Muscle glycogen phosphorylase

Muscle glycogen phosphorylase is a dimer of two identical subunits (842 residues, 97.44 kD). Each subunit contains a pyridoxal phosphate cofactor, covalently linked as a Schiff base to Lys °. Each subunit contains an active site (at the center of the subunit) and an allosteric effector site near the subunit interface (Eigure 15.15). In addition, a regulatory phosphorylation site is located at Ser on each subunit. A glycogen-binding site on each subunit facilitates prior association of glycogen phosphorylase with its substrate and also exerts regulatory control on the enzymatic reaction. 

Muscle Glycogen Phosphorylase Shows Cooperativity in Substrate Binding... 

Villar-Palasi C On the mechanism of inactivation of muscle glycogen phosphorylase by insulin. Biochim Biophys Acta 1994 1224 384. 

Six compounds have vitamin Bg activity (Figure 45-12) pyridoxine, pyridoxal, pyridoxamine, and their b -phosphates. The active coenzyme is pyridoxal 5 -phos-phate. Approximately 80% of the body s total vitamin Bg is present as pyridoxal phosphate in muscle, mostly associated with glycogen phosphorylase. This is not available in Bg deficiency but is released in starvation, when glycogen reserves become depleted, and is then available, especially in liver and kidney, to meet increased requirement for gluconeogenesis from amino acids. 

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. 

Phosphorylase deficiency (McArdle s disease, glycogenosis type V) is an autosomal recessive myopathy caused by a genetic defect of the muscle isoenzyme of glycogen phosphorylase (Fig. 42-1). Intolerance of strenuous exercise is present from childhood, but usually onset is in adolescence, with cramps after exercise [1, 5]. Myoglobinuria occurs in about one-half of patients. If they avoid intense exercise, most patients can live normal lives however, about one-third of them develop some degree of fixed weakness, usually as a late-onset manifestation of the disease. In a few patients, weakness rather than exercise-related cramps and myoglobinuria characterizes the clinical picture. 

McArdle s disease is associated with excessive deposits of glycogen in muscle, and Hers disease with its deposition in liver. In both cases phosphorylase levels in the affected tissues are very low. In spite of this, glycogen synthesis is unimpaired, which is incompatible with glyco-genesis occurring through the action of phosphorylase. 

As is often the case, tissue-specific control mechanisms operate to optimise adaptation to particular conditions. For example, muscle contraction requires an increase in cytosolic calcium ion concentration (see Section 7.2.1, Figure 7.4). During exercise when energy generation needs to be increased, or from a more accurate metabolic point of view, when the ATP-to-ADP ratio falls rapidly, and the accompanying rise in [Ca2 + ] activate (i) glycogen phosphorylase which initates catabolism of... 

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 b Rabbit muscle 6.7 25 4 -12 E. Morild and H. Kryvi... 

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. 

V McArdle Muscle glycogen phosphorylase Musde cramps and weakness on exercise Normal... 

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). 

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.

---