Chapter Review in Chapter 15 The Metabolism of Glycogen in Animals

Chapter Review

Key Terms

Terms in bold are defined in the glossary.

Problems

1. Glycogen as Energy Storage: How Long Can a Game Bird Fly? Since ancient times, people have observed that certain game birds, such as grouse, quail, and pheasants, fatigue easily. The Greek historian Xenophon wrote: “The bustards … can be caught if one is quick in starting them up, for they will fly only a short distance, like partridges, and soon tire; and their flesh is delicious.” The flight muscles of game birds rely almost entirely on the use of glucose 1-phosphate to drive ATP synthesis (Chapter 14). The glucose 1-phosphate derives from the breakdown of stored muscle glycogen, catalyzed by the enzyme glycogen phosphorylase. The rate of ATP production is limited by the rate at which glycogen can be broken down. During a “panic flight,” the game bird’s rate of glycogen breakdown is quite high, approximately $120 μ mol/min$ $120 mu mol slash min$ of glucose 1-phosphate produced per gram of fresh tissue. Given that the flight muscles usually contain about 0.35% glycogen by weight, calculate how long a game bird can fly. (Assume the average molecular weight of a glucose residue in glycogen is $162 g slash mol$ $162 g slash mol$ .)
2. Enzyme Activity and Physiological Function The $V_{\max}$ $upper V Subscript max$ of the glycogen phosphorylase from skeletal muscle is much greater than the $V_{\max}$ $upper V Subscript max$ of the same enzyme from liver tissue.
1. What is the physiological function of glycogen phosphorylase in skeletal muscle? In liver tissue?
2. Why does the $V_{\max}$ $upper V Subscript max$ of the muscle enzyme need to be greater than that of the liver enzyme?
3. Glycogen Phosphorylase Equilibrium Glycogen phosphorylase catalyzes the removal of glucose from glycogen. The $Δ G^{'} °$ $upper Delta upper G prime degree$ for this reaction is 3.1 kJ/mol.
1. Calculate the ratio of $[P_{i}]$ $left-bracket upper P Subscript i Baseline right-bracket$ to [glucose 1-phosphate] when the reaction is at equilibrium. (Hint: The removal of glucose units from glycogen does not change the glycogen concentration.)
2. The measured ratio $[P_{i}] /[glucose 1 -phosphate]$ $left-bracket upper P Subscript i Baseline right-bracket slash left-bracket glucose 1 hyphen phosphate right-bracket$ in myocytes under physiological conditions is more than 100:1. What does this indicate about the direction of metabolite flow through the glycogen phosphorylase reaction in muscle?
3. Why are the equilibrium and physiological ratios different? What is the possible significance of this difference?
4. Regulation of Glycogen Phosphorylase In muscle tissue, the rate of conversion of glycogen to glucose 6-phosphate is determined by the ratio of phosphorylase a (active) to phosphorylase b (less active). Determine what happens to the rate of glycogen breakdown if a broken cell extract of muscle containing glycogen phosphorylase is treated with (a) phosphorylase kinase and ATP (b) PP1 (c) epinephrine.
5. Glycogen Breakdown in Rabbit Muscle The intracellular use of glucose and glycogen is tightly regulated at four points. To compare the regulation of glycolysis when oxygen is plentiful and when it is depleted, consider the utilization of glucose and glycogen by rabbit leg muscle in two physiological settings: a resting rabbit, with low ATP demands, and a rabbit that sights its mortal enemy, the coyote, and dashes into its burrow. For each setting, determine the relative levels (high, intermediate, or low) of AMP, ATP, citrate, and acetyl-CoA and describe how these levels affect the flow of metabolites through glycolysis by regulating specific enzymes. (Hint: In periods of stress, rabbit leg muscle produces much of its ATP by anaerobic glycolysis (lactate fermentation) and very little by oxidation of acetyl-CoA derived from fat breakdown.)
6. Glycogen Breakdown in Migrating Birds Unlike a rabbit, running all-out for a few moments to escape a predator, migratory birds require energy for extended periods of time. For example, ducks generally fly several thousand miles during their annual migration. The flight muscles of migratory birds have a high oxidative capacity and obtain the necessary ATP through the oxidation of acetyl-CoA (obtained from fats) via the citric acid cycle. Compare the regulation of muscle glycolysis during short-term intense activity, as in a fleeing rabbit, and during extended activity, as in a migrating duck. Why must the regulation in these two settings be different?
7. Enzyme Defects in Carbohydrate Metabolism Consider the four clinical case studies, A through D. For each case, determine which enzyme is defective and designate the appropriate treatment from the lists provided at the end of the problem. Justify your choices. Answer the questions contained in each case study. (You may need to refer to information in Chapter 14.)

