Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.3 (phospholipase C)
18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Phosphatidylinositol (PtdIns), phosphatidylinositol 4-phosphate (PtdIns4P) and phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] of turkey erythrocytes were labelled by using either [32P]Pi or [3H]inositol. Although there was little basal release of inositol phosphates from membranes purified from labelled cells, in the presence of guanosine 5'-[gamma-thio]triphosphate (GTP[S]) the rate of accumulation of inositol bis-, tris- and tetrakis-phosphate (InsP2, InsP3 and InsP4) was increased 20-50-fold. The enhanced rate of accumulation of 3H-labelled inositol phosphates was linear for up to 20 min; owing to decreases in 32P specific radioactivity of phosphoinositides during incubation of membranes with unlabelled ATP, the accumulation of 32P-labelled inositol phosphates was linear for only 5 min. In the absence of ATP and a nucleotide-regenerating system, no InsP4 was formed, and the overall inositol phosphate response to GTP[S] was decreased. Analyses of phosphoinositides during incubation with ATP indicated that interconversions of PtdIns to PtdIns4P and PtdIns4P to PtdIns(4,5)P2 occurred to maintain PtdIns(4,5)P2 concentrations; GTP[S]-induced inositol phosphate formation was accompanied by a corresponding decrease in 32P- and 3H-labelled PtdIns, PtdIns4P and PtdIns(4,5)P2. In the absence of ATP, only GTP[S]-induced decreases in PtdIns(4,5)P2 occurred. Since inositol monophosphate was not formed under any condition, PtdIns is not a substrate for the phospholipase C. The production of InsP2 was decreased markedly, but not blocked, under conditions where Ins(1,4,5)P3 5-phosphomonoesterase activity in the preparation was inhibited. Thus the predominant substrate of the GTP[S]-activated phospholipase C of turkey erythrocyte membranes is PtdIns(4,5)P2. Ins(1,4,5)P3 was the major product of this reaction; only a small amount of Ins(1:2-cyclic, 4,5)P3 was released. The effects of ATP on inositol phosphate formation apparently involve the contributions of two phenomena. First, the P2-receptor agonist 2-methylthioadenosine triphosphate (2MeSATP) greatly increased inositol phosphate formation and decreased [3H]PtdIns4P and [3H]PtdIns(4,5)P2 in the presence of a low (0.1 microM) concentration of GTP[S]. ATP over the concentration range 0-100 microM produced effects in the presence of 0.1 microM-GTP[S] essentially identical with those observed with 2MeSATP, suggesting that the effects of low concentrations of ATP are also explained by a stimulation of P2-receptors. Higher concentrations of ATP also increase inositol phosphate formation, apparently by supporting the synthesis of substrate phospholipids.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Phosphoinositide hydrolysis by guanosine 5'-[gamma-thio]triphosphate-activated phospholipase C of turkey erythrocyte membranes. 284 74

Brain cell membranes are known to abound in polyphosphoinositides (PPI) which contain large amounts of arachidonic acid and stearic acid. When a state of cerebral ischemia comes about, there occurs severe energy depletion and decomposition of PPI into diglyceride (DG) and inositol triphosphate (IP3) through activation of phospholipase C. Previous studies clarified rapid postischemic degradation of PPI, a time during which the metabolically active fraction of PPI is lost, but there have been no reports on PPI metabolism after the establishment of recirculation following ischemia. The authors examined relationship between the duration of the ischemia and the reversibility of PPI metabolism in rats with cerebral ischemia lasting 5 or 30 min that was followed by recirculation, and, further studied acyl group composition of PPI and DG in rats with 30 min of ischemia. Global cerebral ischemia was produced in male Wistar rats (220-250 g) by occlusion of basilar and bilateral common carotid arteries. The brains were frozen in situ at 1, 5, or 30 min of ischemia, or at 30 or 60 min of recirculation following either 5 or 30 min of ischemia. Phosphatidylinositol (PI), phosphatidylinositol, 4-phosphate (PIP), phosphatidylinositol, 4, 5-bisphosphate (PIP2), and DG were measured by TLC, and GLC. And also their acyl group compositions were determined. PI showed no significant changes. In contrast, both PIP and PIP2 sharply decreased immediately after onset of cerebral ischemia. then continued to fall gradually from 5 min onwards. And PIP and PIP 2 increased after onset of recirculation in both 5 and 30 min ischemia groups.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Polyphosphoinositide metabolism in temporary cerebral ischemia--the reversibility after recirculation]. 285 44

