FIGURE 15-24 Regulation of muscle glycogen phosphorylase by covalent modification. In the more active form of the enzyme, phosphorylase a, Ser14 residues, one on each subunit, are phosphorylated. Phosphorylase a is converted to the less active form, phosphorylase b, by enzymatic loss of these phosphoryl groups, catalyzed by phosphorylase a phosphatase (PP1). Phosphorylase b can be reconverted (reactivated) to phosphorylase a by the action of phosphorylase b kinase.

glycogen phosphorylase b, which is less active (Fig. 15-24). Subsequent studies by Earl Sutherland showed that phosphorylase b predominates in resting muscle, but during vigorous muscular activity the hormone epinephrine triggers phosphorylation of a specific Ser residue in phosphorylase b, converting it to its more active form, phosphorylase a. (Note that glycogen phosphorylase is often referred to simply as phosphorylase—so honored because it was the first phosphorylase to be discovered; the shortened name has persisted in common usage and in the literature.)

The enzyme (phosphorylase b kinase) responsible for activating phosphorylase by transferring a phosphoryl group to its Ser residue is itself activated by epinephrine or glucagon through a series of steps shown in Figure 15-25. Sutherland discovered the second messenger cAMP, which increases in concentration in response to stimulation by epinephrine (in muscle) or glucagon (in liver). Elevated [cAMP] ini

Earl W. Sutherland, Jr., 1915-1974

tiates an enzyme cascade, in which a catalyst activates a catalyst, which activates a catalyst. Such cascades allow for large amplification of the initial signal (see pink boxes in Fig. 15-25). The rise in [cAMP] activates cAMP-dependent protein kinase, also called protein kinase A (PKA). PKA then phosphorylates and activates phos-phorylase b kinase, which catalyzes the phosphoryla-tion of Ser residues in each of the two identical subunits of glycogen phosphorylase, activating it and thus stimulating glycogen breakdown. In muscle, this provides fuel for glycolysis to sustain muscle contraction for the fight-or-flight response signaled by epinephrine. In liver, glycogen breakdown counters the low blood glucose signaled by glucagon, releasing glucose. These different roles are reflected in subtle differences in the regulatory mechanisms in muscle and liver. The glycogen phosphorylases of liver and muscle are isozymes, encoded by different genes and differing in their regulatory properties.

In muscle, superimposed on the regulation of phos-phorylase by covalent modification are two allosteric control mechanisms (Fig. 15-25). Ca2 + , the signal for muscle contraction, binds to and activates phosphory-lase b kinase, promoting conversion of phosphorylase b to the active a form. Ca2+ binds to phosphorylase b kinase through its 8 subunit, which is calmodulin (see Fig. 12-21). AMP, which accumulates in vigorously contracting muscle as a result of ATP breakdown, binds to and activates phosphorylase, speeding the release of glucose 1-phosphate from glycogen. When ATP levels are adequate, ATP blocks the allosteric site to which AMP binds, inactivating phosphorylase.

When the muscle returns to rest, a second enzyme, phosphorylase a phosphatase, also called phospho-protein phosphatase 1 (PP1), removes the phosphoryl groups from phosphorylase a, converting it to the less active form, phosphorylase b.

Like the enzyme of muscle, the glycogen phospho-rylase of liver is regulated hormonally (by phosphoryla-tion/dephosphorylation) and allosterically. The dephos-phorylated form is essentially inactive. When the blood glucose level is too low, glucagon (acting by the same cascade mechanism shown in Fig. 15-25) activates phosphorylase b kinase, which in turn converts phos-phorylase b to its active a form, initiating the release of glucose into the blood. When blood glucose levels return to normal, glucose enters hepatocytes and binds to an inhibitory allosteric site on phosphorylase a. This binding also produces a conformational change that exposes the phosphorylated Ser residues to PP1, which catalyzes their dephosphorylation and inactivates the phosphorylase (Fig. 15-26). The allosteric site for glucose allows liver glycogen phosphorylase to act as its own glucose sensor and to respond appropriately to changes in blood glucose.

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