Glycogen initiation

Figure 9-28. Frequency distribution of equilibrium densities of mitochondria (cytochrome oxidase), peroxisomes (urate oxidase), and lysosomes (acid phosphatase). Mitochondrial fractions from rat liver equilibrated in a gradient of glycogen (initially linear from 0 to 30.6 g/lOO ml) in 0.5M sucrose and in a linear sucrose gradient (59.7-117.0 g/100 ml). [From H. Beaufay et al., Biochem. /., 92 184 (1964).]...

Stage 1. Assembly of Primer. In 1972 Krisman first provided firm evidence to show that a glycoprotein primer was required for the synthesis of glycogen. Subsequently Krisman and Barengo (1975) extended this study and distinguished between a glycogen initiator synthetase and the well-known glycogen synthetase of liver. 

Glycogen initiator synthetase was a membrane-bound enzyme. In the presence of high concentrations of salt it was shown to add glucosyl residues from UDPGlc to a protein acceptor, so that they became attached by a bond which was labile to acid. These glucosyl residues were 1,4-linked and... 

Bergstrom et al. (1967) examined the relationship between initial muscle glycogen content and the capacity for prolonged submaximal exercise. Subjects cycled to exhaustion at 75% VO2 max on three occasions, each separated by three days. 

Figure 10. The relationship between the initial glycogen content in vastus lateralis muscle and work time in six subjects who cycled to exhaustion at 75% VO2 max. Each subject cycled to exhaustion on three occasions. The first experiment was preceded by a mixed diet (a), the second by a carbohydrate-poor diet (o), and the third by a carbohydrate-rich diet ( ). The energy contents of the diets were identical. In all experiments depletion of the muscle glycogen store coincided with exhaustion and muscle fatigue. From Bergstrom et al. (1967) with permission from the publisher.

In starvation, glucose must be ptovided for the brain and erythrocytes initially, this is supphed from hver glycogen reserves. To spare glucose, muscle and other tissues reduce glucose uptake in response to lowered insuhn secretion they also oxidize fatty acids and ketone bodies preferentially to glucose. 

The carbohydrate metabolic routes in various tissues of the organism discussed above differ in intensity, which is defined by metabolic features specific of each tissue and organ. However, from the standpoint of activity of the whole organism, certain specializations of the carbohydrate metabolic routes in individual tissues are profitably complementary. For example, strenuous muscular exertion requires energy which is initially supplied by the breakdown of glycogen to lactic acid. The latter compound is excreted into the blood to be supplied... 

Welsh, G. I., Miller, C. M Loughlin, A. J., Price, N. T., and Proud, C. G. (1998). Regulation of eukaryotic initiation factor eIF2B Glycogen synthase kinase-3 phosphor-ylates a conserved serine which undergoes dephosphorylation in response to insulin. FEBS Lett. 421, 125-130. 

During product development, many of the initial non-clinical studies were undertaken in GAA knockout mice (i.e. mice devoid of a functional GAA gene), which serves as an animal model for Pompe s disease. The mice proved useful in assessing the pharmacodynamic effect of Myozyme on glycogen depletion and helped establish appropriate dosage regimens. The mice were also used to evaluate pharmacokinetics and biodistribution of GAA following its administration at clinically relevant doses. 

Studies on the breakdown and synthesis of glycogen are particularly associated with the work of Carl and Gerti Cori in the 1930s and 1940s. They emigrated to the U.S. from Vienna in 1922 initially to Buffalo, N. Y. and later moved to Washington University School of Medicine at St. Louis in 1931, when they worked together on carbohydrate metabolism, work for which they received a Nobel prize in 1947. 

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. 

Calcium ions released from the SR are required to initiate contraction and activate glycogen phosphorylase kinase... 

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