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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Three TG lipases have been identified in muscle (i.e., acid, neutral, and alkaline), but as yet we do not know which enzyme is responsible for tissue TG hydrolysis. Over the past 8 yr, work in our laboratory has focused on intracellular lipoprotein lipase (LPL). The results show that this lipase is regulated by the classical cAMP cascade and that the activity of this enzyme is inversely related to endogenous TG concentration. Using these results as a foundation we plan to examine molecular mechanisms involved in the synthesis, compartmentalization, and transport of the alkaline TG lipase. Further, the evidence suggests that this enzyme may be regulated by protein phosphorylation mediated by cyclic AMP-dependent protein kinase. We plan to test this possibility.
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PMID:Role of the alkaline TG lipase in regulating intramuscular TG content. 307 Feb 56

In the mammalian myocardium, an active triglyceride synthesis pathway is operating, (re)esterifying activated fatty acids from endogenous or exogenous sources, with the glycolytically derived three-carbon intermediates dihydroxyacetone-phosphate and glycerol-3-phosphate by the so-called Kennedy pathway. The seven enzymes of triglyceride synthesis are membrane bound and located at the sarcoplasmic reticulum. The first enzyme in the glycerol-3-phosphate pathway, glycerol-3-phosphate acyltransferase, is proposed to be rate limiting for triglyceride formation. This microsomal enzyme is regulated by phosphorylation (inactiycation)-dephosphorylation (activation) coupled to the beta-receptor--adenyl cyclase--protein kinase system. Additional regulatory steps in triglyceride formation are the reactions catalyzed by the microsomal phosphatidic acid phosphatase and diglyceride acyltransferase. Intracellular triglycerides occur as free floating cytosolic droplets, membrane-bound particles and lipid-filled lysosomes. No consensus exists about the metabolically active portion of myocardial triglycerides. Various lipases have been proposed to be involved in endogenous lipolysis: the lysosomal acid, microsomal and soluble neutral triglyceride, intracellular lipoprotein lipases and the microsomal di- and monoglyceridase. It has been acknowledged that the bulk of the intracellular neutral lipase represents the precursor of vascular lipoprotein lipase. The presence of a neutral lipase, as distinct from lipoprotein lipase, in the rat heart was recently advocated. Endogenous lipolysis is a hormone-sensitive process. Hormone-sensitivity may involve direct alteration of enzyme activity by protein phosphorylation-dephosphorylation but is also dependent on the removal rate of product fatty acids, since feedback inhibition is a common property of all lipases in the heart.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Synthesis, storage and degradation of myocardial triglycerides. 331 Oct 5

The effect of halothane on isoproterenol-stimulated lipolysis was determined in isolated rat epididymal fat cells. The maximal lipolytic response (Emax) activated by isoproterenol was 350 +/- 61 nmol of glycerol/10(5) cells/hr with an EC50 of 5.1 X 10(-9) M. When the adipocytes were simultaneously bubbled with 2.5% halothane, the Emax decreased to 158 +/- 43 nmol of glycerol/10(5) cells/hr and the dose response curve for isoproterenol was shifted to the right (EC50 3.5 X 10(-8) M, p less than 0.05). When lipolysis was maximally stimulated with (-)-isoproterenol (10(-6)M), the inhibitory effect of halothane was found to be both dose dependent (IC50 approximately 2.5%, v/v) and reversible following washout. Neither the nonhydrolyzable cAMP analog, 8-(4-chlorophenylthio) adenosine 3',5'-cyclic monophosphate (2 X 10(-3)M), nor forskolin (10(-6) M) was able to normalize lipolysis in the presence of halothane. The activation of cAMP-dependent protein kinase (EC 2.7.1.37) activity by isoproterenol was not different in halothane-exposed cells when compared to unexposed cells. When control adipocytes were exposed to isoproterenol (10(-6) M), there was a 2.5-fold increase in the activity of hormone-sensitive lipase (EC 3.1.1.3) from 0.64 +/- 0.13 to 1.53 +/- 0.32 pkat (pmol/sec) per mg (p less than 0.005, n = 10). However, in the presence of halothane (2.5%, v/v) isoproterenol stimulation of hormone-sensitive lipase was attenuated by 50% to values of 1.06 +/- 0.23 pkat/mg (p less than 0.01, n = 10). Halothane had no direct inhibitory effect on hormone-sensitive lipase since this enzyme's activity was unaffected when homogenates of isoproterenol-stimulated control cells were incubated with halothane. These studies suggest that halothane impairs the activation of hormone-sensitive lipase by cAMP-dependent protein kinase and in this manner inhibits beta-adrenergic-stimulated lipolysis.
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PMID:Mechanism of halothane-induced inhibition of isoproterenol-stimulated lipolysis in isolated rat adipocytes. 335 97