In the membranous signal transduction process, hormone-binding to receptors causes receptor interaction with signal-transducing components; these components transfer the stimulus to effector systems, which generate intracellular signals. Several guanine nucleotide-binding proteins (N- or G-proteins) have been identified as membranous signal-transducing components. Two N-proteins are involved in the hormonal regulation of adenylate cyclase activity, one of which being stimulatory (Ns), the other one being inhibitory (Ni). Ns, Ni and a third N-protein, No, whose function is unknown, occur ubiquitously. On the other hand, transducin, an N-protein, which functionally couples light-activated rhodopsin to a cGMP phosphodiesterase, is specific for the retina. In addition to their established role as transducers regulating adenylate cyclase and retinal cGMP phosphodiesterase, N-proteins proteins may be involved in two mechanisms by which the cytoplasmic calcium concentration is elevated, i.e. hormonal stimulation of a phospholipase C catalyzing phosphatidyl-inositol 4,5-diphosphate hydrolysis (Pi response) and hormone-induced opening of receptor-operated calcium channels; the membrane-bound forms of cAMP phosphodiesterase and guanylate cyclase, stimulated by insulin and atrial natriuretic factor, respectively, are also likely to be regulated via N-proteins. Guanine nucleotide-binding proteins appear to play a universal role in transmembranous signalling processes, controlling effector systems (i.e. enzymes and ion channels) that regulate cytoplasmic concentrations of intracellular messengers such as cyclic AMP, cyclic GMP and calcium.
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PMID:[Principles of transmembranous signal transduction in the action of hormones and neurotransmitters]. 286 63

Proteins encoded by ras genes have recently been reported to couple certain growth factor receptors to phospholipase C, the enzyme catalyzing phosphatidylinositol breakdown. To investigate this hypothesis, the normal and the transforming Ha-, Ki-, and N-ras genes were each transfected into Rat-1 fibroblasts under the control of strong promoters. Several cell lines, both normal and transformed, were selected that expressed high levels of p21ras. Phosphatidylinositol turnover was measured in these cells in response to a wide variety of peptide factors; bradykinin was found to have a greatly enhanced effect on the p21ras overexpressors relative to the parental and control cells. Bradykinin receptor numbers were measured in these lines and found to be up to 40-fold higher in the p21ras overexpressors than in the parental cells. This was found to be the case for both normal and transforming forms of all three varieties of ras genes. Receptor number correlated well with the bradykinin-dependent phosphatidylinositol turnover response in all cases. These data indicate that the effects of p21ras on cellular responses to the peptide hormone bradykinin are due to changes in receptor number rather than to direct coupling by p21ras between the receptor and phospholipase C.
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PMID:p21ras-induced responsiveness of phosphatidylinositol turnover to bradykinin is a receptor number effect. 290 Oct 87

On the basis of earlier studies of rabbit pulmonary alveolar macrophages, the incorporation of 14C-labelled polyunsaturated fatty acids into the lipids of human fibroblasts from patients with various phenotypes of Niemann-Pick disease was examined in order to define further the disturbance in metabolism of bis(monoacylglycero)phosphate occurring in these disorders. Docosahexaenoic acid, which had not been studied previously, was found to be incorporated by macrophages into bis(monoacylglycero)phosphate in a highly selective fashion and was therefore used along with arachidonic acid for studies of fibroblasts. Following incubation of fibroblasts in serum-free medium for 60 min, the distribution of arachidonic acid label in lipids was: phosphatidylcholine, 51%; phosphatidylethanolamine, 12%; phosphatidylinositol, 9.5%; and bis(monoacylglycero)phosphate, 2.3%; and of docosahexaenoic acid label was 36, 20, 2.6 and 10.3% respectively. Phosphatidylinositol had the highest specific activity of arachidonic acid label and bis(monoacylglycero)phosphate of docosahexaenoic acid label. Prolongation of incubation to 21 h, with or without removal of label remaining in the medium at 1 h, resulted in proportional redistributions with phosphatidylcholine decreasing and phosphatidylethanolamine increasing. In bis(monoacylglycero)phosphate and phosphatidylinositol, the proportions of arachidonic acid label decreased and increased respectively, whereas the proportions of docosahexaenoic acid label in these lipids were unchanged. As virtually all label taken up by cells was esterified, these redistributions are taken to reflect transacylations. In Niemann-Pick cells, the expected redistribution of arachidonic acid label in bis(monoacylglycero)phosphate failed to occur with cell types A and B which are deficient in sphingomyelinase-phospholipase C, and excess label accumulated after a 21-h incubation. Excess docosahexaenoic acid label also accumulated in the bis(monoacylglycero)phosphate of these cells. The highly selective incorporation of docosahexaenoic acid in two cell types suggests a special role for bis(monoacylglycero)phosphate in the metabolism of n-3 polyunsaturated fatty acids. A high specific activity found early in incubations of macrophages suggests that polyunsaturated fatty acids may be incorporated into phospholipids during de novo synthesis of phosphatidic acid.
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PMID:Incorporation of polyunsaturated fatty acids into bis(monoacylglycero)phosphate and other lipids of macrophages and of fibroblasts from control and Niemann-Pick patients. 293 57

