Glycogen synthase catalyzes the addition of a glucose molecule (from UDP-Glucose) in an 1,4 linkage to a growing glycogen chain. Glycogen synthase catalyzes the principal regulatory step of glycogen synthesis. Phosphorylation of the enzyme by cAMP-dependent Protein Kinase converts it from an independent, active form (called gycogen synthase I) to a dependent, less active form (called glycogen synthase D) whose activity is dependent on glucose-6-phosphate. cAMP-dependent protein kinase can phosphorylate glycogen synthase I directly, or it can phosphorylate SPK (also known as phosphorylase b kinase), which in turn is activated to phosphorylate glycogen synthase I (Figures 16.11 and 16.12). Phosphorylation converts glycogen synthase I to glycogen synthase D.

Conversion of the D form back to the I form requires action of the enzyme phosphoprotein phosphatase I. Glycogen synthase I is called the independent form of glycogen synthase, since it does not require glucose-6-phosphate for activity.

cAMP-dependent protein kinase requires cAMP for activity. Therefore, hormones, such as epinephrine and glucagon, which increase cAMP levels, tend to inactivate synthesis of glycogen due to conversion of glycogen synthase I to the dependent form (glycogen synthase D).

Conversely, hormones, such as insulin, which reduce cAMP levels and counteract the effects of cAMP-dependent protein kinase activity, stimulate dephosphorylation of glycogen synthase D to the independent form (I) and favor glycogen synthesis.