Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The arachidonic acid content of plasma lipoproteins is altered during dietary magnesium deficiency, although the tissue arachidonic acid content seems to be unchanged. The primary event triggering these changes is probably the loss of extracellular Mg2+, as it is not clear whether dietary magnesium deficiency produces loss of intracellular Mg2+. In the isolated rabbit heart, in vitro perfusion conditions which produce loss of intracellular Mg2+ also result in disturbances of arachidonic acid metabolism. The metabolism of exogenous arachidonic acid to prostaglandins is increased without changing the Km or Vmax of cyclo-oxygenase. The incorporation of arachidonic acid into tissue phospholipids is significantly reduced, although the incorporation of oleate, stearate, and linolenate is either increased or unchanged. These data indicate that the activity of the enzymes (CoA synthetases and acyl transferases) which mediate arachidonate incorporation is reduced during Mg2+ depletion. Since protein-kinase-C-mediated phosphorylation of both CoA synthetase and acyl transferase reduces their activity, and since protein kinase C has an Mg2+ binding site, it is possible to speculate that loss of intracellular Mg2+ may lead to the activation of protein kinase C, with the consequent reduction of arachidonic acid reacylation enzyme activity.
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PMID:Magnesium and arachidonic acid metabolism. 827 64

The intracellular signalling systems involved in the chronic insulin-antagonistic, anti-lipogenic effects and also the lipolytic effect of GH have been investigated in sheep adipose tissue in an in vitro tissue culture system. During culture, chronic exposure to GH decreased the rate of lipogenesis and prevented the increase in lipogenesis induced by insulin. GH also increased glycerol release into the culture medium. GH had no acute, insulin-like effect on lipogenesis in sheep adipose tissue. Pretreatment with phorbol ester to down-regulate isoforms of protein kinase C or addition of the protein serine kinase inhibitor staurosporine decreased the anti-lipogenic effect of GH while the protein serine kinase inhibitor H7 eliminated it completely. Pretreatment with phorbol ester or addition of H7 also decreased the insulin-antagonistic effect of GH on lipogenesis. Addition of the protein serine phosphatase inhibitor okadaic acid or the phosphatidyl choline phospholipase C inhibitor D609 both diminished the anti-lipogenic and insulin-antagonistic effects of GH. Chronic exposure of adipose tissue to GH had no effect on the total activity of acetyl CoA carboxylase or its activation status but it did diminish the increase in activation status induced by insulin. H7 and okadaic acid also diminished the increase in activation status of acetyl CoA carboxylase induced by insulin but did not alter the effect of GH on this variable. Okadaic acid decreased total acetyl CoA carboxylase activity. Pretreatment with phorbol ester or the addition of H7, staurosporine or okadaic acid increased glycerol release into the culture medium to the same extent as GH itself; the effects of GH and these various agents were not additive. These studies suggest that the anti-lipogenic, insulin-antagonistic effects of GH involve both protein serine kinases and phosphatases, possibly including one or more isoforms of protein kinase C, and a phosphatidyl choline-specific phospholipase C. Comparison with studies by others on the GH enhancement of preadipocyte differentiation and prolactin stimulation of lipogenesis in mammary tissue suggests involvement of protein kinase C at an early stage in all three systems. In contrast, effects of okadaic acid vary with the system, suggesting the involvement of protein serine phosphatase activity in a late stage of the action of GH. The effects of GH on lipogenesis and lipolysis do not occur via identical mechanisms.
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PMID:GH inhibition of lipogenesis and stimulation of lipolysis in sheep adipose tissue: involvement of protein serine phosphorylation and dephosphorylation and phospholipase C. 870 54

