Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:6.4.1.2 (acetyl-CoA carboxylase)
 2,876 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adrenalin and glucagon inhibit glycogen, fatty acid and cholesterol synthesis by elevation of cyclic AMP, activation of cyclic AMP-dependent protein kinase and increased phosphorylation of the rate-limiting enzymes of these pathways. Here, we review recent evidence which indicates that inhibition of these biosynthetic pathways in muscle, adipose tissue and liver is much more indirect than has previously been supposed. In particular, cyclic AMP-dependent protein kinase does not appear to inhibit glycogen synthase, acetyl-CoA carboxylase and HMG-CoA reductase by phosphorylating them directly. It appears to achieve the same end result by inactivation of the protein phosphatases which dephosphorylate these regulatory enzymes in vivo, although this has only been established definitively in the case of glycogen synthesis.
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PMID:The actions of cyclic AMP on biosynthetic processes are mediated indirectly by cyclic AMP-dependent protein kinase. 165 40

Incubation of hepatocytes in conditions known to increase their volume, i.e. with amino acids or in hypo-osmotic media, resulted in the parallel activation of glycogen synthase and acetyl-CoA carboxylase. The activation of both enzymes by glutamine was antagonized by the addition of raffinose to prevent cell swelling, or by glucagon and microcystin. The findings are consistent with the involvement of a common mechanism for the activation of the two enzymes.
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PMID:Swelling of rat hepatocytes activates acetyl-CoA carboxylase in parallel to glycogen synthase. 168 Mar 22

The hyperinsulinaemic-glucose-clamp technique, in combination with measurement of glucose turnover in conscious unrestrained rats, was used to assess the effects of nutritional status on insulin sensitivity in vivo and glucose metabolism. Liver, heart and quadriceps skeletal-muscle glycogen content and activities of pyruvate dehydrogenase (PDH) and glycogen synthase were measured both basally and at the end of a 2.5 h glucose clamp (insulin 85 munits/h) in rats 6, 24 and 48 h after food withdrawal. Clamp glucose requirement and glucose turnover were unchanged by fasting. Activation of glycogen synthase and glycogen deposition in liver and skeletal muscle during the clamps were also not impaired in rats after a prolonged fast. By contrast with skeletal muscle, activation of cardiac-muscle glycogen synthase and glycogen deposition during the clamps were markedly impaired by 24 h of fasting and were undetectable at 48 h. Skeletal-muscle PDH activity fell with more prolonged fasting (6 h, 15.3 +/- 3.4%; 24 h, 4.7 +/- 0.7%; 48 h, 4.3 +/- 0.6% active; P less than 0.005), but at 24 and 48 h was stimulated by the clamp to values unchanged by the duration of fasting. Stimulation of cardiac PDH activity by the clamp was, however, impaired in rats fasted for 24 or 48 h. Basal hepatic PDH did not change significantly with fasting (6 h, 5.3 +/- 1.1%; 24 h, 4.6 +/- 0.7%; 48 h, 3.9 +/- 0.5%), and, although it could be partly restored at 24 h, very little stimulation occurred at 48 h. Hepatic pyruvate kinase and acetyl-CoA carboxylase activity were both stimulated by the clamps, and this was not impaired with more prolonged fasting. During the glucose clamps, blood concentrations of lactate, pyruvate and alanine were increased to a greater extent in rats fasted for 24 and 48 h than in rats studied 6 h after food withdrawal. The findings suggest that, although sensitivity to insulin of whole-body glucose disposal is unchanged with fasting, there may be qualitative differences in the metabolism of glucose.
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PMID:Effect of nutritional status on insulin sensitivity in vivo and tissue enzyme activities in the rat. 249 4

In addition to acetyl-CoA carboxylase and HMG-CoA reductase, the AMP-activated protein kinase phosphorylates glycogen synthase, phosphorylase kinase, hormone-sensitive lipase and casein. A number of other substrates for the cyclic AMP-dependent protein kinase, e.g., L-pyruvate kinase and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase, are not phosphorylated at significant rates. Examination of the sites phosphorylated on acetyl-CoA carboxylase, hormone-sensitive lipase, glycogen synthase and phosphorylase kinase suggests a consensus recognition sequence in which the serine residue phosphorylated by the AMP-activated protein kinase has a hydrophobic residue on the N-terminal side (i.e., at -1) and at least one arginine residue at -2, -3 or -4. Substrates for cyclic AMP-dependent protein kinase which lack the hydrophobic residue at -1 are not substrates for the AMP-activated protein kinase.
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PMID:The substrate and sequence specificity of the AMP-activated protein kinase. Phosphorylation of glycogen synthase and phosphorylase kinase. 256 85

