Principles of Biochemistry, Volume 2 - A. Lehninger 1985

Bioenergetics and Metabolism
Biosynthesis of carbohydrates in animal tissues
Glycogen synthase and glycogen phosphorylase are reciprocally regulated

We have previously seen that Glycogen breakdown is regulated through covalent and allosteric modulation of Glycogen phosphorylase (Section 15.11). Phosphorylase a, the active form of the enzyme containing Serine residues essential for catalytic activity, is dephosphorylated by phosphorylase phosphatase and converted into phosphorylase b—a significantly less active form that can be activated by AMP (its allosteric modulator). Phosphorylase kinase converts phosphorylase b back into phosphorylase a at the expense of ATP, which phosphorylates the aforementioned serine residues.

Glycogen synthase also exists in two forms—phosphorylated and dephosphorylated—but it is regulated reciprocally with respect to glycogen phosphorylase, i.e., in a directly opposite manner (Fig. 20-11). Its active form, glycogen synthase a, is dephosphorylated. As a result of protein kinase-catalyzed phosphorylation utilizing ATP at two serine hydroxyl groups, glycogen synthase a is converted into the less active form, glycogen synthase b.

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Fig. 20-10. Scheme illustrating how a new branch point is introduced into the glycogen molecule during its synthesis. A branching enzyme participates in its formation. The portion of the chain highlighted in red is transferred to a glucose residue located in the same chain but closer to the "core," as indicated by the dashed arrow. The transferred fragment is attached by an a(1→6) linkage.

The transition of the less active glycogen synthase b back into the active form is catalyzed by phosphoprotein phosphatase, which cleaves phosphate groups from the serine residues.

Fig. 20-11. Regulation of Glycogen synthase activity via enzymatic phosphorylation and dephosphorylation. The protein kinase itself also exists in two forms, active and inactive; their ratio is regulated by Hormones (Chapter 25).

Thus, glycogen phosphorylase and glycogen synthase are regulated reciprocally: while one of the Enzymes is activated, The activity of the other is suppressed (Fig. 20-12). This implies that both enzymes apparently cannot exhibit full activity simultaneously.

Glycogen synthase also alters its activity under METABOLISM/18.html">The Influence of allosteric modulators. The less active form, glycogen synthase b, is activated by its allosteric modulator, glucose-6-phosphate. Because the activity of this form of glycogen synthase depends on glucose-6-phosphate, it is termed the dependent form, or D-form. Glycogen synthase a is not activated by glucose-6-phosphate, i.e., it is independent of it, and is therefore termed the independent form, or I-form.

The balance between the rates of Glycogen Synthesis and degradation in the Liver is ultimately regulated by two hormones: epinephrine (produced by The adrenal medulla) and Glucagon (produced by the Pancreas). These hormones act by altering The ratio of the active and inactive forms of glycogen phosphorylase and glycogen synthase. Epinephrine secretion stimulates glycogen breakdown in The Liver and Muscles by increasing the ratio of phosphorylase a to phosphorylase b while simultaneously decreasing the ratio of glycogen synthase a to glycogen synthase b. Glucagon elicits the same ultimate effect but acts differently. We will examine the Hormonal Regulation of Glycogen Metabolism in detail in Chapter 25.

Fig. 20-12. Reciprocal Regulation of glycogen synthase and glycogen phosphorylase via phosphorylation and dephosphorylation. The active form of each enzyme is shown in red, the inactive form in black. The symbol denotes phosphorylated serine residues.