It is unknown whether peroxisome proliferators decrease hepatic fatty acid oxidation via uncoupling of respiration or if they inhibit extramitochondrial fatty acyl CoA synthesis. Therefore, the purpose of this study was to examine both processes simultaneously using the isolated perfused liver, a whole cell preparation where enzymes and biochemical processes can be monitored continuously under nearly physiological conditions. Accordingly, ketone body formation (beta-hydroxybutyrate + acetoacetate) from lipid metabolism and oxygen uptake, which is increased by uncoupling agents, were monitored at the same time. 2-Bromooctanoate, a known inhibitor of acyl CoA synthetase, decreased ketone body formation in a dose-dependent manner without altering cellular respiration (half-maximal inhibition, approximately 25 microM) and concomitantly increased protein kinase C nearly fourfold also in a dose-dependent fashion. Ketogenesis was also blocked maximally 50-66% with mono(ethylhexyl)phthalate, 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio acetic acid (WY-14,643), and nafenopin, potent peroxisome proliferators and tumor promoters. These compounds also increased protein kinase C three- to fourfold without altering oxygen uptake significantly. Thus, lipid metabolism appears to be the prime target of potent peroxisome proliferators most likely on actions via acyl CoA synthetase rather than oxidative phosphorylation. In contrast, weak peroxisome proliferators and tumor promoters, di(ethylhexyl)phthalate and 2-ethylhexanol, did not affect ketogenesis, oxygen consumption, or protein kinase C at similar concentrations. Additionally, octanoate increased ketone body formation in the presence of nafenopin. Because octanoate is metabolized by mitochondrial acyl CoA synthetase independent of carnitine acyltransferase, these results indicate that nafenopin does not inhibit mitochondrial beta-oxidation. Taken together, it is concluded that potent peroxisome proliferators preferentially block ketogenesis without altering cellular respiration in the liver. This phenomenona, which occurs due to inhibition of acyl CoA synthetase, leads to an elevation of free fatty acids that stimulates protein kinase C and promotes cell proliferation.
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PMID:Potent peroxisome proliferators inhibit beta-oxidation in the isolated perfused rat liver. 888 48

Sphingosine induces many protein kinase C-dependent and -independent effects on biological systems. In parallel, C2-ceramide used by investigators as an unnatural, cell permeable analog of long-chain acyl-ceramides, possesses biological activities similar with natural ceramides. We have recently characterized a membrane-associated. CoA-independent transacetylase that can transfer the acetate group from PAF to sphingosine and form C2-ceramide. This enzyme has a strict stereochemical configuration requirement for sphingosine; only the naturally-occurring D-erythro-isomers of sphingosine accepts the acetate from PAF. Also, it has a rigid substrate specificity for sphingolipid-related analogues. Dipalmitoyl-glycerophosphocholine (-GPC) or hexadecylarachidonoyl-GPC can not transfer their long-chain acyl groups directly to sphingosine and sphingosine can not be acetylated by acetyl-CoA:lyso-PAF acetyltransferase. Results obtained from studies on pH optima, subcellular distribution, temperature sensitivities, inhibitors, tissue distributions, and expression of enzyme activities in Xenopus oocytes suggest that PAF:sphingosine transacetylase is similar, but not identical to the PAF:lysophospholipid transacetylase we have previously identified. The transacetylases function to diversify the biological responses of PAF.
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PMID:Acetylation of sphingosine by PAF-dependent transacetylase. 913 Nov 36

Acyl analogs of platelet-activating factor (PAF) (1-acyl-2-acetyl-sn-glycero-3-phosphocholine, acylacetyl -GPC) are the predominant products synthesized during thrombin or ionophore A23187-mediated activation of endothelial cells. However, the biosynthetic pathway responsible for the production of acylacetyl-GPC is not well understood. In the present investigation, we have demonstrated that the acyl analogs of PAF are also the major products from calf pulmonary artery endothelial cells in response to a time-dependent stimulation of ATP (10(-3) M), bradykinin (10(-8) M), or ionophore A23187 (2 microM). In addition, we have found that the CoA-independent PAF:acyllyso-GPC transacetylase recently identified by us is concurrently and transiently induced with maximal 4-fold enhancement at 5 min and returned to near basal level by 10 min treatment of endothelial cells with ATP. Acid phosphatase reduces the increased PAF:acyllyso-GPC transacetylase activity from the homogenates of ATP-activated endothelial cells. Reduced PAF:acyllyso-GPC transacetylase activity can be restored by incubating the acid phosphatase-treated homogenates with ATP (5 mM) and Mg2+ (10 mM). Furthermore, okadaic acid, a protein phosphatase 1 and 2A inhibitor, incubated with endothelial cells in a dose-dependent manner (1-100 nM) for 10-min potentiates and sustained the stimulation of PAF:acyllyso-GPC transacetylase activity by ATP. On the other hand, genistein, tyrphostin-25 (inhibitors of tyrosine-specific protein kinase), and calphostin C (an inhibitor of protein kinase C) block the activation of PAF:acyllyso-GPC transacetylase by ATP. These results are consistent with the notion that ATP regulates the transacetylase activity by reversible activation and inactivation via the phosphorylation and dephosphorylation cycle. ATP also augments the activities of alkyllyso-GPC/acyllyso-GPC:acetyl-CoA acetyltransferase. However, the activation of the acetyltransferases precedes that of the transacetylase with peak activation occurring at 1-2 min of the ATP treatment. In addition, sodium vanadate, also an inhibitor of protein phosphatase, stimulates the increase in the incorporation of [3H]acetate into acyl[3H]acetyl-GPC of the ATP-treated endothelial cells. Collectively, our data show that both acetyltransferases and transacetylase participate in and contribute to the biosynthesis of acyl analogs of PAF in a coordinate fashion in endothelial cells.
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PMID:The role of platelet-activating factor-dependent transacetylase in the biosynthesis of 1-acyl-2-acetyl-sn-glycero-3-phosphocholine by stimulated endothelial cells. 921 86

