Glycogenesis

The principal enzymes controlling glycogen metabo-lism—glycogen phosphorylase and glycogen synthase— are regulated by allosteric mechanisms and covalent modifications due to reversible phosphorylation and dephosphorylation of enzyme protein in response to hormone action (Chapter 9).

Cyclic AMP (cAMP) (Figure 18-5) is formed from ATP by adenylyl cyclase at the inner surface of cell membranes and acts as an intracellular second messenger in response to hormones such as epinephrine, nor-epinephrine, and glucagon. cAMP is hydrolyzed by phosphodiesterase, so terminating hormone action. In liver, insulin increases the activity of phosphodiesterase.

Phosphorylase Differs Between Liver & Muscle

In liver, one of the serine hydroxyl groups of active phosphorylase a is phosphorylated. It is inactivated by hydrolytic removal of the phosphate by protein phos-phatase-1 to form phosphorylase b. Reactivation requires rephosphorylation catalyzed by phosphorylase kinase.

Muscle phosphorylase is distinct from that of liver. It is a dimer, each monomer containing 1 mol of pyridoxal phosphate (vitamin Bg). It is present in two forms: phosphorylase a, which is phosphorylated and active in either the presence or absence of 5'-AMP (its allosteric modifier); and phosphorylase b, which is dephosphorylated and active only in the presence of 5'-AMP. This occurs during exercise when the level of 5'-AMP rises, providing, by this mechanism, fuel for the muscle. Phosphorylase a is the normal physiologically active form of the enzyme.

cAMP Activates Muscle Phosphorylase

Phosphorylase in muscle is activated in response to epi-nephrine (Figure 18-6) acting via cAMP. Increasing the concentration of cAMP activates cAMP-dependent

O-O 4- Glucosidic bond

O Unlabeled glucose residue

• 14C-labeled glucose residue

O-O 4- Glucosidic bond

O Unlabeled glucose residue

• 14C-labeled glucose residue

Glycogenesis
Figure 18-3. The biosynthesis of glycogen. The mechanism of branching as revealed by adding 14C-labeled glucose to the diet in the living animal and examining the liver glycogen at further intervals.
Glycogenesis

PHOSPHORYLASE

GLUCAN TRANSFERASE

DEBRANCHING ENZYME

• ® \ Glucose residues joined by 0_q J 1 ^ 4- glucosidic bonds

Glucose residues joined by 1 ^ 6- glucosidic bonds

• ® \ Glucose residues joined by 0_q J 1 ^ 4- glucosidic bonds

Glucose residues joined by 1 ^ 6- glucosidic bonds

Figure 18-4. Steps in glycogenolysis.

protein kinase, which catalyzes the phosphorylation by ATP of inactive phosphorylase kinase b to active phosphorylase kinase a, which in turn, by means of a further phosphorylation, activates phosphorylase b to phosphorylase a.

Ca2+ Synchronizes the Activation of Phosphorylase With Muscle Contraction

Glycogenolysis increases in muscle several hundred-fold immediately after the onset of contraction. This involves the rapid activation of phosphorylase by activation of phosphorylase kinase by Ca +, the same signal as that which initiates contraction in response to nerve stimulation. Muscle phosphorylase kinase has four

o-ch2

Figure 18-5. 3',5'-Adenylic acid (cyclic AMP; cAMP).

types of subunits—a, P, Y, and 6—in a structure represented as (aPY6)4. The a and P subunits contain serine residues that are phosphorylated by cAMP-dependent protein kinase. The 6 subunit binds four Ca2+ and is identical to the Ca2+-binding protein calmodulin (Chapter 43). The binding of Ca2+ activates the catalytic site of the Y subunit while the molecule remains in the dephosphorylated b configuration. However, the phosphorylated a form is only fully activated in the presence of Ca2+. A second molecule of calmodulin, or TpC (the structurally similar Ca2+-binding protein in muscle), can interact with phosphorylase kinase, causing further activation. Thus, activation of muscle contraction and glycogenolysis are carried out by the same Ca2+-binding protein, ensuring their synchronization.

Glycogenolysis in Liver Can Be cAMP-Independent

In addition to the action of glucagon in causing formation of cAMP and activation of phosphorylase in liver, a1-adrenergic receptors mediate stimulation of glyco-genolysis by epinephrine and norepinephrine. This involves a cAMP-independent mobilization of Ca2+ from mitochondria into the cytosol, followed by the stimulation of a Ca2+/calmodulin-sensitive phosphory-lase kinase. cAMP-independent glycogenolysis is also caused by vasopressin, oxytocin, and angiotensin II acting through calcium or the phosphatidylinositol bisphosphate pathway (Figure 43-7).

Protein Phosphatase-1 Inactivates Phosphorylase

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 ki-nase. Thus, cAMP controls both the activation and in-activation 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 phosphor-ylase kinase.

