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Chapter 15: Problem 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 cAMPbinding 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.

Short Answer

Expert verified
Mutations lead to disrupted glycogen metabolism, ranging from reduced breakdown to excessive glycogen storage.

Step by step solution

01

Understanding PKA Role in Glycogen Metabolism

Protein Kinase A (PKA) is activated by cyclic AMP (cAMP), which binds to its regulatory subunits. This dissociation leads to the activation of the catalytic subunits of PKA, which are involved in the phosphorylation of various enzymes in glycogen metabolism. Without this binding capability, PKA remains inactive.
02

Effect of Loss of cAMP Binding on PKA

If PKA lacks the cAMP binding site due to mutation, PKA will remain inactive. Consequently, enzymes like glycogen phosphorylase are not activated, leading to reduced glycogen breakdown. Simultaneously, unopposed glycogen synthase activity could lead to excessive glycogen accumulation.
03

Role of Protein Phosphatase Inhibitor in Glycogen Metabolism

Protein phosphatase inhibitors, such as inhibitor 1, prevent the dephosphorylation of enzymes that regulate glycogen metabolism. When protein phosphatase inhibitor is lost, phosphatases will freely dephosphorylate enzymes, reversing the effects that promote glycogen breakdown.
04

Effect of Loss of Protein Phosphatase Inhibitor

With the loss of protein phosphatase inhibitor, there will be increased dephosphorylation of enzymes like glycogen phosphorylase, reducing the rate of glycogen breakdown. This could potentially lead to an increase in glycogen storage.
05

Understanding Phosphorylase b Kinase in Glycogen Metabolism

Phosphorylase b kinase activation converts phosphorylase b to its active form (phosphorylase a), promoting glycogen breakdown. Overexpression leads to a high level of activation, enhancing glycogenolysis.
06

Effect of Overexpression of Phosphorylase b Kinase

When phosphorylase b kinase is overexpressed, it results in excessive activation of glycogen phosphorylase, leading to increased breakdown of glycogen, often exceeding normal physiological demands.
07

Understanding Glucagon's Role in Glycogen Metabolism

Glucagon binds to its receptors in the liver, stimulating a cascade that activates glycogenolysis. It serves as a signal for energy release from glycogen stores, especially in fasting conditions.
08

Effect of Defective Glucagon Receptors

Defective glucagon receptors prevent the binding of glucagon, thereby inhibiting its ability to trigger glycogen breakdown. This results in decreased glycogenolysis, causing potential energy shortages during fasting.

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Key Concepts

These are the key concepts you need to understand to accurately answer the question.

Mutant Enzymes
Mutant enzymes can have profound impacts on cellular metabolism by altering the normal function of metabolic pathways. In the context of glycogen metabolism, mutations in enzymes can disrupt the balance between glycogen synthesis and breakdown.
- **Mutation Effects**: When a mutation affects an enzyme's activity or its regulatory ability, it can lead to metabolic disorders. For example, if an enzyme responsible for breaking down glycogen becomes non-functional, glycogen can accumulate excessively.
- **Impact on Homeostasis**: Enzymes are crucial for maintaining energy homeostasis. Mutations can lead to conditions like hypoglycemia or hyperglycemia, depending on whether there is insufficient or excessive glycogen breakdown.
Thus, understanding the effects of such mutant enzymes is vital in predicting the metabolic outcomes that might occur in the body.
Protein Kinase A (PKA)
Protein kinase A (PKA) plays a key role in glycogen metabolism by regulating enzyme activity through phosphorylation.
- **Activation by cAMP**: PKA becomes active when cyclic AMP (cAMP) binds to its regulatory subunits. This causes the catalytic subunits of PKA to dissociate and become active, leading to the phosphorylation of target enzymes involved in glycogen metabolism.
- **Effects of Mutations**: If a mutation prevents cAMP from binding, PKA remains inactive. This lack of activation stops important enzymes like glycogen phosphorylase from functioning properly, reducing glycogen breakdown while increasing storage.
- **Signaling Pathways**: PKA is part of a larger network of signaling pathways that respond to hormonal signals such as adrenaline, playing a significant role in energy release during fasting or fight-or-flight situations.
Phosphorylase b Kinase
Phosphorylase b kinase is an enzyme that catalyzes the conversion of glycogen phosphorylase b to its active form, phosphorylase a. This activation is critical for glycogenolysis, or the breakdown of glycogen.
- **Enzyme Regulation**: Normally, phosphorylase b kinase is tightly regulated to balance the body's energy needs. However, overexpression of this enzyme can lead to overactive glycogen breakdown.
- **Consequences of Overexpression**: When phosphorylase b kinase is produced in excessive amounts, it can result in excessive glycogenolysis, potentially causing the depletion of glycogen stores.
- **Physiological Impacts**: Overactivity may disrupt normal physiology, leading to conditions such as a drop in blood glucose levels or muscle fatigue during exercise.
Glucagon Receptors
Glucagon receptors are proteins on liver cells that respond to glucagon, a hormone released when blood sugar levels are low.
- **Function in Glycogen Metabolism**: Upon glucagon binding, these receptors initiate a signaling cascade that triggers the breakdown of glycogen into glucose, providing energy especially during fasting.
- **Impact of Defective Receptors**: If glucagon receptors are defective, they fail to respond to glucagon, halting the cascade needed for glycogenolysis. This disruption can cause insufficient glucose release, leading to hypoglycemia.
- **Overall Importance**: The proper functioning of glucagon receptors is crucial for maintaining energy balance, particularly during periods of fasting or increased energy demand.