Case A: The patient develops vomiting and diarrhea shortly after milk ingestion. The physician administers a lactose tolerance test. (The patient ingests a standard amount of lactose, and the physician measures the glucose and galactose concentrations in his blood plasma at intervals. In individuals with normal carbohydrate metabolism, the levels increase to a maximum in about 1 hour, then decline.) The patient’s blood glucose and galactose concentrations do not increase during the test. Why do blood glucose and galactose increase and then decrease during the test in healthy individuals? Why do they fail to rise in the patient?

Case B: The patient develops vomiting and diarrhea after ingestion of milk. Blood tests show a low concentration of glucose but a much higher than normal concentration of reducing sugars. The urine tests positive for galactose. Why is the concentration of reducing sugar in the blood high? Why does galactose appear in the urine?

Case C: The patient complains of painful muscle cramps when performing strenuous physical exercise but has no other symptoms. A muscle biopsy indicates a muscle glycogen concentration much higher than normal. Why does glycogen accumulate?

Case D: The patient is lethargic, her liver is enlarged, and a biopsy of the liver shows large amounts of excess glycogen. She also has a lower than normal blood glucose level. What is the reason for the low blood glucose in this patient?

Defective Enzyme
1. Muscle PFK-1
2. Phosphomannose isomerase
3. Galactose 1-phosphate uridylyltransferase
4. Liver glycogen phosphorylase
5. Triose kinase
6. Lactase in intestinal mucosa
7. Maltase in intestinal mucosa
8. Muscle debranching enzyme
Treatment
1. Jogging 5 km each day
2. Fat-free diet
3. Low-lactose diet
4. Avoiding strenuous exercise
5. Large doses of niacin (the precursor of NAD)
6. Frequent feedings (smaller portions) of a normal diet
8. Effects of Insufficient Insulin in a Person with Diabetes A man with insulin-dependent diabetes is brought to the hospital emergency department in a near-comatose state. While vacationing in an isolated place, he lost his insulin medication and has not taken any insulin for two days.
1. For each tissue listed at the end of the problem, is each pathway faster, slower, or unchanged in this patient, compared with the normal level when he is getting appropriate amounts of insulin?
2. For each pathway, describe at least one control mechanism responsible for the change you predict.
  - Tissue and Pathways
    1. Adipose: fatty acid synthesis
    2. Muscle: glycolysis; fatty acid synthesis; glycogen synthesis
    3. Liver: glycolysis; gluconeogenesis; glycogen synthesis; fatty acid synthesis; pentose phosphate pathway
9. Blood Metabolites in Insulin Insufficiency For the patient described in Problem 8, predict the levels of each listed metabolite in his blood before treatment in the emergency room, relative to levels maintained during adequate insulin treatment: (a) glucose (b) ketone bodies (c) free fatty acids.
10. Metabolic Effects of Mutant Enzymes Predict and explain the effect on glycogen metabolism of each of the listed defects caused by mutation: (a) Loss of the cAMP-binding site on the regulatory subunit of protein kinase A (PKA) (b) Loss of the protein phosphatase inhibitor (inhibitor 1 in Fig. 15-16) (c) Overexpression of phosphorylase b kinase in liver (d) Defective glucagon receptors in liver.
11. Hormonal Control of Metabolic Fuel Between your evening meal and breakfast, your blood glucose drops and your liver becomes a net producer rather than consumer of glucose. Describe the hormonal basis for this switch, and explain how the hormonal change triggers glucose production by the liver.
12. Altered Metabolism in Genetically Manipulated Mice Researchers can manipulate the genes of a mouse so that a single gene in a single tissue either produces an inactive protein (a “knockout” mouse) or produces a protein that is always (constitutively) active. What effects on metabolism would you predict for mice with the listed genetic changes? (a) Knockout of glycogen debranching enzyme in the liver (b) Knockout of hexokinase IV in liver (c) Knockout of FBPase-2 in liver (d) Constitutively active FBPase-2 in liver (e) Constitutively active AMPK in muscle (f) Constitutively active ChREBP in liver (see Fig. 14-28)

Data Analysis Problem

13. Optimal Glycogen Structure Muscle cells need rapid access to large amounts of glucose during heavy exercise. This glucose is stored in liver and skeletal muscle in polymeric form as particles of glycogen. The typical glycogen β-particle contains about 55,000 glucose residues (see Fig. 15-2). Meléndez-Hevia, Waddell, and Shelton (1993) explored some theoretical aspects of the structure of glycogen, as described in this problem.
1. The cellular concentration of glycogen in liver is about $0.01 mu upper M$ $0.01 mu upper M$ . What cellular concentration of free glucose would be required to store an equivalent amount of glucose? Why would this concentration of free glucose present a problem for the cell?
  Glucose is released from glycogen by glycogen phosphorylase, an enzyme that can remove glucose molecules, one at a time, from one end of a glycogen chain (see Fig. 15-3). Glycogen chains are branched (see Fig. 15-2), and the degree of branching — the number of branches per chain — has a powerful influence on the rate at which glycogen phosphorylase can release glucose.
2. Why would a degree of branching that was too low (i.e., below an optimum level) reduce the rate of glucose release? (Hint: Consider the extreme case of no branches in a chain of 55,000 glucose residues.)
3. Why would a degree of branching that was too high also reduce the rate of glucose release? (Hint: Think of the physical constraints.)
  Meléndez-Hevia and colleagues did a series of calculations and found that two branches per chain (see Fig. 15-2) was optimal for the constraints described above. This is what is found in glycogen stored in muscle and liver.
  
