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:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Isolated sheep hepatocytes were used to obtain estimates of kinetic parameters, identify substrate preference and interactions and study regulation of gluconeogenesis. Respective Vmax estimates for propionate, pyruvate and alanine conversion to glucose were 59.5, 12.8 and 21.5 mol glucose formed X (h X g dry weight)-1. Respective KS estimates for propionate and pyruvate were 1 mM and 18 to 40 microM. Rates of lactate utilization varied among cell preparations, possibly because of loss of lactate dehydrogenase during isolation. Dihydroxyacetone and glycerol were utilized for glucose synthesis at similar rates of 8.6 and 8.7 mumol glucose formed X (h X g dry weight)-1, respectively. Respective rates of glucose synthesis from 5 mM fructose and 10 mM galactose were 63.2 and 31.4 mumol X (h X g dry weight)-1. Maximum rates of pyruvate carboxylase and phosphoenolpyruvate carboxykinase were estimated to be 101.6 and 160.4 mumol substrate converted X (h X g dry weight)-1, respectively. Neither butyrate nor acetate accelerated gluconeogenesis from propionate while acetate increased glucose synthesis from pyruvate, presumably through activation of pyruvate carboxylase. Glucagon stimulated gluconeogenesis from propionate. Dibutyrylcyclic AMP mimicked the effect of glucagon, implying that the glucagon effect is translated via the adenyl cyclase system as in rats. The kinetic parameters established in these experiments should be useful in future experiments and in computer modeling analyses of ruminant liver and whole animal metabolism where Michaelis-Menten type equations are widely used.
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PMID:Gluconeogenesis in isolated lamb hepatocytes. 381 90

The steady-state relationship between the activation state of cAMP-dependent protein kinase (A-kinase) and lipolysis has been defined quantitatively. A-kinase activation was assessed by measuring the ( +/- cAMP) activity ratio in adipocyte extracts, and lipolysis was determined by measuring glycerol release from cells. Both processes were stimulated either by incubating cells in a ligand-free environment achieved with adenosine deaminase or by addition of lipolytic hormones. A response spectrum was obtained with a variety of adenylate cyclase stimulators and inhibitors, both receptor- and nonreceptor-mediated. Regardless of the ligands used to manipulate adipocyte activity, lipolysis varied from nil to maximal as the A-kinase activity ratio varied from approximately 0.05 to 0.3-0.35. These data provide a quantitative description of the steady-state relationship between A-kinase activity and lipolysis and indicate that the various lipolytic and antilipolytic agents tested act on the lipolytic process exclusively by altering adenylate cyclase activity and, thus, cellular cAMP concentrations. The data reveal also that transient "peaking" of cAMP, as measured by A-kinase activity ratios, is not an inherent feature of adipocyte metabolism. Moreover, the concentration requirements for lipolytic hormone action are critically dependent on the ambient concentration of antilipolytic agents, and t concentration requirements for antilipolytic agents are dependent on the extent to which cells are stimulated. The data in this paper provide the basis for assessing the relationship between A-kinase activity ratio and lipolysis in the presence of insulin (Londos, C., Honnor, R. C., and Dhillon, G. S. (1985) J. Biol. Chem. 260, 15139-15145).
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PMID:cAMP-dependent protein kinase and lipolysis in rat adipocytes. II. Definition of steady-state relationship with lipolytic and antilipolytic modulators. 387 23

Prostaglandin E(1) (PGE(1)) at a concentration of 1 ng/ml antagonized theophylline, and norepinephrine induced release of glycerol and free fatty acids (FFA) in human fat cell preparations. Insulin at higher doses also inhibited theophylline-stimulated lipolysis. The N(6)-2-0'dibutyryl derivative of cyclic adenosine monophosphate (DCAMP) stimulated lipolysis. Prostaglandin E(1) did not significantly inhibit the lipid mobilizing effects of DCAMP. Changes in glycogen phosphorylase activity after treatment with theophylline, norepinephrine, DCAMP, and PGE(1) paralleled those of lipolysis. These results suggest that in man as in experimental animals lipolysis and phosphorylase activity are regulated through processes involving cyclic AMP and that PGE(1) appears to exert its antilipolytic effect in human fat cells, as in rat fat cells, by interfering at the level of adenyl cyclase with the accumulation of cyclic AMP.
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PMID:Hormonal regulation of lipolysis and phosphorylase activity in human fat cells. 430 1