Hormone-sensitive lipase has been purified to near homogeneity from bovine perirenal adipose tissue. The purification method involves isoelectric precipitation at pH 5.0, followed by partial solubilisation in Triton N-101 and ion-exchange chromatography on DE-52. After additional solubilisation, the enzyme is further purified by chromatography on phenyl-Sepharose and heparin-Sepharose. This procedure can be completed within three working days and yields approx. 30 units of enzyme with a specific activity of 30 U/mg. The enzyme has been identified as a polypeptide of Mr 84 000 by affinity labelling with [3H]diisopropyl fluorophosphate. This polypeptide comprises approx. 60-80% of the protein in the final preparation, as judged by scanning densitometry of SDS-polyacrylamide gels stained with silver or with Coomassie blue R. The polypeptide of Mr 84 000 serves as a substrate for cyclic AMP-dependent protein kinase, phosphorylation correlating with activation of the lipase. Polyclonal antibody to the lipase has been raised in a rabbit and shown to specifically cross-react with the Mr 84 000 subunit.
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PMID:Hormone-sensitive lipase from bovine adipose tissue. 370 11

Evidence is presented that all lipase activities present in the vascular and myocardial tissue from rat heart are regulated by product inhibition. Lipoprotein lipase activity, which plays a role in the uptake of circulating triglycerides, is determined by its reaction products, e.g. fatty acids and, predominantly, monoglycerides. Tissue acid and neutral lipase activities are regulated by product fatty acids and their coenzyme A (CoA) and carnitine ester derivatives. The order of potency is palmitoyl CoA approximately palmitoyl carnitine greater than palmitate for neutral lipase and palmitoyl carnitine greater than palmitoyl CoA palmitate for acid lipase activity. Product inhibition of extracellular and intracellular lipolytic processes warrants a close coupling between the supply of substrate fatty acids and the rate of fatty acid oxidation as determined by cardiac contractile activity. None of the lipases studied was directly affected by catabolic hormones (norepinephrine, glucagon) or their intracellular second messengers (cyclic AMP, protein kinase, Ca2+, calmodulin).
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PMID:Regulation of lipases involved in the supply of substrate fatty acids for the heart. 400 68

Glycerol 3-phosphate acyltransferase (GPAT) activity and triglyceride lipase (TGL) activity were measured in homogenates from hearts perfused with adrenergic agonists and antagonists. Perfusion with adrenalin or the beta-agonist isoprenaline produced an increase in TGL activity and a fall in GPAT activity. These changes could be imitated by incubation of heart homogenates with cAMP-dependent protein kinase. The alpha 2-agonist clondine produced the opposite effect, thus it increased GPAT activity and decreased TGL activity. Methoxamine, an alpha 1-agonist, had no effect on TGL activity but reduced GPAT activity. Continuous perfusion of the beta-antagonist atenolol reduced TGL activity to half that found in controls but also reduced GPAT activity. No change was seen on continuous perfusion of alpha 1- or alpha 2-antagonists. Changes in GPAT activity were localized mainly in the microsomal enzyme. These changes are consistent with both enzymes being regulated via a cyclic-AMP dependent protein kinase system and via alpha-adrenergic mechanisms.
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PMID:The effect of adrenergic agents on the activities of glycerol 3-phosphate acyltransferase and triglyceride lipase in the isolated perfused rat heart. 404 45

Brief incubation of partially purified preparations of hormone-sensitive lipase from rat epididymal fat pads with ATP, Mg(++), cyclic adenosine 3':5'-monophosphate and rabbit muscle protein kinase (phosphorylase b kinase kinase) resulted in enhancement of lipolytic activity (44-93%). Little or no activation was observed when either the cofactor mixture or the protein kinase was omitted. When the fat pads were incubated with epinephrine prior to homogenization, addition of kinase and cofactors to the soluble supernatant fraction caused no activation whereas good activation was obtained in preparations from paired fat pads not exposed to epinephrine. The results indicate that the cyclic AMP-mediated activation of hormone-sensitive lipase in adipose tissue involves a protein phosphorylation step. Whether the lipase itself is phosphorylated and thus activated or whether the protein kinase is activating a mediating enzyme, in analogy with its action in the glycogen phosphorylase system, remains to be determined.
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PMID:ATP-dependent and cyclic AMP-dependent activation of rat adipose tissue lipase by protein kinase from rabbit skeletal muscle. 431 80

