility to premature myocardial infarction.
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PMID:No evidence that the PLA1/PLA2 polymorphism of platelet glycoprotein IIIa is implicated in angiographically characterized coronary atherosclerosis and premature myocardial infarction. 1461 55

Pseudonaja textilis, an Australian Elapid, is known to produce a highly toxic venom. Both protein profiling and N-terminal sequence analysis showed the presence of four new phospholipases A(2) in this venom. Besides being non-lethal, the phospholipase A(2) proteins were found to be moderately active enzymes and they showed procoagulant property. cDNA cloning and characterization indicated the presence of two isoforms of PLA(2) proteins in a single snake, each containing the "pancreatic loop," characteristic of group IB phospholipase A(2). The genomic cloning also confirmed the presence of two genes each containing four exons that are interrupted by three introns. Phylogenetic analysis showed that the venom group IB PLA(2) gene is primitive and could have evolved from the same ancestor as the mammalian and venom group IA PLA(2) genes. In the present study, we report that the Pt-PLA2 gene could be responsible for the production of PL1, 2, and 3 possibly via RNA editing process.
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PMID:Group IB phospholipase A2 from Pseudonaja textilis. 1467 80

In order to discover novel invertebrate cytokines from the budding tunicate, Polyandrocarpa misakiensis, we treated the water-insoluble fraction of tunicate homogenates with trypsin. The extracts showed remarkable activities to promote the growth and motility of tunicate cells. The activities were heat-stable and proteinase K-resistant. After anion exchange chromatography, the activities were eluted with detergents such as 0.1% deoxycholic acid. The Fourier transform infrared spectrum indicated large amounts of fatty acids and phospholipids instead of polypeptides in the extracts. Consistently, the activities were extractable with organic solvents such as chloroform. Long chains of n-3 polyunsaturated free fatty acids (FFA), phosphatidylinositol (PI), phosphatidylcholine (PC), phosphatidylethanolamine (PE) and phosphatidylserine (PS) were the major components in the lipid-soluble fraction. A cDNA for FFA-releasing enzyme phospholipase A(2) (PLA(2)) was cloned. The expression of this gene could be seen in epidermal cells during budding. The recombinant protein, as in the case of the authentic PLA2, preferred PC and PE as substrates, followed by PS and PI. The resultant FFAs only promoted cell growth, while the remaining lysophospholipids stimulated cell motility. The former contained unsaturated fatty acids (C18:1, C20:5, and C22:6) while the latter did not, suggesting that unsaturated fatty acids are responsible for mitogenic activity in tunicate cells. These results show for the first time that phospholipids and their derivatives are bio-mediators promoting cell growth and cell motility in invertebrates.
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PMID:Phospholipids and their derivatives as mitogen and motogen of budding tunicates. 1499 11

The whole seed extract of S. nux vomica (in low doses) effectively neutralized Daboia russelii venom induced lethal, haemorrhage, defibrinogenating, PLA2 enzyme activity and Naja kaouthia venom induced lethal, cardiotoxic, neurotoxic, PLA2 enzyme activity. The seed extract potentiated polyvalent snake venom antiserum action in experimental animals. An active compound (SNVNF) was isolated and purified by thin layer chromatography and silica gel column chromatography, which effectively antagonised D. russelii venom induced lethal, haemorrhagic, defibrinogenating, oedema, PLA2 enzyme activity and N. kaouthia induced lethal, cardiotoxic, neurotoxic, PLA, enzyme activity. Polyvalent snake venom antiserum action was significantly potentiated by the active compound. Spectral studies revealed it to be a small, straight chain compound containing methyl and amide radicals. Detailed structure elucidation of the compound (SNVNF) is warranted before its clinical trials as a snake venom antagonist.
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PMID:Antisnake venom activity of ethanolic seed extract of Strychnos nux vomica Linn. 1523 70

Bacterial vaginosis (BV) is presently being cited as a probable cause of premature labour, where it is thought that an abnormal excess of phospholipase A2 enzyme (PLA2 ), generated by infecting organisms, prematurely liberates prostaglandins, which trigger-off the labour process. PLA levels of pregnant and non-pregnant women, with and without BV infection were compared. The in vitro concentrations of PLA2 in broth cultures of infecting organisms were also measured. Mean PLA2 level in non-infected pregnant women was 777 units per mg but was raised to 1226 U/mg in those with BV ( P= <0.001). Mean level in non-infected normal women was 21 U/mg, but was raised to 97 U/mg in those having BV ( P= <0.001). PLA2 concentrations in broth cultures of the causative organisms showed that most Bacteroides strains produced the enzyme, having a mean concentration of 95 U/mg, but that it was generated by only 34% of Gardnerella vaginalis strains, their mean concentration being 32 U/mg.
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PMID:The determination of phospholipase A2 enzyme activity in the vaginal secretions of pregnant and non-pregnant women with bacterial vaginosis-and in culture exudates of its causative organisms. 1551 58

