UNIPROT:P00750 - FACTA Search

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)

The proteins that bind phospholipase A2 (PLA2) isozymes of Trimeresurus flavoviridis (habu snake, crotalinae) venom were fractionated from sera on four columns, each conjugated with one of four PLA2 isozymes. Five proteins, termed PLA2 inhibitors (PLI) I-V, were obtained as the binding components. The combinations of the binding components differed depending on the PLA2 isozymes. PLI-IV and PLI-V correspond to PLI-A and PLI-B, respectively, which were known to bind to a major [Asp49]PLA2, PLA2, and contained a segment similar to the carbohydrate-recognition domain of C-type lectins. PLI-I, which is a major component of inhibitory proteins against three basic PLA2 isozymes, PLA-B (a basic [Asp49]PLA2) and basic proteins I and II (both [Lys49]PLA2s), has been isolated, and its partial amino acid sequence has been determined. A cDNA encoding PLI-I was isolated from a T. flavoviridis liver cDNA library and sequenced. PLI-I cDNA encoded 200 amino acid residues, including a signal peptide of 19 amino acid residues. One sugar chain was predicted to occur at position 157. A gene coding for PLI-I was isolated. It is 9.6-kb long and consists of five exons and four introns. Comparison of the exon-intron structure of the PLI-I gene with those of genes encoding urokinase-type-plasminogen-activator receptor (uPAR), Ly-6, CD59 and neurotoxins showed that they have characteristic unit encoding approximately 90 amino acid residues, which is divided over two exons. This strongly suggests that the PLI-I gene belongs to the uPAR, Ly-6, CD59 and neurotoxin gene family. There are two types of structurally different inhibitors against PLA2 isozymes in T. flavoviridis serum with different evolutionary origins.
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PMID:Characterization and evolution of a gene encoding a Trimeresurus flavoviridis serum protein that inhibits basic phospholipase A2 isozymes in the snake's venom. 939 34

The irreversible proteinase inhibitor Pefabloc (4-[2-aminoethyl] benzenesulfonyl fluoride) inactivates LDL-catalyzed hydrolysis of the short-chain fluorescent phospholipid C6-NBD-PC (1-acyl-2-(N-4-nitrobenzo-2-oxa-1,3-diazole)-aminocaproyl phosphatidylcholine). The dose-dependence of this inactivation is similar to that obtained previously for the inhibitory effect of Pefabloc on the hydrolysis of platelet activating factor (PAF) by the LDL-associated PAF acetylhydrolase (PAF-AH), in agreement with the notion that the hydrolysis of C6-NBD-PC and PAF is catalyzed by the same enzyme (LDL-associated phospholipase A; LDL-PLA). This conclusion is also supported by the finding that hydrolysis of C6-NBD-PC by LDL becomes inactivated by LDL oxidation only at late stages of the oxidation, similar to the effect of oxidation on the hydrolysis of PAF by the LDL-associated PAF-AH. Under conditions of complete inactivation of this enzyme towards C6-NBD-PC, the kinetics of lipid peroxidation, induced either by copper ions or by the free radical generator AAPH at varying doses of the prooxidant, was similar to that observed when the PLA was active (i.e., in the absence of Pefabloc). Hence, LDL-associated PLA (PAF-AH) does not protect LDL lipids from peroxidation. Similar results were obtained with fractionated LDL in albumin-containing buffer and for non-fractionated serum, in which copper-induced peroxidation was also not influenced by inactivation of the enzyme responsible for hydrolysis of C6-NBD-PC. Phospholipolysis of short chain phospholipids by LDL-PLA may still play a protective role against the toxic effects of oxidized phospholipids by reducing their internalization into cells (Schmitt et al. 1995).
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PMID:LDL-associated phospholipase A does not protect LDL against lipid peroxidation in vitro. 962 86

