Biochemistry - The Chemical Reactions of Living Cells, Volume 2 - D. Metzler 1980

Biosynthesis: how new molecules are formed
Regulation of biosynthetic processes
Synthesis and catabolism of glycogen

The system regulating the formation and breakdown of Glycogen in animal Muscle is among the best-studied systems controlling metabolic processes [47–49]. This system is schematically shown in Fig. 11-10. The thick dashed line indicates The conversion of glycogen to glucose-1-phosphate catalyzed by Glycogen phosphorylase (ch. 7, sect. B, 5; ch. 8, sect. D, 3, d).

The sequence of synthetic reactions responsible for producing UDPG and glycogen from glucose-1-phosphate is shown by the thick solid lines. In resting muscle, glycogen synthase (E₃ in Fig. 11-10) is active, whereas phosphorylase is in an inactive form known as phosphorylase b (E₂ in Fig. 11-10). Under normal conditions, inactive phosphorylase b is allosterically activated by AMP. A sudden burst of muscle activity can lead to a surge in ATP sufficient to trigger glycogen phosphorolysis.

However, a more crucial regulatory role is played by factors governed by the stimulatory Action of Hormones and The Nervous system. When Blood epinephrine levels rise, the hormone binds to receptors on The Cell membrane surface, activating cyclic AMP production (ch. 7, sect. D, 8). Similarly, in the Liver, Glucagon receptors bind the hormone and stimulate cyclic AMP formation. Cyclic AMP, in turn, activates protein Kinases that modify various Proteins, including phosphorylase kinase (E₁ in Fig. 11-10) and glycogen synthase. In resting muscle, phosphorylase kinase exists in an inactive form; phosphorylation by protein kinase converts it into an active form, in which state it catalyzes the phosphorylation (at the expense of ATP) of a specific Serine residue in phosphorylase b. The modified (phosphorylated) enzyme, known as phosphorylase a, is a fully active enzyme responsible for glycogen breakdown. Phosphorylase a exhibits a completely different pathway of Allosteric Regulation, which involves inhibition of the enzyme by glucose-6-phosphate (Fig. 11-10). Thus, an increase in glucose-6-phosphate concentration leads to a decreased rate of Glycogenolysis.

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FIG. 11-10. Regulation of Glycogen breakdown and synthesis in muscle: thick solid arrows represent synthesis, dashed (thin and thick) arrows represent Catabolism, (→) denotes phosphorylation reactions utilizing ATP, (→) denotes Hydrolysis Reactions Catalyzed by Phosphatases, and thick light arrows indicate The Effect of active forms of modified Enzymes.

¹⁾ Phosphorylase kinase is a very large enzyme with a Molecular Weight of 1.3 million, containing Three types of subunits and likely having the composition a₄ß₄y₄. Protein kinase, whose activity depends on cyclic AMP, phosphorylates both a- and ß-subunits, with phosphorylation of the ß-subunits appearing to be responsible for activation [49, 49a]. Phosphorylase kinase can also undergo autoactivation involving the phosphorylation of sites not acted upon by protein kinase [49a].

By stimulating phosphorylase activity through the series of mechanisms described above, cyclic AMP also activates protein kinase, which then proceeds to phosphorylate the active form (I-form, or independent form) of glycogen synthase. Consequently, the phosphorylated form of glycogen synthase (D-form, or dependent form) is inactive in the absence of a specific activator. Thus, the initiation of glycogen phosphorolysis is accompanied by the inhibition of further glycogen synthesis. The phosphorylated form of glycogen synthase (D-form) is allosterically activated by glucose-6-phosphate. Therefore, if a rapid increase in metabolite levels occurs, it not only inhibits the phosphorylase reaction but also stimulates glycogen synthesis, even if all the glycogen synthase has been converted into the inactive form (D-form).

