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)

The characteristics of neutral cholesteryl ester hydrolase activities found in the microsomal and cytosolic subcellular fractions of rat lactating mammary tissue were investigated. The enzymes were assayed using cholesteryl oleate dispersed as a mixed micelle with phosphatidylcholine and sodium taurocholate (molar ratio 1:4:2) as substrate. This method gave activities approx. 20-fold higher than those seen when cholesteryl oleate was added in ethanol. Addition of phosphatidylcholine and sodium taurocholate to the assays using the ethanol-dissolved substrate did not increase the activities observed. When the cholesteryl oleate was dispersed with phosphatidylcholine only (molar ratio, 1:4) the activity of the two neutral cholesteryl ester hydrolases was also decreased considerably compared to that found with mixed micelles. In this case, however, approx. 60% of the cytosolic, but only 10% of the microsomal activity, was restored by separate addition of sodium taurocholate. The activities of both the microsomal and the cytosolic neutral cholesteryl ester hydrolases were inhibited by MgCl2, and this inhibition was almost completely reversed by the addition of an equimolar concentration of ATP. At a fixed concentration of MgCl2 increasing concentrations of ATP increased the enzyme activities in a dose-dependent way. The activity of the microsomal, but not the cytosolic enzyme was enhanced by a cyclic AMP-dependent protein kinase and both activities were inhibited by alkaline phosphatase (bovine milk). These results provide evidence for the regulation of neutral cholesteryl ester hydrolases in the rat lactating mammary gland by mechanisms involving phosphorylation-dephosphorylation and therefore suggest that these enzymes may be under hormonal control.
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PMID:Neutral cholesteryl ester hydrolase in the rat lactating mammary gland: regulation by phosphorylation-dephosphorylation. 217 66

Short term regulation of hepatic cholesterol ester hydrolase by reversible phosphorylation is described. Two different kinase systems seem to be involved in this regulation. The addition of ATP, cyclic AMP and Mg2+ to rat liver 104,000 X g supernatant (S104) produced a 100-140% increase in cholesterol ester hydrolase activity. This stimulation was abolished when protein kinase inhibitor was added prior to the addition of ATP, cyclic AMP and Mg2+. Cholesterol ester hydrolase activity was also stimulated when calcium ions, phosphatidylserine, and diolein were added to S104 along with ATP and Mg2+. Diolein in this reaction could be substituted by phorbol 12-myristate 13-acetate. Preincubation of S104 with alkaline phosphatase resulted in a deactivation of cholesterol ester hydrolase. The addition of increasing concentrations of Mg2+ to S104 produced increasing inhibition of cholesterol ester hydrolase activity, and this effect was blocked by NaF. It is suggested that rat liver cholesterol ester hydrolase is activated by cyclic AMP dependent protein kinase and protein kinase C. Deactivation is accomplished by dephosphorylation catalyzed by a phosphoprotein phosphatase, dependent on Mg2+.
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PMID:Activation of rat liver cholesterol ester hydrolase by cAMP-dependent protein kinase and protein kinase C. 255 47

The effects of the slow Ca++ channel blocker, nifedipine, and ACAT inhibitor, octimibate, on the cholesterol metabolism of cholesterol-loaded macrophages were compared. We demonstrated that apolipoprotein A-I containing high density lipoproteins (HDL) bind to specific receptor sites on macrophages, are internalized, take up cholesterol, and are then released from the cells as native lipoproteins. The ACAT inhibitor enhances HDL receptor activity and promotes HDL-mediated cholesterol efflux from cultured mouse peritoneal macrophages. In contrast, the Ca++ antagonist increases acetyl LDL-mediated cholesterol influx, abolishes the increase in HDL binding induced by cholesterol accumulation, enhances apo E synthesis, and promotes cholesterol efflux by a mechanism independent of the presence of HDL in the surrounding medium. Concomitantly, a decrease in nucleoside transporter activity, an increase in intracellular ATP hydrolysis, adenosine and cyclic AMP concentration, and a stimulation of the activities of acid and neutral cholesteryl ester hydrolase and ACAT indicated that protein kinase A-catalyzed phosphorylation reactions might be involved in the increase in cholesterol efflux. The Ca++ antagonist-induced efflux occurred only with lysosomal-associated cholesterol, while the ACAT inhibitor acted on the formation of cytoplasmic lipid droplets. The secreted lipoprotein particles contained 68% unesterified cholesterol and 21% phospholipids, 8% esterified cholesterol, and 3% triglycerides. The phospholipid components were: 72% phosphatidylcholine, 22% sphingomyelin, and 6% phosphatidylserine, phosphatidylinositol, and phosphatidylethanolamine. We conclude that macrophages release cholesterol in two ways: 1) an HDL-mediated release of unesterified cholesterol increasing upon ACAT inhibition, and 2) an HDL-independent secretion of cholesterol which can be amplified by Ca++ antagonists.
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PMID:Ca++ antagonists and ACAT inhibitors promote cholesterol efflux from macrophages by different mechanisms. I. Characterization of cellular lipid metabolism. 282 3

