As Joseph Larner (1990) pointed out, glycogen has been a major catalyst in the formulation of many concepts of modern biology. A number of broad principles have emerged from studies of glycogen metabolism. Thus, covalent regulation by phosphorylation was originally described as the mechanism of activation of glycogen phosphorylase. Phosphorylase kinase was the second enzyme described as being activated by this mechanism. The third enzyme known to be controlled by phosphorylation was glycogen synthase, although in this case the regulation was inverse since phosphorylation caused the inactivation of the enzyme. The discovery of cyclic AMP and the development of the intracellular messenger concept emerged from the study of the regulation of glycogen phosphorylase by glucagon and adrenaline. These studies also led tot he notion of the cascade of phosphorylation reactions. The concept and emerging significance of multiple phosphorylation also originated in the research of the control of glycogen synthase. Later, this evolved into the theory of hierarchical phosphorylation. Parallel studies on the dephosphorylation of glycogen synthase showed the ability ofinsulin to modify the activity of protein kinases and protein phosphatases. In Larner's words, "glycogen has sparked its fair share of major discoveries in biology".
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