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)

The regulation of mevalonic acid synthesis requires both nonsterol isopentenoid and sterol regulatory signal molecules. A primary target of this multivalent control process is the enzyme which catalyzes mevalonate synthesis: 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (EC 1.1.1.34). In this report Staphylococcus aureus alpha-toxin perforated Chinese hamster ovary cells were used to facilitate the identification of isopentenoidogenic reactions and metabolites required for mevalonate-mediated loss of HMG-CoA reductase activity. alpha-Toxin-perforated cells retained the capacity to decrease, upon demand, HMG-CoA reductase activity and protein in response to mevalonate or isopentenoid pyrophosphate esters. Also, it was deduced with highly specific metabolic inhibitors, that conversion of farnesyl 1-diphosphate to squalene was required for mevalonate-mediated suppression of reductase activity. Since squalene (2 microM) did not downregulate reductase activity, pre-squalene pyrophosphate or a derivative, or polyprenyl-1-pyrophosphate-generated inorganic pyrophosphate, or a combination of these metabolites are proposed as candidate regulatory nonsterol isopentenoid signal molecules.
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PMID:Mevalonate-mediated suppression of 3-hydroxy-3-methylglutaryl coenzyme A reductase function in alpha-toxin-perforated cells. 802 95

Small G-proteins (SMGs) require isoprenylation for their association with membranes. We have examined protein isoprenylation, subcellular distribution of SMGs, cytosolic Ca2+ changes and insulin secretion in HIT-T15 cells after treatment with lovastatin, which inhibits the production of isoprenoids by blocking mevalonate production by 3-hydroxy-3-methylglutaryl-CoA reductase. Numerous proteins in the 20-70 kDa range were found to be isoprenylated. Most of these proteins co-migrated with SMGs (21-27 kDa). Lovastatin treatment (25 microM, 24 h) decreased protein isoprenylation and affected the distribution of several SMGs, causing a large accumulation in the cytosol and a detectable decrease in membranes. Lovastatin selectively attenuated the potentiating action of bombesin and vasopressin, which activate phospholipase C in these cells, on insulin secretion stimulated by nutrients (glucose + leucine + glutamine). This lovastatin effect was overcome by mevalonate. Insulin secretion stimulated by nutrients alone or insulin release in the presence of the potentiating agents forskolin or phorbol myristate acetate remained unaffected. As the modulation of insulin secretion by isoprenaline and somatostatin were not altered by lovastatin, the drug does not non-selectively affect the binding of ligands to their receptors. Lovastatin did not interfere with the activation of phospholipase C by bombesin and vasopressin, since the rise in cytosolic Ca2+ induced by these agents was not changed. Limonene, proposed to block specifically prenyl-protein transferases of SMGs, did not alter protein isoprenylation patterns, but inhibited the stimulated insulin secretion. In conclusion, lovastatin selectively attenuated the potentiation of nutrient-induced insulin secretion by bombesin and vasopressin without affecting their activation of phospholipase C. The concomitant changes in SMG isoprenylation and their subcellular distribution after lovastatin treatment suggest that SMGs could play an important role in the bombesin and vasopressin action on insulin secretion.
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PMID:Blockade of mevalonate production by lovastatin attenuates bombesin and vasopressin potentiation of nutrient-induced insulin secretion in HIT-T15 cells. Probable involvement of small GTP-binding proteins. 842 83

When sphingomyelin is digested by sphingomyelinase in the plasma membrane of rat astrocytes, productions of sphingomyelin, diacylglycerol, and phosphatidylcholine are stimulated. D609, an inhibitor of phosphatidylcholine-specific phospholipase C, suppressed these effects. Similarly, when apolipoprotein A-I removed cellular cholesterol, phosphatidylcholine, and sphingomyelin to generate high density lipoprotein, cholesterol synthesis from acetate subsequently increased, and sphingomyelin synthesis from acetate and serine also increased. D609 inhibited these effects again. D609 also inhibited the cholesterol removal by apoA-I not only from the astrocytes but also from BALB/3T3 and RAW264 cells. D609 decreased cholesterol synthesis, although D609 did not directly inhibit hydroxymethylglutaryl-CoA reductase. ApoA-I-stimulated translocation of newly synthesized cholesterol to cytosol was also decreased by D609. A diacylglycerol analog increased the apoA-I-mediated cholesterol release, whereas ceramide did not influence it. We concluded that removal of cellular sphingomyelin by apolipoproteins is replenished by transfer of phosphorylcholine from phosphatidylcholine to ceramide, and this reaction may limit the removal of cholesterol by apoA-I. This reaction also produces diacylglycerol that potentially triggers subsequent cellular signal cascades and regulates intracellular cholesterol trafficking.
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PMID:Apolipoprotein-mediated cellular lipid release requires replenishment of sphingomyelin in a phosphatidylcholine-specific phospholipase C-dependent manner. 1222 36