Efficiency of substrates for cholesterol esterase (EC 3.1.1.13) assay, and regulation of the activity were investigated in rat epididymal adipose tissue. The activity in the supernatant was activated by cyclic AMP-dependent protein kinase, cyclic AMP, ATP and Mg2+, both with micellar and liposomal substrates. However, the micellar substrate was more suitable for the assay than the liposomal with respect to Vmax and Km. Thus, the micellar substrate was employed. Pretreatment of the supernatant with exogenous cyclic AMP-dependent protein kinase enhanced the activity dose dependently, whereas that with cyclic AMP decreased the activity slightly. The cyclic AMP-dependent protein kinase activity in the assay mixture was within the range which can cause changes in cholesterol esterase activity. These results suggest that the amount of cyclic AMP-dependent protein kinase, rather than the cyclic AMP level, plays an important role in the regulation of cholesterol esterase in tissues with a high cholesterol esterase activity relative to the kinase activity, such as in adipose tissue.
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PMID:Studies on cholesterol esterase in rat adipose tissue: comparison of substrates and regulation of the activity. 284 84

Lipolysis of intracellular triglycerides in the heart has been shown to be regulated by hormones. However, activation of myocardial triglyceride lipase in a cell-free system has not been directly demonstrated. In the present studies, initial attempts to demonstrate cAMP-dependent activation of triglyceride lipase using the 1,000 X g supernatant fraction (S1) of mouse heart homogenate were unsuccessful, presumably due to the masking effects of high levels of lipoprotein lipase activity even when assayed at pH 7.4 and in the absence of apolipoprotein C-II. Myocardial lipoprotein lipase in the 40,000 X g supernatant fraction was then removed by heparin-Sepharose affinity chromatography. The lipoprotein lipase-free fractions were shown to contain neutral triglyceride lipase and neutral cholesterol esterase of about equal activities. The triglyceride lipase and cholesterol esterase activities fell progressively during preincubation in the presence of 5 mM Mg2+. Additions of cAMP and ATP resulted in 40-70% activation of both triglyceride lipase and cholesterol esterase. The activation was blocked by protein kinase inhibitor and was restored by the addition of exogenous cAMP-dependent protein kinase. Since lipoprotein lipase has no activity toward cholesteryl oleate, activation of cholesterol esterase in untreated S1 was readily demonstrable. Both triglyceride lipase and cholesterol esterase activities were present in homogenates prepared from isolated rat heart myocytes. We conclude that the myocardium contains a hormone-sensitive lipase that is regulated in a fashion similar to that of the adipose tissue enzyme.
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PMID:Activation of myocardial neutral triglyceride lipase and neutral cholesterol esterase by cAMP-dependent protein kinase. 298 7

Cultured arterial smooth muscle cells have been found to contain an activatable neutral cholesteryl esterase (EC 3.1.1.13). This enzyme is similar to that previously described in adipose tissue, adrenal cortex, and aortic homogenates. Although both the lysosomal (acid) and cytoplasmic (neutral) cholesteryl esterases were activated two- to threefold by the addition of 100 microM dibutyryl cyclic AMP, only neutral cholesteryl esterase was responsive to 100 microM dibutyryl cyclic AMP, 10 mM MgATP, and 50 micrograms/ml exogenous protein kinase when added together. Protein kinase inhibitor (10 micrograms/ml) reversed the action of cyclic AMP-dependent protein kinase; deactivation of neutral cholesteryl esterase was also shown to occur with 50 micrograms/ml phosphoprotein phosphatase. In addition, 0.2 microM prostacyclin, 50 microM forskolin, and an agonist of the beta-adrenergic receptor, 5 microM isoproterenol, significantly stimulated intracellular cyclic AMP accumulation and activated cholesteryl esterase in arterial smooth muscle cells. The data indicate that neutral cholesteryl esterase in arterial smooth muscle cells can be modulated by a phosphorylation-dephosphorylation system involving the cyclic AMP-dependent protein kinase-phosphoprotein phosphatase. Regulation of cholesteryl esterase by this mechanism may affect lipid accumulation in these arterial cells.
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PMID:Regulation of neutral cholesteryl esterase in arterial smooth muscle cells: stimulation by agonists of adenylate cyclase and cyclic AMP-dependent protein kinase. 301 Aug 80