Although glucocorticoid and thyroid hormones are known to act synergistically to stimulate surfactant production, they have opposite effects on other parameters of fetal lung maturation. We recently reported that the developmental increases in de novo fatty acid synthesis and glycogen accumulation in fetal rat lung were accelerated by dexamethasone but prevented by triiodothyronine and that the dexamethasone-induced increases were diminished when the two hormones were administered together. We have now examined the effects of maternal administration of these hormones on activities of enzymes of lung fatty acid synthesis and glycogen metabolism in the rat. There was a developmental increase in fatty-acid synthase activity between 19 and 21 days gestation. This activity was increased by dexamethasone but decreased by triiodothyronine. When the two hormones were administered together the stimulatory effect of dexamethasone was decreased from 56% to 29%. The stimulatory effect on fatty-acid synthase was also observed in fetal lung explants cultured in the presence of dexamethasone. This shows that the effect of the hormone was directly on the fetal lung. Dexamethasone had no effect on liver fatty-acid synthase. There was a developmental decrease in acetyl-CoA carboxylase activity but it was not affected by the hormones. These data show that the developmental and hormone-induced changes in fetal lung de novo fatty acid synthesis are mediated by fatty-acid synthase. Although there were developmental changes in fetal lung 6-phosphofructokinase, glycogen synthase and glycogen phosphorylase activities, these enzymes were not affected by the hormones.
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PMID:Effects of glucocorticoid and thyroid hormones on regulatory enzymes of fatty acid synthesis and glycogen metabolism in developing fetal rat lung. 288 79

The phosphorylase phosphatases in rat and rabbit liver cytosol that are markedly stimulated by histone H1, protamine and polylysine were identified as protein phosphatases-2A0, 2A1 and 2A2 by anion-exchange chromatography, gel-filtration and immunotitration experiments. Histone H1 and protamine also stimulated the dephosphorylation of phosphorylase kinase, glycogen synthase, fructose-1,6-bisphosphatase, pyruvate kinase, acetyl-CoA carboxylase and phenylalanine hydroxylase by phosphatases-2A1 and 2A2, and with several of these substrates activation was even more striking (20-100-fold) than that observed with phosphorylase (approximately 5-fold). Activation by basic polypeptides did not involve dissociation of these phosphatases to the free catalytic subunit. The dephosphorylation of phosphorylase by protein phosphatase-1 was suppressed by basic polypeptides, protamine and polylysine being the most potent inhibitors. However, the dephosphorylation of glycogen synthase, pyruvate kinase and acetyl-CoA carboxylase were markedly stimulated by histone H1 and protamine (2-13-fold). Consequently, with the appropriate substrates, protein phosphatase-1 can also be regarded as a basic-polypeptide-activated protein phosphatase. Heparin stimulated (1.5-2-fold) the dephosphorylation of phosphorylase by phosphatases-2A0 and 2A1, provided that Mn2+ was present, but phosphatase-2A2 and the free catalytic subunit of phosphatase-2A were unaffected. Heparin, in conjunction with Mn2+, also stimulated (1.5-fold) the dephosphorylation of glycogen synthase (labelled in sites 3 abc), phosphorylase kinase and phenylalanine hydroxylase by phosphatase-2A1, but not by phosphatase-2A2. By contrast, the dephosphorylation of phosphorylase and phosphorylase kinase by protein phosphatase-1 was inhibited by heparin. However, dephosphorylation of glycogen synthase and pyruvate kinase by phosphatase-1 was stimulated by this mucopolysaccharide. The studies demonstrate that basic proteins can be used to distinguish protein phosphatase-1 from protein phosphatase-2A, but only if phosphorylase is employed as substrate. Optimal differentiation of the two phosphatases is observed at 30 micrograms/ml protamine or at heparin concentrations greater than 150 microM.
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PMID:The protein phosphatases involved in cellular regulation. 1. Modulation of protein phosphatases-1 and 2A by histone H1, protamine, polylysine and heparin. 298 84

A multifunctional protein kinase, purified from rat liver as ATP-citrate lyase kinase, has been identified as a glycogen synthase kinase. This kinase catalyzed incorporation of up to 1.5 mol of 32PO4/mol of synthase subunit associated with a decrease in the glycogen synthase activity ratio from 0.85 to a value of 0.15. Approximately 65-70% of the 32PO4 was incorporated into site 3 and 30-35% into site 2 as determined by reverse phase high performance liquid chromatography. Release of 32PO4 from the phosphopeptides during automated Edman degradation confirmed the site 3 and 2 assignment. Thermal stability studies established that the phosphorylations of sites 3 and 2 were catalyzed by the same kinase. This multifunctional kinase was distinguished from glycogen synthase kinase-3 on the basis of nucleotide (ATP versus GTP) and protein substrate (glycogen synthase, ATP-citrate lyase, and acetyl-CoA carboxylase) specificities. Since the phosphate contents in glycogen synthase of sites 3 and 2 are altered in diabetes and by insulin administration, the possible involvement of the multifunctional kinase was explored. Glycogen synthase purified from diabetic rabbits was phosphorylated in vitro by this multifunctional kinase at only 10% of the rate compared to synthase purified from control rabbits. Treatment of the diabetics with insulin restored the synthase to a form that was readily phosphorylated in vitro.
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PMID:Phosphorylation of sites 3 and 2 in rabbit skeletal muscle glycogen synthase by a multifunctional protein kinase (ATP-citrate lyase kinase). 393 Apr 92