A partially purified hormone-sensitive triglyceride lipase of human adipose tissue was found to be activated twofold by the addition of cyclic 3',5'-AMP, ATP, and magnesium ions. Lipase activities against diolein and monoolein were not affected. Addition of protein kinase inhibitor at zero time completely inhibited activation, and this inhibition was prevented by prior addition of an excess of exogenous protein kinase (from rabbit skeletal muscle). Addition of protein kinase inhibitor during the activation step blocked the activation process without a time lag, suggesting that protein kinase operates directly on hormone-sensitive lipase. Further purification yielded a fraction free of protein kinase, and lipase activation in this fraction depended absolutely on addition of exogenous kinase. Incubation of human fat with epinephrine or isoproterenol stimulated lipolysis and caused conversion of nonactivated hormone-sensitive lipase to its activated form, as indicated by a decrease in the activation subsequently obtainable in fractions prepared from such hormone-treated tissues. These findings strongly suggest that the stimulation of lipolysis by hormonal treatment is the consequence of the activation of hormone-sensitive triglyceride lipase by cyclic 3',5'-AMP-dependent protein kinase.
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PMID:The mechanism of activation of hormone-sensitive lipase in human adipose tissue. 436 Aug 57

Hormone-sensitive lipase partially purified from adipose tissue of laying hens was markedly activated by cyclic AMP-dependent protein kinase. Activation was approximately 4-fold (ranging up to as great as 10-fold) compared with the much lower degree of activation obtained with analogous preparations from rat and human adipose tissues (59 and 86%, respectively). The partially purified preparations contained adequate endogenous protein kinase activity to effect complete activation with addition of cyclic AMP, ATP, and Mg(2+). Activation was blocked by protein kinase inhibitor (from rabbit skeletal muscle) but could be restored fully by addition of excess exogenous protein kinase (from bovine skeletal muscle). The fully activated lipase was slowly deactivated by dialysis at 4 degrees C and then rapidly and almost fully reactivated by addition of cyclic AMP and ATP-Mg(2+). Reactivation was blocked by protein kinase inhibitor. This deactivation-reactivation cycle was rapid at 23 degrees C with dialysis against charcoal and could be demonstrated repeatedly using a single preparation. The reversible deactivation of protein kinase-activated enzyme is presumed to reflect the action of a lipase phosphatase. Lipase prepared from tissue previously exposed to glucagon yielded a much smaller degree of activation than lipase prepared from tissue not exposed to the lipolytic hormone, indicating that the physiological hormone-induced activation is probably similar to or identical with the protein kinase activation demonstrated in the cell-free preparations. Under the conditions of assay used, the partially purified lipase fraction contained diglyceride, monoglyceride, and lipoprotein lipase activities. However, treatment with cyclic AMP-dependent protein kinase had virtually no effect on these lipase activities.
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PMID:Reversible protein kinase activation of hormone-sensitive lipase from chicken adipose tissue. 437 88

We have studied the effects of somatostatin on lipid metabolism in liver and adipose tissue of fasted mice. The animals were injected subcutaneously with 8 micrograms somatostatin and killed 5 min after injection. In vivo incorporation of [14C]acetate into triglycerides in both tissues and into hepatic cholesterol was significantly enhanced by somatostatin. Concomitantly, a decrease of triglyceride lipase activity was observed, which corresponds well with the variation undergone by cyclic AMP-protein kinase system. In addition, a marked increase of serum cholesterol levels was observed. Additionally, in vitro experiments were also performed by employing 2.4 X 10(-6) M somatostatin. The results showed that the direct effect of somatostatin on liver seems to be a decrease in acetate uptake. The results obtained with the adipose tissue were similar to those obtained in in vivo conditions. On the other hand, when somatostatin was administered in vivo, the ability to incorporate ortho[32P]phosphate into phospholipids was enhanced in both tissues. Likewise in the in vitro experiments with [14C]acetate, the somatostatin seems to act by decreasing the ortho[32 P]phosphate uptake in liver. While in adipose tissue the somatostatin only caused a strong increase in the specific activity of phosphatidylcholine. These data demonstrate in fasted mice that somatostatin is able to counteract the lipolytic manifestations of the fasted state.
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PMID:Evidence for a role of somatostatin in lipid metabolism of liver and adipose tissue. 614 94


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