The cellular events following interaction between matrix proteins and cells are important requisites for physiological mechanisms as well as the progress of a number of diseases. Cellular adhesion to fibronectin, an important component of the extracellular matrix has been demonstrated to be associated with translocation of protein kinase C (PKC) by an integrin-dependent pathway. For this process G-proteins may play an important role as coupling proteins. Membrane association and activity of G-proteins has been shown to be regulated by isoprenylation. We therefore studied whether fibronectin mediated adhesion resulted in PKC translocation and if isoprenylation of cellular proteins may play a role for this integrin-dependent pathway of PKC activation. Chinese hamster ovary (CHO) cells were pretreated with either the Hydroxy-methylglutaryl(HMG)-CoA reductase inhibitor lovastatin or prenylation inhibitor limonene. For the stimulation by extracellular matrices, CHO cells were plated on tissue culture dishes coated with fibronectin or bovine serum albumin and PKC activity was determined. To investigate direct effects of inhibition of isoprenylation on cytoskeletal organization, phalloidin-stained stress fibers were characterized after adhesion on different matrices. CHO cells seeded on fibronectin displayed over twice the PKC translocation to the particulate fraction in comparison to that measured in cells on albumin. Pretreatment of CHO cells with lovastatin or limonene resulted in partial suppression of PKC activation after cell-seeding on the specific matrix fibronectin. Changed PKC distribution was not due to a disorganization of the actin skeleton. These data show that inhibition of isoprenylation of cellular proteins, possibly small Guanosine triphosphate(GTP)-binding proteins, alters only the integrin-mediated PKC distribution but does not greatly influence constitutive PKC distribution.
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PMID:Protein kinase C activation after cellular adhesion on fibronectin: partial suppression after inhibition of protein isoprenylation. 923 6

3-Hydroxy-3-methylglutaryl Coenzyme A (HMG-CoA) reductase inhibitors (statins) are therapeutically used to lower plasma cholesterol levels. In addition, these drugs can block vascular smooth muscle cell (VSMC) proliferation. The present study addressed the question whether the inhibitory effect of lovastatin on premitotic DNA synthesis correlates with a downregulation of c-fos mRNA levels, a marker of signaling efficiency, in human SMC. Here we show that in human SMC exposed to individual growth factors (platelet-derived growth factor, epidermal growth factor, alpha-thrombin, insulin, insulin-like growth factor I (IGF-I)) and human serum, the maximal [3H]thymidine incorporation and c-fos mRNA expression are closely correlated. Only alpha-thrombin elicited overexpression of c-fos as compared with its effect on [3H]thymidine incorporation. Lovastatin efficiently inhibited [3H]thymidine uptake promoted by all mitogens tested (76-87%); however, it significantly inhibited upregulation of c-fos mRNA levels induced only by insulin (33-67%, P < 0.05) and IGF-I (31 57%, P < 0.05). This inhibition was overcome by mevalonate and geranylgeraniol, and partially by farnesol. c-fos mRNA expression induced by 4-beta-phorbol-12-myristate-13-acetate, an activator of protein kinase C, was insensitive to lovastatin treatment. Thus, in human vascular SMC, lovastatin impairs premitotic DNA synthesis induced by growth factors, but only c-fos expression promoted by insulin and IGF-I. These data indicate that statin-sensitive and -insensitive pathways seem to be involved in the regulation of c-fos in the response of human SMC to proliferative stimuli, and suggest a prominent role of isoprenylated proteins in the activation of VSMC through the IGF-I/insulin dependent pathways.
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PMID:Mevalonate deprivation impairs IGF-I/insulin signaling in human vascular smooth muscle cells. 943 Mar 71

Under Ca2+-free conditions, activation of the pancreatic beta-cell with forskolin and 12-O-tetradecanoylphorbol 13-acetate (TPA) is permissive for the augmentation of insulin release by glucose and other nutrients. The ability of fatty acids to mimic the effect of glucose and thereby augment insulin secretion in the absence of extracellular Ca2+ is the focus of the present study. In the absence of extracellular Ca2+, glucose, palmitate, and myristate had no effect on insulin release. When, under Ca2+-free conditions, the islets were treated with forskolin to raise cyclic AMP levels and activate protein kinase A and with TPA to activate protein kinase C, glucose, palmitate, and myristate all augmented release to approximately the same extent. No other saturated fatty acid with chain lengths in the C = 6-22 range augmented the release of insulin. This selective augmentation by palmitate or myristate was not seen with forskolin alone, and was seen slightly with TPA and strongly with the combination of forskolin and TPA. The response, which developed slowly and had a time course similar to that of second-phase insulin release, was abolished by the physiological inhibitor norepinephrine. The results suggest that the mechanism underlying the Ca2+-independent augmentation of insulin release by glucose and other nutrients involves the proposed malonyl-CoA/long-chain acyl-CoA pathway with specificity for myristoyl- and palmitoyl-CoA esters and/or their derivatives.
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PMID:Palmitate and myristate selectively mimic the effect of glucose in augmenting insulin release in the absence of extracellular Ca2+. 951 39