The effects of Pasteurella haemolytica leukotoxin (LKT) on the activity of phospholipase D (PLD) and the regulatory interaction between PLD and phospholipase A(2) (PLA(2)) were investigated in assays using isolated bovine neutrophils labeled with tritiated phospholipid substrates of the two enzymes. Exposure of [(3)H]lysophosphatidylcholine-labeled neutrophils to LKT caused concentration- and time-dependent production of phosphatidic acid (PA), the product of PLD. LKT-induced generation of PA was dependent on extracellular calcium. Both production of PA and metabolism of [(3)H]-arachidonate ([(3)H]AA)-labeled phospholipids by PLA(2) were inhibited when ethanol was used to promote the alternative PLD-mediated transphosphatidylation reaction, resulting in the production of phosphatidylethanol rather than PA. The role of PA in regulation of PLA(2) activity was then confirmed by means of an add-back experiment, whereby addition of PA in the presence of ethanol restored PLA(2)-mediated release of radioactivity from neutrophil membranes. Considering the involvement of chemotactic phospholipase products in the pathogenesis of pneumonic pasteurellosis, development and use of anti-inflammatory agents that inhibit LKT-induced activation of PLD and PLA(2) may improve therapeutic management of the disease.
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PMID:Role of phospholipase D in Pasteurella haemolytica leukotoxin-induced increase in phospholipase A(2) activity in bovine neutrophils. 1041 36

Prostaglandins (PGs) are important mediators of acute and chronic inflammation. The production of PGs in synovial tissues is catalyzed by an enzyme cascade that includes phospholipase A(2)s (PLA(2)s), cyclooxygenases (COXs), and terminal PG synthases. There are two isoforms of COX expressed in synovial tissues. COX-1 is constitutively expressed in synovia, particularly in synovial lining cells. COX-2, on the other hand, is localized most strikingly to the vascular endothelial cells, mononucler inflammatory cells, and subsynovial fibroblasts. There are no significant differences in immunostaining of COX-1 in vivo in inflammatory compared with non-inflammatory arthritis. COX-2 expression is increased in inflammatory arthritis. In-vitro, COX-2 expression in synovial cells is dramatically increased by proinflammatory cytokines, phorbol ester, and stimulation of certain cell surface receptors. A number of different transcription factors are likely to be involved in the up-regulation of COX-2 in synovial tissues. Expression of COX-2 is inhibited by glucocorticoids in synovial cells as in other cell types. Taken together, these data suggest that COX-2 is likely to be responsible for increased local PG production during inflammation of synovial tissues.
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PMID:COX-2 in synovial tissues. 1041 82

The report describes a method for the assay of five enzymatic activities involved in establishing the stratum corneum permeability barrier: beta-glucocerebrosidase, acid phosphatase, phospholipase A(2) (PLA(2)) and two serine proteases: chymotrypsin and its activator in the stratum corneum, trypsin. The specific activities of these different enzymes have been determined along with their pH profiles and sensivities to specific inhibitors. It can be noted that only two presented a pH optimum similar to the pH of the stratum corneum. This could suggest that their activities are regulated by local variations in pH. The method was applied to a pathological situation, that of a non-eczematous dry atopic dermatitis. Atopic skin had significantly reduced trypsin activity, increased acid phosphatase and no change in the activities of three other studied enzymes. Understanding these activities can provide a tool for the characterization of skin pathologies and for the development of a certain number of applications in cosmetology and therapeutics.
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PMID:Characterisation and assay of five enzymatic activities in the stratum corneum using tape-strippings. 1042 Jan 38

Type II-secreted phospholipase A(2) (type II-sPLA(2)) is expressed in smooth muscle cells during atherosclerosis or in response to interleukin-1beta. The present study shows that the induction of type II-sPLA(2) gene by interleukin-1beta requires activation of the NFkappaB pathway and cytosolic PLA(2)/PPARgamma pathway, which are both necessary to achieve the transcriptional process. Interleukin-1beta induced type II-sPLA(2) gene dose- and time-dependently and increased the binding of NFkappaB to a specific site of type II-sPLA(2) promoter. This effect was abolished by proteinase inhibitors that block the proteasome machinery and NFkappaB nuclear translocation. Type II-sPLA(2) induction was also obtained by free arachidonic acid and was blocked by either AACOCF(3), a specific cytosolic-PLA(2) inhibitor, PD98059, a mitogen-activated protein kinase kinase inhibitor which prevents cytosolic PLA(2) activation, or nordihydroguaiaretic acid, a lipoxygenase inhibitor, but not by the cyclooxygenase inhibitor indomethacin, suggesting a role for a lipoxygenase product. Type II-sPLA(2) induction was obtained after treatment of the cells by 15-deoxy-Delta(12,14)-dehydroprostaglandin J(2), carbaprostacyclin, and 9-hydroxyoctadecadienoic acid, which are ligands of peroxisome proliferator-activated receptor (PPAR) gamma, whereas PPARalpha ligands were ineffective. Interleukin-1beta as well as PPARgamma-ligands stimulated the activity of a reporter gene containing PPARgamma-binding sites in its promoter. Binding of both NFkappaB and PPARgamma to their promoter is required to stimulate the transcriptional process since inhibitors of each class block interleukin-1beta-induced type II-sPLA(2) gene activation. We therefore suggest that NFkappaB and PPARgamma cooperate at the enhanceosome-coactivator level to turn on transcription of the proinflammatory type II-sPLA(2) gene.
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PMID:Interleukin 1beta induces type II-secreted phospholipase A(2) gene in vascular smooth muscle cells by a nuclear factor kappaB and peroxisome proliferator-activated receptor-mediated process. 1043 77