New information has challenged our traditional concepts that the forms and functions of PLA(2) are highly homologous, suggesting now that distinct PLA(2)s may be assigned distinct functions in normal and pathological processes. The nonpancreatic type II 14-kDa PLA(2) and the recently identified type IV "cytosolic" 85-kDa PLA(2) are the two forms most studied in inflammation. Observations in the past suggested that the type II 14-kDa PLA2 is a secreted enzyme that functions extracellularly. Evidence is now emerging that the type II 14-kDa PLA(2) or its recently discovered low-molecular-weight isoforms may be localized and act intracellularly. In view of this, a more complex notion of distinctly functioning PLA(2)s in arachidonic acid release and/or eicosanoid generation can be envisioned. A comparison of the structural and biochemical features of the type II 14-kDa and the 85-kDa PLA(2)s reveals that the enzymes are more distinct than similar. These two enzymes would appear to have distinctly different genetic and biochemical regulatory mechanisms, suggesting that their functions could be quite distinct. Inhibitors of the 14-kDa PLA(2) and to a lesser extent the 85-kDa PLA(2) have been used to obtain a greater understanding of their cellular roles. The concept that the two distinct enzymes might hydrolyze arachidonic acid from different pools and/or supply distinct metabolizing systems in a single cell system has emerged. At this time an intriguing hypothesis can be formed suggesting distinct functional modalities for the two the PLA(2) enzymes in a single cell system. Evidence continues to build implicating the role of the type II 14-kDa PLA(2) in disease, providing a strong rationale for targeting this enzyme in designing novel antiinflammatory therapeutics.
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PMID:Modulation of arachidonic acid metabolism: focus on phospholipase A2(S). 1561 55

Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) has been shown to play a crucial role in atherosclerosis, and has been proposed as a promising target for drug discovery. Here, we cloned the Lp-PLA(2) gene from differentiated THP-1 cells, and inserted a carboxy-terminal His(6)-tagged version of the gene into the pPIC9 Pichia expression vector. The Lp-PLA(2) fusion protein was successfully expressed in Pichia pastoris expression system and could be rapidly purified to apparent homogeneity using a single-step purification method. The activity of our recombinant Lp-PLA(2) was strong when [3H] PAF was used as a substrate, and the Lp-PLA(2) inhibitor SB435495 exhibited an inhibitory curve against the recombinant Lp-PLA2 (IC50 = 15.93 +/- 1 microM). This novel recombinant Lp-PLA(2) could prove useful as a screening model for Lp-PLA(2) inhibitors, and may facilitate further investigation of this protein in atherosclerosis.
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PMID:Cloning, expression, and purification of lipoprotein-associated phospholipase A(2) in Pichia pastoris. 1669 Oct 4

The prevalence rates of the platelet glycoprotein IIb/IIIa Leu33Pro allele (PLA2), and factor V G1691A Leiden mutation were determined in 109 appropriate for gestational age neonates with grade I intraventricular haemorrhage (IVH) and in 118 IVH-free control infants. The PLA2 allele frequency was 16.4 % in the group of full-term infants with grade I IVH, while it was 9.5 % in the relevant controls (p < 0.005); there was no difference in the PLA allele frequencies on comparing the IVH affected (8.34 %) and unaffected (9.2 %) premature infants. By contrast, the factor V Leiden allele frequency was increased only in the subgroup of premature infants with grade I IVH as compared with the appropriate premature controls (9.25 % vs. 3.34 %, respectively, p < 0.005). These data suggest that besides the factor V Leiden mutation, the PLA2 allele, which has already been suggested to have a role in neonatal alloimmune thrombocytopenia and certain subtypes of adult stroke, can have significance in the development of the events of IVH.
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PMID:Increased prevalence of glycoprotein IIb/IIIa Leu33Pro polymorphism in term infants with grade I intracranial haemorrhage. 1677 3

Phospholipase A2 (PLA(2)) has been implicated in neurodevelopmental processes and in the early development of the nervous system. We investigated the effects of the inhibition of calcium-dependent and calcium-independent subtypes of cytosolic PLA2 (cPLA2 and iPLA2) on the development and viability of primary cultures of cortical and hippocampal neurons. PLA2 in these cultures was continuously inhibited with methylarachidonyl-fluorophosphonate (MAFP), an irreversible inhibitor of cPLA2 and iPLA2, or with bromoenol lactone (BEL), an irreversible selective iPLA2 inhibitor. The effect of PLA2 inhibitors on the development of neuronal cultures was ascertained by total cell count and morphological characterisation. Neuronal viability was quantified with MTT assays. Inhibition of PLA2 resulted in reduction of neuritogenesis and neuronal viability, disrupting neuronal homeostasis and leading to neuronal death. We conclude that the functional integrity of both calcium-dependent and calcium-independent cytosolic PLA2 is necessary for the in vitro development of cortical and hippocampal neurons.
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PMID:Inhibition of phospholipase A2 reduces neurite outgrowth and neuronal viability. 1718 73


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