Phosphorylase b kinase and

In contrast to the situation in the adipocyte, hypothyroidism potentiates /3-ad-renergic receptor-mediated cAMP and glycogen phosphorylase response in rat he-patocytes [88]. Thyroid hormones suppress /3-adrenergic-stimulated phosphorylase b kinase and phosphorylase a activities, while enhancing phosphoprotein phosphatase activity in the same cells [89,90]. In other words, thyroid hormones seem to... 

Two key regulatory enzymes involved in the control of glycogen metabolism were first recognized as targets of cAMP and cAMP-dependent protein kinase in liver and skeletal muscle. These are phosphorylase b kinase and glycogen synthase. The molecular details of the phosphorylation and regulation of these enzymes are better understood in muscle than in liver since the liver enzymes have only recently been purified to homogeneity in the native form. However, it appears that they share many key features in common. 

Other effects of cyclic AMP in vitro - In a recent paper, Appleman and co-workers " concluded that many similarities exist between the ATP-cyclic AMP activation of phosphorylase b kinase and the conversion of glycogen synthetase from the independent to the glucose 6-phosphate-dependent form. 

Studies by Lamer and coworkers showed that 3 5 -cyclic AMP is an important factor that regulates the interconversion of the two forms of glycogen synthetase. The conversion of the independent into the dependent form is catalyzed by a kinase requiring ATP and Mg +, the activity of which is increased by cyclic AMP. Huijing and Lamer and others showed that muscle kinase appears to be similar to, but not identical with, phosphorylase b kinase, - and that the two enzymes seem to be equally sensitive to stimulation by cyclic AMP. It has been suggested - that cyclic AMP may in this instance act by increasing the affinity of an allosteric site for magnesium on the kinases. As epinephrine and other hormones increase the level of... 

Posner, J. B., Stem, R., and Krebs, E. G., 1965, Effects of electrical stimulation and epinephrine on muscle phosphorylase, phosphorylase b kinase, and adenosine 3, 5 -phosphate, J. Biol. Chem. 240 982. 

Glycogenosis type VIII (phosphorylase b kinase deficiency) gives rise to myopathy and liver disease, either singly or in combination. Phosphorylase b kinase (PBK) converts the inactive b form of both muscle and liver phosphorylases to the active a forms of the enzymes. The ischemic lactate test sometimes shows a flat result as in McArdle s disease, but is more likely to be normal. Histochemical demonstration of myophosphorylase activity in tissue sections shows a near-normal reaction due to the presence of phosphorylase a. Accumulation of glycogen is modest and found mainly in type 2 (fast-twitch glycolytic) muscle fibers. 

Glycogen and its enzymes are compartmentalized. Glycogen granules are only present in astrocytes of adult animals but are found in both astrocytes and neurons of immature animals. Of the enzymes involved in glycogen metabolism, glycogen phosphorylase is found in astrocytes only. Under steady-state conditions, it is probable that less than 10% of phosphorylase in brain is in the unphosphorylated b form (requiring AMP). This form is probably not very active at the low AMP concentrations present when intracellular glucose is sufficient to maintain ATP synthesis. Brain phosphorylase b kinase is activated indirectly by cAMP and by the molar concentrations... 

In the 1940s Carl and Gertrude Cori isolated and purified an active form (phosphorylase a) and an inactive form (phosphorylase b) of an enzyme from muscle. Phosphorylase b is activated by AMP (see page 64). In 1955, Fischer Krebs found an enzyme that catalysed the conversion of phosphorylase b to phosphorylase a, together with hydrolysis of ATP to ADP. Thus it appeared to bring about phosphorylation of the enzyme. The enzyme was termed phosphorylase b kinase, was partially purified and the interconversion was established as... 

Phosphorylase b-kinase converts the enzyme phosphorylase from its low activity form (phosphorylase b) to the high activity form (phosphorylase a) by phosphorylation. The enzyme activity of phosphorylase b-kinase is correlated with the increase of phosphorylase activity in the probands sample and is measured by determining the amount of P, produced by phosphorylase activity. 

Besley GTN (1987) Phosphorylase b kinase deficiency in glycogenosis type VIII differentiation of different phenotypes and heterozygotes by erythrocyte enzyme assay. J Inherit Metab Dis 10 115-118... 

Responses to various hormones can cross-talk by means of multiple interactions/modifications. One example has already been discussed Phosphorylase b kinase is responsive both to cAMP and to Ca2+ ions. Receptors can themselves be phosphorylated by protein... 

Metabolic Effects of Mutant Enzymes Predict and explain the effect on glycogen metabolism of each of the following defects caused by mutation (a) loss of the cAMP-binding site on the regulatory subunit of protein kinase A (PKA) (b) loss of the protein phosphatase inhibitor (inhibitor 1 in Fig. 15-40) (c) overexpression of phosphorylase b kinase in liver (d) defective glucagon receptors in liver. 

Both liver and muscle phosphorylase b kinase are large Mt (1.3 million) proteins with a tetrameric structure (afiy8)4 [70,71]. The molecular weights of the subunits are a, 140000-145000 (3, 116000-130000 y, 4100045000 S, 17000. White and red muscles contain isozymic forms differing in the Mr of the a-subunit. The S sub-... 

The major substrate of phosphorylase b kinase is phosphorylase b which is phos-phorylated on a single serine residue at position 14, resulting in conversion to the more catalytically active form phosphorylase a [70], Phosphorylation of skeletal muscle phosphorylase also results in conversion of the Mr 200000 dimeric b form to the Mr 400000 tetrameric a form, whereas phosphorylation of the liver enzyme does not alter its dimeric structure [82]. Phosphorylase a is much less dependent than phosphorylase b upon the allosteric activator AMP [82], Since the activity of phosphorylase is rate-limiting for glycogen breakdown, its activation by phosphorylase b kinase results in enhanced glycogenolysis and glucose release from the liver. 

The first enzyme in this sequence and the one which is affected by cyclic AMP is a protein kinase. It catalyses the transfer of the terminal phosphate of ATP to phosphorylase b kinase, thereby activating the enzyme. 

Hepatic glycogenosis (type VI) (G.H. Hers, 1959) is due to hepatic phosphorylase deficiency. Subtype Via is caused by a lack of phos-phorylase-B kinase, and it is transmitted by the x-chromosomal recessive route. Subtype Vib shows a deficiency in glycogen phosphorylase, and its transmission is autosomal recessive. In the musculature, the analogous enzyme is, however, intact. Nevertheless, there is pronounced genetic and phenotypical heterogeneity. 

The two errzymes involved in the synthesis and break down of glycogen exist in active and inactive forms. Thus, glycogen synthase is present as glycogen syn-thase-I (independent form or active) and glycogen synthase-D (dependent form or inactive) of which the former can be inactivated by protein kinase which, in turn, is activated by cyclic AMP. Similarly, glycogen phosphorylase exists as phosphorylase-a (highly active) and phosphorylase-b (poorly active) forms. The formation of active phosphorylase-a occurs in the presence of phosphorylase-b kinase which per se is activated by a cAMP dependent protein kinase (Chart-4). 

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