Phosphorylation of cholesterol ester hydrolase by cyclic AMP-dependent protein kinase results in activation of both cholesterol ester and triacylglycerol hydrolase activities. Activation against both substrates correlates closely with phosphorylation in time course experiments. Proteolytic digestion of phosphorylated cholesterol ester hydrolase, followed by peptide mapping, indicates the presence of a single phosphorylation site on the enzyme. Phosphoserine is the only phosphoamino acid detected following partial acid hydrolysis of the phosphorylated enzyme.
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PMID:Regulation of cholesterol ester hydrolase by cyclic AMP-dependent protein kinase. 301 11

Herpesvirus infection has been shown to alter the cholesteryl ester cycle in avian arterial smooth muscle cells, resulting in cytoplasmic cholesteryl ester accumulation (Hajjar, D. P., Falcone, D. J., Fabricant, C. G., and Fabricant, J. (1985) J. Biol. Chem. 260, 6124-6128). In this study, we attempted to define some of the regulatory mechanisms associated with the control of cytoplasmic cholesteryl esterase in Marek's disease herpesvirus (MDV)-infected cells. We found that cholesteryl esterase activity in MDV-infected cells could not be activated by dibutyryl cyclic AMP, dibutyryl cyclic AMP added together with protein kinase, or agonists of adenylate cyclase. Activation of cytoplasmic cholesteryl esterase activity occurred in uninfected cells and in cells infected with a control virus, turkey herpesvirus. Furthermore, the rate of cholesterol efflux from arterial smooth muscle cells challenged with dibutyryl cyclic AMP was unchanged in MDV-infected cells as compared to uninfected or turkey herpesvirus-infected cells in which efflux was increased. We propose that the reduced cytoplasmic cholesteryl esterase activity in lipid-laden, herpesvirus-infected cells is due partly to its inability to be activated by the cyclic AMP-protein kinase mechanism. This may contribute to the pathologic changes seen in MDV-infected arterial cells, including accumulation of intracellular cholesteryl esters.
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PMID:Herpesvirus infection prevents activation of cytoplasmic cholesteryl esterase in arterial smooth muscle cells. 301 90

The conversion of cholesterol to pregnenolone by adrenocortical mitochondria is the rate-limiting step in steroidogenesis. This process is stimulated dramatically by the action of ACTH through the sequential reactions, in which adenyl cyclase, cAMP-dependent protein kinase, cholesterol esterase and ribosomal protein synthesis are all involved. The de novo synthesized protein, the so-called labile protein with a half-life of approx 10 min, is believed to stimulate the cholesterol side chain cleavage reaction by an unknown mechanism. Available evidence indicates that the electron on transfer reaction from NADPH to P-450scc is mediated rapidly by adrenodoxin reductase and p-450 scc. In addition, these redox components are inactivated slowly with a half-life of 3.5 days after hypophysectomy. It is known that the corticoid output from adrenocortical cells starts within 5 min and reaches the maximum after 10-15 min of ACTH administration to animals. One can assume that under normal physiological conditions, both O2 and NADPH are not limiting. Additionally, mitochondrial inner membranes are poor in cholesterol. In this context, the availability of substrate cholesterol to P450scc is the most likely candidate for the regulatory mechanism.
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PMID:Transduction of ACTH signal from plasma membrane to mitochondria in adrenocortical steroidogenesis. Effects of peptide, phospholipid, and calcium. 302 55

The rate-limiting step in adrenal steroidogenesis is associated with the mitochondrial-cytochrome-P450scc-dependent production of pregnenolone from cholesterol. This sterol side-chain cleavage reaction is influenced by the supply of cholesterol to the mitochondria. Cholesterol is stored as cholesterol esters while the cytosol contains a hormone-sensitive cholesterol ester hydrolase. This enzyme is activated by phosphorylation involving a cyclic AMP-dependent protein kinase and ATP; this enzyme preferentially attacks cholesterol oleate or cholesterol linoleate. The lipid composition of the adrenal cortex is influenced by diet so that animals on a low-fat diet tend to store cholesterol oleate and as the linoleate content of the diet is increased, the cholesterol linoleate content of the adrenal cortex increases. Animals maintained on a high erucate diet tend to store large amounts of cholesterol erucate in the adrenal cortex; such animals have an impaired adrenal cortical function. Animals maintained on a low-fat diet (marginally deficient in essential fatty acids), a linoleate-replete diet or a moderate erucate diet, all exhibited normal responses to ACTH and normal corticosterone production rates.
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PMID:Dietary effects on certain adrenal cortical functions in the rat. 625 93


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