Epinephrine, norepinephrine, ACTH, and dibutyryl 3',5'-cyclic AMP reduced adipocyte ATP levels during 60 min incubation; glucose displayed a protective effect. The reduction in adipocyte ATP levels could not be attributed solely to: a direct hormone effect, deficiency in metabolic substrate, activation of adenyl cyclase with ATP consumption, loss of adenine nucleotide from the cell or loss of cells during incubation, lipolytic rate per se, or extracellular accumulation of FFA or glycerol. To determine whether intracellular FFA accumulation was a causative factor, intracellular FFA levels were measured during hormone-stimulated lipolysis. This was accomplished by using sucrose-U-(14)C as a marker for the extracellular space to correct for contamination of cells by extracellular albumin-bound FFA. These experiments showed that the fall in adipocyte ATP correlated with FFA saturation of medium albumin and progressive accumulation of FFA within the adipocyte. Furthermore, the protective effect of glucose noted above was associated with a marked reduction in intracellular FFA as compared to the extracellular FFA pool. On the basis of these studies, combined with those in the literature, it is concluded that in vitro effects of lipolytic agents on adipocyte ATP levels are the net result of imparied ATP synthesis (uncoupled oxidative phosphorylation) in the face of normal or augmented ATP consumption.
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PMID:Reduction in adipocyte ATP by lipolytic agents: relation to intracellular free fatty acid accumulation. 432 9

In isolated fat cells, the same maximal rate of glycerol production can be induced by epinephrine or ACTH, alone or in combination with each other or with glucagon. With fat cells from rats weighing 150-175 g, the maximal rate of lipolysis attained with glucagon was 75-80% of that produced by epinephrine or ACTH, and with increasing size of the donor rat, the magnitude of the effect of glucagon relative to that of the other hormones declined markedly. In particulate preparations from fat cells of rats weighing 100-125 g, the maximal effect of glucagon on adenyl cyclase activity was about 60% of that of epinephrine, and was significantly less (30%) in preparations from 350-400 g rats. These data are consistent with the hypothesis that with growth of the rat there is a selective decline in the number of glucagon receptors relative to those for epinephrine or ACTH in the fat cell membrane.
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PMID:Selective loss of adipose cell responsiveness to glucagon with growth in the rat. 433 20

The number of fat cells contained in the rat epididymal fat pad was found to increase rapidly as the rats grew to a weight of about 300 g. Additional increases in cell number above this weight were minimal. By contrast, cell size, as measured by the amount of triglyceride per cell, increased linearly until the rats reached about 600 g. Glycerol release per 10(6) cells in response to norepinephrine in vitro was observed to be independent of cell size. Basal release expressed in this manner showed a slight but significant positive correlation with increasing cell size. When the rate of lipolysis was based either on the amount of triglyceride in the incubation medium, as is the usual custom, or on the cell surface area, lipolysis was inversely related to cell size. In addition to these observations on lipolysis, it was also demonstrated that norepinephrine-activated adenyl cyclase activity expressed per 10(6) cells was unaffected by cell size. This leads to the suggestion that the number of adrenergic receptors in the fat cell is fixed and is independent of the size of the cell; as the cell enlarges, these receptors are merely distributed over a greater surface area.
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PMID:Lipolytic response and adenyl cyclase activity of rat adipocytes as related to cell size. 436 45

The influence of forskolin, an adenylate cyclase activator, and of dibutyryl cyclic AMP (Bt2cAMP) on [3H]glycerol incorporation into glycerolipids was investigated in human platelets. It was found that preincubation with 2.5 mM Bt2cAMP produced a 2-4-fold increase in thrombin-induced incorporation into phospholipids compared to platelets activated by thrombin alone. Pretreatment with forskolin, which increased cellular cAMP content, also resulted in an increase in thrombin-stimulated [3H]glycerol incorporation into phospholipids. These findings demonstrate that a rise in platelet cAMP can accentuate thrombin-induced de novo synthesis of phospholipids from [3H]glycerol. Since the content of cellular cAMP was correlated with its ability to inhibit platelet activation monitored by serotonin release, it seems likely that glycerolipid, in particular phospholipid biosynthesis, is involved in controlling platelet activation by thrombin.
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PMID:Effects of dibutyryl cyclic AMP and forskolin on phospholipid biosynthesis in thrombin-stimulated human platelets. 609 Dec 92