The phospholipid requirement for Ca2+-stimulated, Mg2+-dependent ATP hydrolysis (Ca2+/Mg2+-ATPase) and Mg2+-stimulated ATP hydrolysis (Mg2+-ATPase) in rat brain synaptosomal membranes was studied employing partial delipidation of the membranes with phospholipase A2 (Hog pancreas), phospholipase C (Bacillus cereus) and phospholipase D (cabbage). Treatment with phospholipase A2 caused an increase in the activities of both Ca2+/Mg2+-ATPase and Mg2+-ATPase whereas with phospholipase C treatment both the enzyme activities were inhibited. Phospholipase D treatment had no effect on Ca2+/Mg2+-ATPase but Mg2+-ATPase activity was inhibited. Inhibition of Mg2+-ATPase activity after phospholipase C treatment was relieved with the addition of phosphatidylinositol-4,5-bisphosphate (PIP2) and to a lesser extent with phosphatidylinositol-4-phosphate (PIP) and phosphatidylcholine (PC). Phosphatidylserine (PS), phosphatidic acid (PA), PIP and PIP2 brought about the reactivation of Ca2+/Mg2+-ATPase. Phosphatidylinositol (PI) and PA inhibited Mg2+-ATPase activity. Kms for Ca2+ (0.47 microM) and Mg2+ (60 microM) of the enzyme were found to be unaffected after treatment with the phospholipases.
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PMID:Phospholipid requirement of Ca2+-stimulated, Mg2+-dependent ATP hydrolysis in rat brain synaptic membranes. 294 70

5-Methyltryptamine, through a GTP-dependent mechanism, stimulated breakdown of endogenous [3H]inositol-labeled phosphoinositides in membranes prepared from blowfly salivary gland homogenates through a phospholipase C exhibiting a pH optimum of approximately 7.0. Unlabeled membranes, prepared from salivary gland homogenates, hydrolyzed exogenous [3H]phosphatidylinositol 4,5-bisphosphate substrate with generation of labeled inositol phosphates. Inositol trisphosphate formation was increased approximately 200% by 10 microM guanosine 5'-(O-thio)-trisphosphate (GTP gamma S) within 30 s. 5-Methyltryptamine, in the presence of 10 microM GTP gamma S, increased the rate of inositol trisphosphate formation by approximately 500% within 30 s. Half-maximal activation of hormone-stimulated breakdown of exogenous substrate required approximately 0.05 microM GTP gamma S. [3H]Phosphatidylinositol was also hydrolyzed during incubation with membranes, resulting in the generation of inositol, glycerol phosphoinositol, and inositol monophosphate. Formation of inositol monophosphate was stimulated approximately 30% by 10 microM GTP gamma S and 10 microM 5-methyltryptamine. Neither inositol nor glycerol phosphoinositol formation was affected by hormone. These results indicate that in a cell-free system from blowfly salivary glands, 5-methyltryptamine, through a GTP-dependent mechanism, directly activates a phospholipase C which mediates phosphoinositide hydrolysis.
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PMID:5-Methyltryptamine stimulates phospholipase C-mediated breakdown of exogenous phosphoinositides by blowfly salivary gland membranes. 299 46