A rat liver cAMP-independent protein kinase that phosphorylates peptide b of ATP-citrate lyase (Ramakrishna, S., Pucci, D. L., and Benjamin, W. B. (1983) J. Biol. Chem. 258, 4950-4956) has been purified to apparent homogeneity. The molecular weight, determined by polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate, sucrose density gradient, and by gel filtration, was found to be 36,000. This protein kinase phosphorylates in vitro ATP-citrate lyase, acetyl-CoA carboxylase, and glycogen synthase and does not phosphorylate phosphorylase, phosphorylase kinase, histone, phosvitin, and casein. It has Fa (activity factor) activity stimulating the ATP X Mg-dependent phosphatase and is therefore named a multifunctional protein kinase. This kinase differs from glycogen synthase kinase-3 with regard to substrate specificity, kinetic parameters, and physicochemical properties.
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PMID:Cyclic nucleotide-independent protein kinase from rat liver. Purification and characterization of a multifunctional protein kinase. 404 96

Acetyl-CoA carboxylase phosphatase has been purified from the rat epididymal fat pad. The phosphatase occurs in a complex with the carboxylase. In the purification of the phosphatase, the high molecular weight complex was initially separated by sucrose gradient centrifugation, and the phosphatase was isolated from the complex by adjusting to 80% saturation with ethanol and by chromatography on Sephadex G-75. The molecular weight of the phosphatase is 71,000 as determined by sodium dodecyl sulfate gel electrophoresis and gel chromatography on Sephacryl-200 in the presence of 6 M urea. The Km for acetyl-CoA carboxylase and glycogen phosphorylase a are 1.5 microM and 37 microM, respectively. The phosphatase has a broad substrate specificity, being active toward glycogen synthase, 3-hydroxy-3-methylglutaryl-CoA reductase, phosphorylase a, phosphoprotamine, and p-nitrophenyl phosphate, in addition to acetyl-CoA carboxylase from fat tissue and liver. Acetyl-CoA carboxylase inhibits the dephosphorylation of phosphoprotamine, indicating that the same activity is responsible for dephosphorylating both substrates. The phosphatase requires no metal ion for activity and is not inhibited by the rat liver phosphorylase phosphatase inhibitor protein. The significance of these findings is discussed in relation to the regulation of acetyl-CoA carboxylase, and the phosphatase is compared to other phosphoprotein phosphatases.
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PMID:Purification and properties of acetyl-CoA carboxylase phosphatase. 625 18

The MgATP-dependent phosphorylase phosphatase was found to have a broad substrate specificity. Its activity against all phosphoproteins tested was dependent upon preincubation with the activating factor FA and MgATP. The enzyme dephosphorylated and inactivated phosphorylase kinase and inhibitor 1, and dephosphorylated and activated glycogen synthase and acetyl-CoA carboxylase. Glycogen synthase was dephosphorylated at similar rates whether it had been phosphorylated by cyclic-AMP-dependent protein kinase, phosphorylase kinase or glycogen synthase kinase 3. The enzyme also catalysed the dephosphorylation of ATP citrate lyase, initiation factor eIF-2, and troponin I. The properties of the MgATP-dependent protein phosphatase from either dog liver or rabbit skeletal muscle showed a remarkable similarity to highly purified preparations of protein phosphatase 1 from rabbit skeletal muscle. The relative activities of the two enzymes against all phosphoproteins tested was very similar. Both enzymes dephosphorylated the beta-subunit of phosphorylase kinase 40-fold faster than the alpha-subunit, and both enzymes were inhibited by identical concentrations of the two proteins termed inhibitor 1 and inhibitor 2, which inhibit protein phosphatase 1 specifically. These results demonstrate that the MgATP-dependent protein phosphatase is a type-1 protein phosphatase, and is distinct from type-2 protein phosphatases which dephosphorylate the alpha-subunit of phosphorylase kinase and are unaffected by inhibitor 1 and inhibitor 2. The possibility that the MgATP-dependent protein phosphatase is an inactive form of protein phosphatase 1 and that both proteins share the same catalytic subunit is discussed.
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PMID:The MgATP-dependent protein phosphatase and protein phosphatase 1 have identical substrate specificities. 626 81


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