  To determine the optimum number of glucose residues per chain, Meléndez-Hevia and coauthors considered two key parameters that define the structure of a glycogen particle: $t = the number of tiers$ $t equals the number of tiers$ $of glucose chains in a particle$ $of glucose chains in a particle$ (the mole-cule in Fig. 15-2 has five tiers); $g_{c} = the number of glucose$ $g Subscript c Baseline equals the number of glucose$ $residues in each chain$ $residues in each chain$ . They set out to find the values of t and $g_{c}$ $g Subscript c$ that would maximize three quantities: (1) the amount of glucose stored in the particle $(G_{T})$ $left-parenthesis upper G Subscript upper T Baseline right-parenthesis$ per unit volume; (2) the number of unbranched glucose chains $(C_{A})$ $left-parenthesis upper C Subscript upper A Baseline right-parenthesis$ per unit volume (i.e., number of A chains in the outermost tier, readily accessible to glycogen phosphorylase); and (3) the amount of glucose available to phosphorylase in these unbranched chains $left-parenthesis upper G Subscript PT Baseline right-parenthesis$ $left-parenthesis upper G Subscript PT Baseline right-parenthesis$ .
4. Show that $C_{A} = 2^{t - 1}$ $upper C Subscript upper A Baseline equals 2 Superscript t minus 1$ . This is the number of chains available to glycogen phosphorylase before the action of the debranching enzyme.
5. Show that $C_{T}$ $upper C Subscript upper T$ , the total number of chains in the particle, is given by $C_{T} = 2^{t} - 1$ $upper C Subscript upper T Baseline equals 2 Superscript t Baseline minus 1$ . For purposes of this calculation, consider the primers to be a single chain. Thus $G_{T} = g_{c} (C_{T}) = g_{c} (2^{t} - 1)$ $upper G Subscript upper T Baseline equals g Subscript c Baseline left-parenthesis upper C Subscript upper T Baseline right-parenthesis equals g Subscript c Baseline left-parenthesis 2 Superscript t Baseline minus 1 right-parenthesis$ , the total number of glucose residues in the particle.
6. Glycogen phosphorylase cannot remove glucose from glycogen chains that are shorter than five glucose residues. Show that $G_{PT} = (g_{c} - 4) (2^{t - 1})$ $upper G Subscript PT Baseline equals left-parenthesis g Subscript c Baseline minus 4 right-parenthesis left-parenthesis 2 Superscript t minus 1 Baseline right-parenthesis$ . This is the amount of glucose readily available to glycogen phosphorylase.
7. Based on the size of a glucose residue and the location of branches, the thickness of one tier of glycogen is $0.12 g Subscript c Baseline nm plus 0.35 nm$ $0.12 g Subscript c Baseline nm plus 0.35 nm$ . Show that the volume of a particle, $V_{s}$ $upper V Subscript s$ , is given by the equation $V_{s} = \frac{4}{3} π t^{3} {(0.12 g_{c} + 0.35)}^{3} {nm}^{3}$ $upper V Subscript s Baseline equals four-thirds pi t cubed left-parenthesis 0.12 g Subscript c Baseline plus 0.35 right-parenthesis cubed nm Superscript 3$ .
  Meléndez-Hevia and coauthors then determined the optimum values of t and $g_{c}$ $g Subscript c$ — those that gave the maximum value of a quality function, f, that maximizes $G_{T}$ $upper G Subscript upper T$ , $C_{A}$ $upper C Subscript upper A$ , and $G_{PT}$ $upper G Subscript PT$ , while minimizing $V_{s} : f = \frac{G_{T} C_{A} G_{PT}}{V_{s}}$ $upper V Subscript s Baseline colon f equals StartFraction upper G Subscript upper T Baseline upper C Subscript upper A Baseline upper G Subscript PT Baseline Over upper V Subscript s Baseline EndFraction$ . They found that the optimum value of $g_{c}$ $g Subscript c$ is independent of t.
8. Choose a value of t between 5 and 15 and find the optimum value of $g_{c}$ $g Subscript c$ . How does this compare with the $g_{c}$ $g Subscript c$ found in liver glycogen (see Fig. 15-2)? (Hint: You may find it useful to use a spreadsheet program.)

Reference

Meléndez-Hevia, E., T.G. Waddell, and E.D. Shelton. 1993. Optimization of molecular design in the evolution of metabolism: the glycogen molecule. Biochem. J. 295:477–483.