Malonyl CoA is a regulator of carnitine palmitoyl transferase 1 (CPT1), the enzyme that controls the transfer of long chain fatty acyl CoA into mitochondria where it is oxidized. Recent studies indicate that in skeletal muscle the concentration of malonyl CoA is acutely (minutes) regulated by changes in its fuel supply and energy expenditure. In response to changes in fuel supply, regulation appears to be due to alterations in the cytosolic concentration of citrate, which is both an allosteric activator of acetyl CoA carboxylase (ACC), the enzyme that catalyzes malonyl CoA synthesis and a source of its precursor, cytosolic acetyl CoA. During exercise and immediately thereafter regulation by citrate appears to be lost and malonyl CoA levels diminish as the result of a decrease in ACC activity secondary to phosphorylation. Sustained increases in the concentration of malonyl CoA have been observed in muscle of a number of insulin-resistant rodents including the Zucker (fa/fa) and GK rats, KKAgy mice, glucose-infused rats and rats in which muscle has been made insulin resistant by denervation. Available data suggest that malonyl CoA could be linked to insulin resistance in these rodents by virtue of its effects on the cytosolic concentration of long chain fatty acyl CoA (LCFA CoA) and one or more protein kinase C isozymes. Whether similar alterations occur in other tissues and contribute to the pathophysiology of the insulin resistance syndrome remains to be determined.
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PMID:Malonyl CoA as a metabolic switch and a regulator of insulin sensitivity. 978 32

Malonyl-CoA is an allosteric inhibitor of carnitine palmitoyltransferase (CPT) I, the enzyme that controls the transfer of long-chain fatty acyl (LCFA)-CoAs into the mitochondria where they are oxidized. In rat skeletal muscle, the formation of malonyl-CoA is regulated acutely (in minutes) by changes in the activity of the beta-isoform of acetyl-CoA carboxylase (ACCbeta). This can occur by at least two mechanisms: one involving cytosolic citrate, an allosteric activator of ACCbeta and a precursor of its substrate cytosolic acetyl-CoA, and the other involving changes in ACCbeta phosphorylation. Increases in cytosolic citrate leading to an increase in the concentration of malonyl-CoA occur when muscle is presented with insulin and glucose, or when it is made inactive by denervation, in keeping with a diminished need for fatty acid oxidation in these situations. Conversely, during exercise, when the need of the muscle cell for fatty acid oxidation is increased, decreases in the ATP/AMP and/or creatine phosphate-to-creatine ratios activate an isoform of an AMP-activated protein kinase (AMPK), which phosphorylates ACCbeta and inhibits both its basal activity and activation by citrate. The central role of cytosolic citrate links this malonyl-CoA regulatory mechanism to the glucose-fatty acid cycle concept of Randle et al. (P. J. Randle, P. B. Garland. C. N. Hales, and E. A. Newsholme. Lancet 1: 785-789, 1963) and to a mechanism by which glucose might autoregulate its own use. A similar citrate-mediated malonyl-CoA regulatory mechanism appears to exist in other tissues, including the pancreatic beta-cell, the heart, and probably the central nervous system. It is our hypothesis that by altering the cytosolic concentrations of LCFA-CoA and diacylglycerol, and secondarily the activity of one or more protein kinase C isoforms, changes in malonyl-CoA provide a link between fuel metabolism and signal transduction in these cells. It is also our hypothesis that dysregulation of the malonyl-CoA regulatory mechanism, if it leads to sustained increases in the concentrations of malonyl-CoA and cytosolic LCFA-CoA, could play a key role in the pathogenesis of insulin resistance in muscle. That it may contribute to abnormalities associated with the insulin resistance syndrome in other tissues and the development of obesity has also been suggested. Studies are clearly needed to test these hypotheses and to explore the notion that exercise and some pharmacological agents that increase insulin sensitivity act via effects on malonyl-CoA and/or cytosolic LCFA-CoA.
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PMID:Malonyl-CoA, fuel sensing, and insulin resistance. 988 45


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