BIOCHEMISTRY - L. Stryer - 1984

VOLUME 2

PART II GENERATION AND STORAGE OF METABOLIC ENERGY

CHAPTER 16. GLYCOGEN AND DISACCHARIDE METABOLISM

16.8. The Branching Enzyme Forms Alpha-1,6-Bonds

Glycogen synthase catalyzes exclusively the synthesis of α-1,4-linkages. The formation of α-1,6-linkages, which makes glycogen a branched polymer, requires a different enzyme. Branching is of great physiological importance because it significantly increases glycogen solubility. Furthermore, branching creates A large number of non-reducing chain ends, which serve as the sites of action for Glycogen phosphorylase and glycogen synthase. Thus, branching markedly accelerates both the Synthesis and degradation of glycogen.

Branching occurs after A number of glucosyl residues have been added via α-1,4-linkages by glycogen synthase. A branch is created by cleaving an α-1,4-linkage and forming an α-1,6-linkage, a reaction distinct from the process that removes branches. Typically, a block of seven residues is transferred toward the interior of the molecule. The branching enzyme that catalyzes this reaction exhibits a very high degree of Specificity. The transferred block of approximately seven residues must include a non-reducing end and originate from a chain at least eleven residues long. In addition, the new branch point must be situated at least four residues away from any pre-existing branch point.

16.9. Glycogen Is a Highly Efficient Storage Form of Glucose

What is The Energetic Cost of converting glucose 6-phosphate into glycogen and subsequently converting glycogen back into glucose 6-phosphate? The respective reactions have already been described, with the exception of reaction 5 below, which represents the regeneration of UTP. UDP is phosphorylated by ATP in a reaction catalyzed by nucleoside diphosphate kinase.

1) Glucose 6-phosphate → Glucose 1-phosphate

2) Glucose 1-phosphate + UTP → UDP-glucose + PPi

3) PPi + H₂O → 2Pi

4) UDP-glucose + Glycogen _n → Glycogen _n+1 + UDP

5) UDP + ATP → UTP + ADP

Overall reaction: Glucose 6-phosphate + ATP + Glycogen _n + H₂O → Glycogen _n+1 + ADP + 2Pi

Thus, a single high-energy phosphate bond is consumed when glucose 6-phosphate is incorporated into glycogen. The energy yield upon glycogen breakdown is remarkably high. Approximately 90% of the residues undergo phosphorolytic Cleavage to yield glucose 1-phosphate, which is converted into glucose 6-phosphate without any energetic cost. The remaining 10% of the residues reside at branch points and are cleaved hydrolytically. One molecule of ATP is utilized to phosphorylate each of these glucose molecules into glucose 6-phosphate. Complete oxidation of glucose 6-phosphate yields thirty-seven molecules of ATP, whereas the storage process consumes just over one molecule of ATP per molecule of glucose 6-phosphate, resulting in an overall storage efficiency of approximately 97%.

16.10. Cyclic AMP Plays a Central Role in the Coordinated Control of Glycogen Synthesis and Degradation

The existence of separate pathways for the synthesis and degradation of glycogen implies that these processes must be tightly regulated. If both sets of reactions were fully active simultaneously, it would result in a "futile" Hydrolysis of ATP. In reality, glycogen Synthesis and Breakdown are coordinately regulated such that Glycogen synthase is nearly inactive when phosphorylase is fully active, and vice versa. Glycogen METABOLISM is strongly influenced by specific Hormones. The polypeptide hormone Insulin (Section 2.6) enhances the capacity of the Liver to synthesize glycogen, although the precise mechanism of insulin action remains to be fully elucidated. High Blood insulin levels reflect a state of satiety, whereas low levels signal a fasting state (Section 23.6). Much better understood are the Mechanisms of action of epinephrine and Glucagon, whose effects are antagonistic to those of insulin. Physical exertion or anticipation of it prompts the release of epinephrine from The adrenal medulla. Epinephrine potently stimulates Glycogenolysis in Muscle and, to a lesser extent, in the liver. The liver is particularly responsive to glucagon, a polypeptide hormone secreted by the α-Cells of The Pancreas in response to low blood glucose levels. Glucagon elevates blood sugar by stimulating hepatic glycogen breakdown.

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Earl Sutherland discovered that the effects of epinephrine and glucagon on metabolism are mediated by cyclic AMP. This breakthrough led to the recognition of cyclic AMP as a ubiquitous signaling molecule across all life forms and its pivotal role in regulating biological processes (Chapter 35). The synthesis of this regulatory molecule from ATP is catalyzed by adenylate cyclase, an enzyme bound to Plasma Membranes, a process further driven by the subsequent hydrolysis of pyrophosphate.

Epinephrine and glucagon do not enter their target cells. Instead, they bind to plasma membranes and stimulate adenylate cyclase (Section 35.3). The resulting elevation in intracellular cyclic AMP triggers a cascade of reactions that lead to the activation of phosphorylase and the inhibition of glycogen synthase. We will now examine the structural basis for The regulation of these Key Enzymes in glycogen metabolism and subsequently discuss the reaction cascade that links these enzymes to cyclic AMP.