The activation of phospholipase A(2) (PLA(2)) with release of eicosanoids and prostanoids in mature myeloid cells and the augmentation (priming) of this activity by cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF) are central to the inflammatory process. Yet, there are few data concerning PLA(2) activity and its regulation by growth factors in primary hematopoietic cells. We therefore analyzed the PLA(2) activity of mobilized human CD34 antigen-positive (CD34(+)) stem cells by quantitation of the extracellular release of (3)H-arachidonate. The PLA(2) activity of CD34(+) cells stimulated with calcium ionophore (A23187) was of similar magnitude to that of mature neutrophils and monocytes. Preincubation of CD34(+) cells with stem cell factor (SCF) before A23187-stimulation resulted in primed PLA(2) activity, whereas interleukin-3 (IL-3), GM-CSF, and tumor necrosis factor alpha had no significant effect. When CD34(+) cells were induced to differentiate, PLA(2) activity remained responsive to SCF for several days, but after 8 days, at which stage morphological and functional evidence of maturation was occurring, priming of PLA(2) by SCF could no longer be elicited, whereas responses to GM-CSF and IL-3 had developed. The further metabolism of arachidonic acid to eicosanoids by CD34(+) cells was not detected by either thin-layer chromatography, enzyme immunoassay, or differential spectroscopy. SCF stimulated the rapid but transient activation of ERK2 (p42 MAP kinase) in CD34(+) cells, and we used the MAP kinase kinase inhibitor, PD 098059, which at 30 micromol/L blocks ERK2 activation in CD34(+) cells, to investigate whether SCF-mediated priming of arachidonate release was mediated by this kinase. PD 098059 only partially inhibited A23187-stimulated PLA(2) activity primed by SCF, suggesting the involvement of ERK2 and possibly a further signal transduction pathway. Methyl arachidonyl fluorophosphonate (5 micromol/L), a dual inhibitor of i and cPLA(2) isoforms, completely inhibited arachidonate release without affecting ERK2 activation, demonstrating the lack of cellular toxicity. These data provide the first evidence that primitive myeloid cells have the capacity to release arachidonate, which is regulated by an early acting hematopoietic growth factor important for the growth and survival of these cells.
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PMID:Primitive myeloid cells express high levels of phospholipase A(2) activity in the absence of leukotriene release: selective regulation by stem cell factor involving the MAP kinase pathway. 1043 14

Recent pharmacological studies using specific antagonists of phospholipase A(2) (PLA(2)) activity have suggested that the formation of Golgi membrane tubules, 60-80 nm in diameter and up to several microns long, both in vivo and in a cell-free cytosol-dependent reconstitution system, requires the activity of a cytoplasmic Ca(2+)-independent PLA(2). We confirm and extend these studies by demonstrating that the stimulators of PLA(2), melittin and PLA(2) activating protein peptide (PLAPp), enhance cytosol-dependent Golgi membrane tubulation. Starting with preparations of bovine brain cytosol (BBC), or a fraction of BBC that is highly enriched in tubulation activity, called the gel filtration (GF) fraction, that are at subsaturating concentrations for inducing tubulation in vitro, we found that increasing concentrations of melittin or PLAPp produced a linear and saturable stimulation of Golgi membrane tubulation. This stimulation was inhibited by cytosolic PLA(2) antagonists, including the Ca(2+)-independent PLA(2)-specific antagonist, bromoenol lactone. The stimulatory effect of PLAPp, and its inhibition by PLA(2) antagonists, was reproduced using a permeabilized cell system, which reconstitutes both cytosol-dependent Golgi membrane tubulation and retrograde trafficking to the endoplasmic reticulum (ER). Taken together, these results are consistent with the idea that cytosolic PLA(2) activity is involved in the formation of Golgi membrane tubules, which can serve as trafficking intermediates in Golgi-to-ER retrograde movement.
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PMID:Stimulation of Golgi membrane tubulation and retrograde trafficking to the ER by phospholipase A(2) activating protein (PLAP) peptide. 1044 Sep 36