When glucose was added to a suspension of Saccharomyces cerevisiae in stationary phase, it caused a transient increase in the concentration of cyclic AMP and a more persistent increase in the concentration of hexose 6-phosphate and of fructose 2,6-bisphosphate. These effects of glucose on cyclic AMP and fructose 2,6-bisphosphate but not that on hexose 6-phosphate were greatly decreased in the presence of 0.15 mM acridine orange or when a temperature-sensitive mutant deficient in adenylate cyclase was used at the restrictive temperature. Incubation of the cells in the presence of dinitrophenol and in the absence of glucose increased the concentration of both cyclic AMP and fructose 2,6-bisphosphate, but with a minimal change in that of hexose 6-phosphate. Glucose induced also in less than 3 min a severalfold increase in the activity of 6-phosphofructo-2-kinase and this effect was counteracted by the presence of acridine orange. When a cell-free extract of yeast in the stationary phase was incubated with ATP-Mg and cyclic AMP, there was a 10-fold activation of 6-phosphofructo-2-kinase. Finally, the latter enzyme was purified 150-fold and its activity could then be increased about 10-fold upon incubation with ATP-Mg and the catalytic subunit of cyclic-AMP-dependent protein kinase. This activation resulted from a 4.3-fold increase in V and a 2-fold decrease in Km. Both forms of the enzyme were inhibited by sn-glycerol 3-phosphate. From these results it is concluded that the effect of glucose in increasing the concentration of fructose 2,6-bisphosphate in S. cerevisiae is mediated by the successive activation of adenylate cyclase and of cyclic-AMP-dependent protein kinase and by the phosphorylation of 6-phosphofructo-2-kinase by the latter enzyme. In deep contrast with what is known of the liver enzyme, yeast 6-phosphofructo-2-kinase is activated by phosphorylation instead of being inactivated.
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PMID:The mechanism by which glucose increases fructose 2,6-bisphosphate concentration in Saccharomyces cerevisiae. A cyclic-AMP-dependent activation of phosphofructokinase 2. 609 80

Forskolin at 10 muM caused a 100-fold increase in the intracellular concentration of cyclic AMP and a 6-fold increase in glycerol release in the human adipocyte. These responses are comparable to those prompted by 10 muM isoproterenol. The effects of forskolin on cyclic AMP and lipolysis were dose-dependent. Alpha-2 adrenergic activation, achieved with 10 muM epinephrine and 30 muM propranolol, significantly inhibited forskolin-stimulated cyclic AMP accumulation and glycerol release, shifting the dose-response curves to the right. Forskolin at 10 muM caused a 4.5-fold increase in the adenylate cyclase activity of human adipocyte membranes. When either isoproterenol or epinephrine (0.1 mM) was combined with forskolin, the magnitude of response was substantially greater than the sum of responses achieved by each agent incubated alone.
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PMID:Alpha-2 adrenergic activation inhibits forskolin-stimulated adenylate cyclase activity and lipolysis in human adipocytes. 612 88

It has been suggested that lithium exerts some of its pharmacological actions by inhibition of the membrane-bound enzyme adenylate cyclase. However, the relationship between the lithium inhibition of adenylate cyclase and the corresponding physiological parameters, e.g. lipolysis, has not been investigated. In the present study it was found that lithium inhibited both the norepinephrine-induced accumulation of cAMP and release of glycerol in isolated rat fat cells, but only in the lower dose range of norepinephrine. At maximally effective concentrations of norepinephrine, where in the presence of 40 mM of lithium the formation of cAMP was reduced by approximally 40%, lipolysis remained unaffected. The basal content of cAMP and the basal release of glycerol were not inhibited by lithium. In addition to the inhibitory effect of lithium, lithium was found to stimulate the release of glycerol. This stimulatory effect of lithium may be explained by a prevention by lithium of the feedback inhibition by free fatty acids of adenylate cyclase and/or triglyceride lipase, since it could be avoided by increasing the concentration of bovine serum albumin in the incubation medium. It is concluded that lithium by inhibition of hormone-stimulated adenylate cyclase activity inhibits lipolysis only at submaximal hormone concentrations. This dissociation by lithium of cAMP accumulation and glycerol release may suggest that at least at high concentrations of norepinephrine cAMP-independent factors are involved in lipolysis.
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PMID:Dissociation by lithium of hormone-induced formation of cyclic AMP and release of glycerol in isolated rat fat cells. 624 16


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