Glucose-6-phosphate phosphorylase inhibition

Both phosphorylase a and phosphorylase kinase a are dephosphorylated and inactivated by protein phos-phatase-1. Protein phosphatase-1 is inhibited by a protein, inhibitor-1, which is active only after it has been phosphorylated by cAMP-dependent protein kinase. Thus, cAMP controls both the activation and inactivation of phosphorylase (Figure 18-6). Insulin reinforces this effect by inhibiting the activation of phosphorylase b. It does this indirectly by increasing uptake of glucose, leading to increased formation of glucose 6-phosphate, which is an inhibitor of phosphorylase kinase. 

The glucose concentration is the major factor regulating glycogen synthesis in liver. Glucose activates glucokinase directly as a substrate and indirectly via an increase in the concentration of fructose 6-phosphate. It also activates glycogen synthase but it inhibits glycogen phosphorylase (see text). 

In the well-fed state, glycogen synthase is allosterically activated by glucose 6-phosphate when it is present in elevated concentrations (Figure 11.9). In contrast, glycogen phosphorylase is allosterically inhibited by glucose 6-phosphate, as well as by ATP,... 

The yeast enzyme is a homodimer of Mr2 X 102 500 and has 49% sequence identity to the muscle enzyme. The yeast enzyme is more simply regulated feedback inhibition by the allosteric inhibitor glucose-6-phosphate and activation by a 3 -5 -cyclic AMP-dependent protein kinase or a yeast phosphorylase that phosphorylates Thr-10.55... 

Both forms of phosphorylase are inhibited by glucose or glucose-6-phosphate. Glucose inhibits by binding at the catalytic site while glucose-6-phosphate binds at the same allosteric site as AMP and ATP. A separate inhibitory allosteric site binds adenine, adenosine, or (much more weakly) AMP. 

Under normal conditions the activity of glycogen phosphorylase (phosphorylase a) is regulated by the cellular concentration of glucose 6-phosphate, ATP, and AMP the first two effectors inhibit its activation, and the third promotes its activation. 

---