Trehalase (EC 3.2.1.28) associated with renal and intestinal brush-border membranes was solubilized by highly purified phosphatidylinositol-specific phospholipase C (EC 3.1.4.10) from Bacillus thuringiensis, but not by phosphatidylcholine-hydrolyzing phospholipase C (EC 3.1.4.3) from Clostridium welchii or phospholipase D (EC 3.1.4.4) from cabbage. The solubilized trehalase was not adsorbed on phenyl-Sepharose, indicating that it was hydrophilic. Phosphatidylinositol-specific phospholipase C also converted Triton X-100-solubilized amphipathic trehalase into a hydrophilic form. These results suggest that trehalase is bound to the membrane through a direct and specific interaction with phosphatidylinositol.
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PMID:Solubilization of trehalase from rabbit renal and intestinal brush-border membranes by a phosphatidylinositol-specific phospholipase C. 301 6

Thrombin-induced changes in arachidonate content of platelet phospholipids were quantitated to establish the ultimate origins of this eicosanoid precursor. Fifteen seconds following thrombin addition (15 U/5 X 10(9) platelets), phosphatidylcholine lost 11.8 nmol of arachidonate and phosphatidylethanolamine lost 10.5 nmol. Arachidonate in phosphatidate, phosphatidylinositol, and phosphatidylinositol-4,5-bisphosphate combined decreased by 11.0 nmol. Increases in free and oxygenated arachidonate (41 nmol) exceeded decreases in inositides. Thus phospholipase A2 released at least twice as much arachidonate as phospholipase C-diglyceride lipase. Phosphatidylinositol-4-phosphate levels remained unchanged upon stimulation. Therefore, increases in phosphatidylinositol-4,5-bisphosphate indicated the minimum rate of phosphorylation of phosphatidylinositol to resynthesize phosphatidylinositol-4,5-bisphosphate, following stimulus-induced breakdown by phospholipase C. Phosphatidylinositol-4, 5-bisphosphate increased 1.4 nmol between 10 and 15 sec following thrombin, markedly less than phosphatidylinositol decreased (2.1 nmol). This could be due to phospholipase A2, in addition to phospholipase C, acting directly on phosphatidylinositol to a greater extent than estimated by accumulation of lysophosphatidylinositol, degraded rapidly by lysophospholipase. Thus, upon high-dose thrombin stimulation of human platelets inositide metabolism via phospholipase C directs initial formation of intracellular second messengers, and sequentially, or in parallel, arachidonate release by phospholipase A2 supplies the larger proportion of arachidonate for syntheses of eicosanoids involved in intercellular communication.
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PMID:Stimulated platelets release equivalent amounts of arachidonate from phosphatidylcholine, phosphatidylethanolamine, and inositides. 302 86

Phosphatidylinositol-4-phosphate (PtdIns-P) kinase was purified approximately 30-fold from rat brain cytosol. No contaminating activity of PtdIns kinase or of phosphomonoesterase and phospholipase C using PtdIns-P or PtdIns-P2 as substrate could be detected in the enzyme preparation. The PtdIns-P kinase activity was severalfold higher when PtdIns-P/PtdEtn vesicles rather than PtdIns-P alone were used as substrate. This might be due to increased accessibility of the enzyme for the vesicular substrate, further indicated by the lower activity obtained when PtdCho or PtdIns, phospholipids with bulky head groups, was also present in the vesicles. The product PtdIns-P2 was a competitive inhibitor with respect to PtdIns-P and 50% inhibition of enzyme activity was observed at the same product concentration regardless of whether the substrate-product mixture was presented in vesicular or micellar form, or the substrate and product were added in separate vesicles. The polyamines spermine and spermidine enhanced PtdIns-P kinase activity severalfold. Spermine also caused a shift in the MgCl2 saturation curve from sigmoidal to hyperbolic, lowering the Mg2+ concentration required for optimum kinase activity to the physiological range. Myelin basic protein enhanced the enzyme activity when PtdIns-P/PtdEtn vesicles were used as substrate, whereas it was inhibitory when PtdIns-P was added alone. The possible role of polyamines and the product PtdIns-P2 in the regulation of PtdIns-P kinase activity is discussed.
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PMID:Phosphatidylinositol-4-phosphate kinase from rat brain. Activation by polyamines and inhibition by phosphatidylinositol 4,5-bisphosphate. 302 90


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