Like other kinases, protein kinase and phosphorylase kinase require magnesium ions for their activity. In addition, phosphorylase kinase in its "inactive" form is allosterically activated by Calcium Ions. Recall that the initiation of Muscle contraction is triggered by nerve impulses that stimulate the release of calcium ions from the vesicles of The Endoplasmic reticulum. Thus, calcium ions not only switch on muscle contraction but also accelerate the phosphorylation of phosphorylase b to phosphorylase a. Some steps of the cascade mechanism now become clearer. It turns out that the most crucial stage, catalyzed by phosphorylase kinase, serves to enable the next stage, which is specifically influenced by the calcium ions released during nerve excitation. On the other hand, the ability of phosphorylase kinase to be activated via protein kinase phosphorylation renders the process sensitive to hormonal stimulation.

A characteristic feature of regulatory mechanisms dependent on reversible protein modification is the existence of specialized enzymes that "return" modified proteins to their original "resting" state: Cyclic AMP is hydrolyzed by phosphodiesterase to AMP, and all resulting phosphorylated proteins undergo hydrolysis by phosphoprotein phosphatase, which removes the phosphate groups [50]. These "relaxation" reactions are indicated by dashed lines in Fig. 11-10. The action of phosphatases is also undoubtedly subject to regulation, though we know little about the corresponding mechanisms. Furthermore, when administered to diabetic rats, Insulin likely stimulates—via an indirect pathway—the rapid Conversion of the inactive form (D-form) of liver glycogen synthase into the active (I-form) [51].

The presence of phosphorylase and glycogen synthase alone is insufficient for Glycogen Synthesis and degradation. As noted above, glycogen synthesis requires the creation of branch points, which are formed in the presence of the branching enzyme, amylo-1,4→1,6-transglucosidase. Conversely, glycogen breakdown requires the removal of these branch points, which occurs after the degradation of the long unbranched polysaccharide chains preceding the branch points. This is accompanied by the hydrolytic Cleavage of glucose units catalyzed by amylo-1,6-glucosidase. These enzymes themselves are also likely subjects of regulation.

Addendum 11-D

Genetic Disorders OF Glycogen METABOLISM

In 1951, McArdle described a patient who experienced severe pain and muscle weakness after mild exertion. It was discovered that this individual completely lacked muscle glycogen phosphorylase. Since then, more than 20 cases of this condition have been described. It turned out to be one of several disorders collectively known as Glycogen Storage Diseases. Paradoxically, this disease is not as severe as it might initially appear. It was found that by avoiding intense exertion and taking certain precautions, patients can tolerate moderate exercise without much difficulty. Until McArdle's discovery, it was believed that glycogen was synthesized via the Reversal of the phosphorylase reaction. There was no indication of the UDPG metabolic pathway. Therefore, the accumulation of glycogen in the Muscles of these patients was puzzling. However, after Leloir discovered UDPG around the same time, the causes of this disease became clear.

A number of other, relatively rare inherited disorders are also caused by glycogen accumulation, stemming essentially from the same cause: a severe inhibition of glycogen breakdown within The Glycolytic Pathway, which in turn is related to the deficiency of one of several enzymes: Phosphofructokinase, liver phosphorylase kinase, liver phosphorylase, or liver glucose-6-phosphatase. In the latter case, glycogen accumulation is explained by the inability of liver stores to be released into the blood as free glucose. One such disorder involves a deficiency in the branching enzyme participating in glycogen synthesis, resulting in a glycogen Structure with unusually long unbranched chains. Another form of the disease is associated with a deficiency of the enzyme responsible for cleaving glycogen at branch points, meaning that only a limited amount of glucose can be readily removed from the liver by degrading the outer unbranched branches of glycogen alone.

The most severe form of glycogen storage disease in the liver is not related to the enzyme deficiencies mentioned above. Pompe disease is a disorder characterized by the fatal accumulation of glycogen in the body, which has been shown to result from a deficiency of lysosomal a-1,4-glucosidase. This observation indicates that an entirely different pathway for glycogen breakdown to free glucose within Lysosomes must play a critical role.

Several cases of disorders caused by glycogen synthase deficiency have been reported. The muscles and livers of such patients exhibit a deficiency or total absence of glycogen stores. To prevent hypoglycemia, these patients must consume food at strictly regular intervals.