Glycogen Synthase & Phosphorylase Activity Are Reciprocally Regulated (Figure 18-7)

Like phosphorylase, glycogen synthase exists in either a phosphorylated or nonphosphorylated state. However, unlike phosphorylase, the active form is dephosphory-lated (glycogen synthase a) and may be inactivated to

Epinephrine ß Receptor

Inactive adenylyl cyclase

Active adenylyl cyclase

Inactive adenylyl cyclase

Active adenylyl cyclase

Glycogenesis Enzymes

Inhibitor-1-phosphate (active)

Figure 18-6. Control of phosphorylase in muscle. The sequence of reactions arranged as a cascade allows amplification of the hormonal signal at each step. (n = number of glucose residues; G6P, glucose 6-phosphate.)

Inhibitor-1-phosphate (active)

Figure 18-6. Control of phosphorylase in muscle. The sequence of reactions arranged as a cascade allows amplification of the hormonal signal at each step. (n = number of glucose residues; G6P, glucose 6-phosphate.)

Epinephrine P Receptor (+)

Inactive Active adenylyl _ _^ adenylyl cyclase cyclase

Inactive Active adenylyl _ _^ adenylyl cyclase cyclase

Figure 18-7. Control of glycogen synthase in muscle (n = number of glucose residues). The sequence of reactions arranged in a cascade causes amplification at each step, allowing only nanomole quantities of hormone to cause major changes in glycogen concentration. (GSK, glycogen synthase kinase-3, -4, and -5; G6P, glucose 6-phosphate.)

Figure 18-7. Control of glycogen synthase in muscle (n = number of glucose residues). The sequence of reactions arranged in a cascade causes amplification at each step, allowing only nanomole quantities of hormone to cause major changes in glycogen concentration. (GSK, glycogen synthase kinase-3, -4, and -5; G6P, glucose 6-phosphate.)

glycogen synthase b by phosphorylation on serine residues by no fewer than six different protein kinases. Two of the protein kinases are Ca2+/calmodulin-dependent (one of these is phosphorylase kinase). Another kinase is cAMP-dependent protein kinase, which allows cAMP-mediated hormonal action to inhibit glycogen synthesis synchronously with the activation of glycogenolysis. Insulin also promotes glycogenesis in muscle at the same time as inhibiting glycogenolysis by raising glucose 6-phosphate concentrations, which stimulates the dephosphorylation and activation of glycogen synthase. Dephosphorylation of glycogen syn-thase b is carried out by protein phosphatase-1, which is under the control of cAMP-dependent protein ki-nase.

REGULATION OF GLYCOGEN METABOLISM IS EFFECTED BY A BALANCE IN ACTIVITIES BETWEEN GLYCOGEN SYNTHASE & PHOSPHORYLASE (Figure 18-8)

Not only is phosphorylase activated by a rise in concentration of cAMP (via phosphorylase kinase), but glyco-gen synthase is at the same time converted to the inactive form; both effects are mediated via cAMP-dependent protein kinase. Thus, inhibition of gly-cogenolysis enhances net glycogenesis, and inhibition of glycogenesis enhances net glycogenolysis. Furthermore,

Epinephrine i phosphodiesterase |

Epinephrine i phosphodiesterase |

Figure 18-8. Coordinated control of glycogenolysis and glycogenesis by cAMP-dependent protein kinase. The reactions that lead to glycogenolysis as a result of an increase in cAMP concentrations are shown with bold arrows, and those that are inhibited by activation of protein phosphatase-1 are shown as broken arrows. The reverse occurs when cAMP concentrations decrease as a result of phosphodiesterase activity, leading to glycogenesis.

Figure 18-8. Coordinated control of glycogenolysis and glycogenesis by cAMP-dependent protein kinase. The reactions that lead to glycogenolysis as a result of an increase in cAMP concentrations are shown with bold arrows, and those that are inhibited by activation of protein phosphatase-1 are shown as broken arrows. The reverse occurs when cAMP concentrations decrease as a result of phosphodiesterase activity, leading to glycogenesis.

the dephosphorylation of phosphorylase a, phosphory-lase kinase a, and glycogen synthase b is catalyzed by a single enzyme of wide specificity—protein phos-phatase-1. In turn, protein phosphatase-1 is inhibited by cAMP-dependent protein kinase via inhibitor-1. Thus, glycogenolysis can be terminated and glycogenesis can be stimulated synchronously, or vice versa, because both processes are keyed to the activity of cAMP-dependent protein kinase. Both phosphorylase kinase and glycogen synthase may be reversibly phosphorylated in more than one site by separate kinases and phosphatases. These secondary phosphorylations modify the sensitivity of the primary sites to phosphorylation and dephos-phorylation (multisite phosphorylation). What is more, they allow insulin, via glucose 6-phosphate elevation, to have effects that act reciprocally to those of cAMP (Figures 18-6 and 18-7).

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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