Chapter Summary, Questions Answers - Glycogen Metabolism

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Chapter: Biochemistry : Glycogen Metabolism

The main stores of glycogen in the body are found in skeletal muscle, where they serve as a fuel reserve for the synthesis of ATP during muscle contraction, and in the liver, where they are used to maintain the blood glucose concentration, particularly during the early stages of a fast.


The main stores of glycogen in the body are found in skeletal muscle, where they serve as a fuel reserve for the synthesis of ATP during muscle contraction, and in the liver, where they are used to maintain the blood glucose concentration, particularly during the early stages of a fast. Glycogen is a highly branched polymer of α-D-glucose. The primary glycosidic bond is an α(1→4) linkage. After about eight to ten glucosyl residues, there is a branch containing an α(1→6) linkage. Uridine diphosphate (UDP)-glucose, the building block of glycogen, is synthesized from glucose 1-phosphate and UTP by UDP-glucose pyrophosphorylase (Figure 11.14). Glucose from UDP-glucose is transferred to the nonreducing ends of glycogen chains by primer-requiring glycogen synthase, which makes α(1→4) linkages. The primer is made by glycogenin. Branches are formed by amylo-α(1→4)→α(1→6)-transglucosidase (common name, glucosyl 4:6 transferase), which transfers a set of six to eight glucosyl residues from the nonreducing end of the glycogen chain (breaking an α(1→4) linkage), and attaches it with an α(1→6) linkage to another residue in the chain. Pyridoxal phosphate–requiring glycogen phosphorylase cleaves the α(1→4) bonds between glucosyl residues at the nonreducing ends of the glycogen chains, producing glucose 1-phosphate. This sequential degradation continues until four glucosyl units remain before a branch point. The resulting structure is called a limit dextrin that is degraded by the bifunctional debranching enzyme. Oligo-α(1→4)→α(1→4)-glucantransferase (common name, glucosyl 4:4 transferase) removes the outer three of the four glucosyl residues at a branch and transfers them to the nonreducing end of another chain, where they can be converted to glucose 1-phosphate by glycogen phosphorylase. The remaining single glucose residue attached in an α(1→6) linkage is removed hydrolytically by the amylo-(1→6) glucosidase activity of debranching enzyme, releasing free glucose. Glucose 1-phosphate is converted to glucose 6-phosphate by phosphoglucomutase. In the muscle, glucose 6-phosphate enters glycolysis. In the liver, the phosphate is removed by glucose 6-phosphatase, releasing free glucose that can be used to maintain blood glucose levels at the beginning of a fast. A deficiency of the phosphatase causes glycogen storage disease Type 1a (Von Gierke disease). This disease results in an inability of the liver to provide free glucose to the body during a fast. It affects both glycogen degradation and gluconeogenesis. Glycogen synthesis and degradation are reciprocally regulated to meet whole-body needs by the same hormonal signals (namely, an elevated insulin level results in overall increased glycogenesis and decreased glycogenolysis, whereas an elevated glucagon, or epinephrine, level causes increased glycogenolysis and decreased glycogenesis). Key enzymes are phosphorylated by a family of protein kinases, some of which are cyclic adenosine monophosphate dependent (a compound increased by glucagon and epinephrine). Phosphate groups are removed by protein phosphatase-1 (active when its inhibitor is inactive in response to elevated insulin levels). Glycogen synthase, phosphorylase kinase, and phosphorylase are also allosterically regulated to meet tissues needs. In the well-fed state, glycogen synthase is activated by glucose 6-phosphate, but glycogen phosphorylase is inhibited by glucose 6-phosphate as well as by ATP. In the liver, glucose also serves an an allosteric inhibitor of glycogen phosphorylase. The Ca2+ released from the endoplasmic reticulum in muscle during exercise and in liver in response to epinephrine activates phosphorylase kinase by binding to the enzyme’s calmodulin subunit. This allows the enzyme to activate glycogen phosphorylase, thereby causing glycogen degradation. AMP activates glycogen phosphorylase in muscle.

Figure 11.14 Key concept map for glycogen metabolism in the liver. [Note: Glycogen phosphorylase is phosphorylated by phosphorylase kinase, the “b” form of which can be activated by calcium.] UDP = uridine diphosphate; UTP = uridine triphosphate; P = phosphate.


Study Questions

Choose the ONE best answer.


For Questions 11.1–11.4, match the deficient enzyme to the clinical finding in selected glycogen storage diseases (GSDs).


11.1 Exercise intolerance, with no rise in blood lactate during exercise

Correct answer = E. Myophosphorylase deficiency prevents glycogen degradation in muscle, depriving muscle of glycogen-derived glucose, resulting in decreased glycolysis and its anaerobic product, lactate.

Correct Answer = D. 4:6 Transferase (branching enzyme) deficiency, a defect in glycogen synthesis, results in formation of glycogen with fewer branches and decreased solubility.

Correct answer = B. Acid maltase [a(1→4)-glucosidase] deficiency prevents degradation of any glycogen brought into lysosomes. A variety of tissues are affected, with the most severe pathology resulting from heart damage.

Correct answer = A. Glucose 6-phosphatase deficiency prevents the liver from releasing free glucose into the blood, causing severe fasting hypoglycemia, lacticacidemia, hyperuricemia, and hyperlipidemia.


11.2 Fatal, progressive cirrhosis and glycogen with longer-than-normal outer chains


11.3 Generalized accumulation of glycogen, severe hypotonia, and death from heart failure


11.4 Severe fasting hypoglycemia, lacticacidemia, hyperuricemia, and hyperlipidemia


11.5 Epinephrine and glucagon have which one of the following effects on hepatic glycogen metabolism?

A. Both glycogen phosphorylase and glycogen synthase are activated by phosphorylation but at significantly different rates.

B. Glycogen phosphorylase is inactivated by the resuting rise in calcium, whereas glycogen synthase is activated.

C. Glycogen phosphorylase is phosphorylated and active, whereas glycogen synthase is phosphorylated and inactive.

D. The net synthesis of glycogen is increased.

Correct answer = C. Epinephrine and glucagon both cause increased glycogen degradation and decreased synthesis in the liver through covalent modification (phosphorylation) of key enzymes of glycogen metabolism. Glycogen phosphorylase is phosphorylated and active (“a” form), whereas glycogen synthase is phosphorylated and inactive (“b” form). Glucagon does not cause a rise in calcium.


11.6 In contracting skeletal muscle, a sudden elevation of the sarcoplasmic calcium concentration will result in:

A. activation of cyclic adenosine monophosphate (cAMP)-dependent protein kinase A.

B. conversion of cAMP to AMP by phosphodiesterase.

C. direct activation of glycogen synthase b.

D. direct activation of phosphorylase kinase b.

E. inactivation of phosphorylase kinase a by the action of protein phosphatase-1.

Correct answer = D. Ca2+ released from the sarcoplasmic reticulum during exercise binds to the calmodulin subunit of phosphorylase kinase, thereby allosterically activating the “b” form of this enzyme. The other choices are not caused by an elevation of cytosolic calcium.


11.7 Explain why the hypoglycemia seen with Type Ia glycogen storage disease (glucose 6-phosphatase deficiency) is severe, whereas that seen with Type VI (liver phosphorylase deficiency) is mild.

With Type Ia, the liver is unable to generate free glucose either from glycogenolysis or gluconeogenesis because both processes produce glucose 6-phosphate. With Type VI, the liver is still able to produce free glucose from gluconeogenesis, but glycogenolysis is inhibited.


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