We employed confocal laser-scanning microscopy to monitor cholecystokinin (CCK)-evoked Ca(2+) signals in fluo-3-loaded mouse pancreatic acinar cells. CCK-8-induced Ca(2+) signals start at the luminal cell pole and subsequently spread toward the basolateral membrane. Ca(2+) waves elicited by stimulation of high-affinity CCK receptors (h.a.CCK-R) with 20 pM CCK-8 spread with a slower rate than those induced by activation of low-affinity CCK receptors (l.a. CCK-R) with 10 nM CCK-8. However, the magnitude of the initial Ca(2+) release was the same at both CCK-8 concentrations, suggesting that the secondary Ca(2+) release from intracellular stores is modulated by activation of different intracellular pathways in response to low and high CCK-8 concentrations. Our experiments suggest that the propagation of Ca(2+) waves is modulated by protein kinase C (PKC) and arachidonic acid (AA). The data indicate that h.a. CCK-R are linked to phospholipase C (PLC) and phospholipase A(2) (PLA(2)) cascades, whereas l.a.CCK-R are coupled to PLC and phospholipase D (PLD) cascades. The products of PLA(2) and PLD activation, AA and diacylglycerol (DAG), cause inhibition of Ca(2+) wave propagation by yet unknown mechanisms.
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PMID:Cholecystokinin-evoked Ca(2+) waves in isolated mouse pancreatic acinar cells are modulated by activation of cytosolic phospholipase A(2), phospholipase D, and protein kinase C. 1044 93

Recent work indicates that respiratory muscles generate superoxide radicals during contraction (M. B. Reid, K. E. Haack, K. M. Francik, P. A. Volberg, L. Kabzik, and M. S. West. J. Appl. Physiol. 73: 1797-1804, 1992). The intracellular pathways involved in this process are, however, unknown. The purpose of the present study was to test the hypothesis that contraction-related formation of reactive oxygen species (ROS) by skeletal muscle is linked to activation of the 14-kDa isoform of phospholipase A(2) (PLA(2)). Studies were performed by using an in vitro hemidiaphragm preparation submerged in an organ bath, and formation of ROS in muscles was assessed by using a recently described fluorescent indicator technique. We examined ROS formation in resting and contracting muscle preparations and then determined whether contraction-related ROS generation could be altered by administration of various PLA(2) inhibitors: manoalide and aristolochic acid, both inhibitors of 14-kDa PLA(2); arachidonyltrifluoromethyl ketone (AACOCF(3)), an inhibitor of 85-kDa PLA(2); and haloenol lactone suicide substrate (HELSS), an inhibitor of calcium-independent PLA(2). We found 1) little ROS formation [2.0 +/- 0.8 (SE) ng/mg] in noncontracting control diaphragms, 2) a high level of ROS (20.0 +/- 2.0 ng/mg) in electrically stimulated contracting diaphragms (trains of 20-Hz stimuli for 10 min, train rate 0.25 s(-1)), 3) near-complete suppression of ROS generation in manoalide (3.0 +/- 0.5 ng/mg, P < 0. 001)- and aristolochic acid-treated contracting diaphragms (4.0 +/- 1.0 ng/mg, P < 0.001), and 4) no effect of AACOCF(3) or HELSS on ROS formation in contracting diaphragm. During in vitro studies examining fluorescent measurement of ROS formation in response to a hypoxanthine/xanthine oxidase superoxide-generating solution, manoalide, aristolochic acid, AACOCF(3), and HELSS had no effect on signal intensity. These data indicate that ROS formation by contracting diaphragm muscle can be suppressed by the administration of inhibitors of the 14-kDa isoform of PLA(2) and suggest that this enzyme plays a critical role in modulating ROS formation during muscle contraction.
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PMID:Formation of reactive oxygen species by the contracting diaphragm is PLA(2) dependent. 1044 41

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