Muscle enzymes glycogen phosphorylase

Figure 3.29 Control of an enzyme activity by multiple allosteric regulators. The enzyme glycogen phosphorylase b in muscle is regulated by changes in the concentrations of AMP and inosine monophosphate (IMP) (which are activators) and ATP and glucose 6-phosphate (G6P), which are inhibitors.

Pyridoxine is present in food in the free form and as a glucoside, which may undergo partial hydrolysis in the gut lumen, or may be absorbed intact. Although pyridoxine is associated with the enzyme glycogen phosphorylase in muscles, it is not released in response to a dietary deficiency therefore it cannot be regarded as a storage form of the vitamin. 

Fmax of the enzyme glycogen phosphorylase from skeletal muscle is much greater than the I max of the same enzyme from liver tissue. 

Adrenaline exerts its effect by binding to a receptor site on the cell surfaces of liver and muscle cells, where it initiates a series of signals that ultimately causes an inactive form of the enzyme glycogen phosphorylase to become active. This enzyme is the first in a sequence that leads to the breakdown of glycogen to glucose and other products. 

In the liver and muscle cells, another enzyme, glycogen phosphorylase, breaks down glycogen into glucose molecules, which then enter glycolysis. 

Protein phosphatase-1 (Mg +/ATP-dependent phosphatase multisubstrate protein phosphatase M.W. of catalytic subunit is 35,000 major enzyme in regulation of glycogen metabolism in skeletal muscle dephosphorylates glycogen phosphorylase, jS-subunit of phosphorylase kinase, and at least three sites of glycogen synthase regulated by inhibitor-1, inhibitor-2, and GSK-3 -t- Mg +- ATP). 

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. 

From the earliest measurements of tissue calcium, it was clear that total calcium is largely a measure of stored calcium. Through the years, scientists have used a variety of indirect measures of [Ca2+]j. These include shortening of or tension in muscles secretion from secretory cells the activity of Ca2+-dependent enzymes, most notably glycogen phosphorylase and flux of K+, or K+ currents, as a reflection of Ca2+-activated K+ channels. In addition, investigators often use the radioactive calcium ion [45Ca2+] as an indirect indicator of Ca2+ concentrations and Ca2+ movements. 

Glycogen phosphorylase isoenzymes have been isolated from liver, brain and skeletal muscle. All forms are subject to covalent control with conversion of the inactive forms (GP-b) to the active forms (GP-a) by phosphorylation on specific serine residues. This phosphorylation step, mediated by the enzyme phosphorylase kinase, is initiated by glucagon stimulation of the hepatocyte. Indeed, the same cAMP cascade which inhibits glycogen synthesis simultaneously stimulates glycogenolysis, giving us an excellent example of reciprocal control. 

Muscle glycogen phosphorylase is one of the most well studied enzymes and was also one of the first enzymes discovered to be controlled by reversible phosphorylation (by E.G. Krebs and E. Fischer in 1956). Phosphorylase is also controlled allosterically by ATP, AMP, glucose and glucose-6-phosphate. Structurally, muscle glycogen phosphorylase is similar to its hepatic isoenzyme counterpart composed of identical subunits each with a molecular mass of approximately 110 kDa. To achieve full activity, the enzyme requires the binding of one molecule of pyridoxal phosphate, the active form of vitamin B6, to each subunit. 

Glycogen phosphorylase breaks a-1,4 ycosidic bonds, releasing glucose 1-phosphate from the periphery of the granule. Control of the enzyme in liver and muscle is compared in Table 1-14-2. 

Since glycogen phosphorylase controls the rate of glucose production, the question is how signals from the brain or muscle are relayed to this enzyme. The signaling... 

Glycogen phosphorylase deficiency in muscle gives rise to muscle weakness, frequent cramp and ease of fatigue (McArdle s syndrome). It also gives rise to hypoglycae-mia if the liver enzyme is deficient (Chapter 6). 

The glucose 1-phosphate so formed can be used for ATP synthesis in muscle or converted to free glucose in the liver. Glycogen phosphorylase occurs in two forms the more active phosphorylase a and the less active phosphorylase b (Fig. 6-31). Phosphorylase a has two subunits, each with a specific Ser residue that is phosphorylated at its hydroxyl group. These serine phosphate residues are required for maximal activity of the enzyme. 

FIGURE 15-24 Regulation of muscle glycogen phosphorylase by covalent modification. In the more active form of the enzyme, phosphorylase a, Ser14 residues, one on each subunit, are phosphorylated. Phosphorylase a is converted to the less active form, phosphorylase b, by enzymatic loss of these phosphoryl groups, catalyzed by phosphorylase a phosphatase (PP1). Phosphorylase b can be reconverted (reactivated) to phosphorylase a by the action of phosphorylase b kinase. 

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