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Most popular questions from this chapter

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 \(120 \mu \mathrm{mol} / \mathrm{min}\) 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 \(162 \mathrm{~g} / \mathrm{mol}\). )

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?

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.

Enzyme Activity and Physiological Function The \(V_{\max }\) of the glycogen phosphorylase from skeletal muscle is much greater than the \(V_{\max }\) of the same enzyme from liver tissue. a. What is the physiological function of glycogen phosphorylase in skeletal muscle? In liver tissue? b. Why does the \(V_{\max }\) of the muscle enzyme need to be greater than that of the liver enzyme?

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 \(\beta\)-particle contains about 55,000 glucose residues (see Eig_ 15-2). Meléndez-Hevia, Waddell, and Shelton (1993), explored some theoretical aspects of the structure of glycogen, as described in this problem. a. The cellular concentration of glycogen in liver is about \(0.01 \mu \mathrm{M}\). 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 Eig. 15-3). Glycogen chains are branched (see Eig.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. b. 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.) c. 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 Eig_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 of glucose chains in a particle (the mole-cule in Eig.15-2 has five tiers); \(g_{c}=\) the number of glucose residues in each chain. The \(y\) set out to find the values of \(t\) and \(g_{c}\) that would maximize three quantities: (1) the amount of glucose stored in the particle \(\left(G_{\mathrm{T}}\right)\) per unit volume; (2) the number of unbranched glucose chains \(\left(C_{A}\right)\) 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 \(\left(G_{\mathrm{PT}}\right)\). d. Show that \(C_{A}=2^{t-1}\). This is the number of chains available to glycogen phosphorylase before the action of the debranching enzyme. e. Show that \(C_{\mathrm{T}}\), the total number of chains in the particle, is given by \(C_{\mathrm{T}}=2^{t}-1\). For purposes of this calculation, consider the primers to be a single chain. Thus \(G_{\mathrm{T}}=g_{\mathrm{c}}\left(C_{\mathrm{T}}\right)=g_{c}\left(2^{t}-1\right)\), the total number of glucose residues in the particle. f. Glycogen phosphorylase cannot remove glucose from glycogen chains that are shorter than five glucose residues. Show that \(G_{\mathrm{PT}}=\left(g_{e}-4\right)\left(2^{t-1}\right)\). This is the amount of glucose readily available to glycogen phosphorylase.g. Based on the size of a glucose residue and the location of branches, the thickness of one tier of glycogen is \(0.12 g_{\mathrm{c}} \mathrm{nm}+0.35 \mathrm{~nm}\). Show that the volume of a particle, \(V_{5}\), is given by the equation $$ V_{\mathrm{s}}=4 / 3 \pi t^{3}\left(0.12 g_{\mathrm{c}}+0.35\right)^{3} \mathrm{~nm}^{3} $$ Meléndez-Hevia and coauthors then determined the optimum values of \(t\) and \(g_{c}\) - those that gave the maximum value of a quality function, \(f\), that maximizes \(G_{\mathrm{T}}, C_{A}\), and \(G_{P T}\), while minimizing \(V_{8}: f=\frac{G_{\mathrm{T}} C_{\mathrm{A}} G \mathrm{PT}}{V_{8}}\). They found that the optimum value of \(g_{c}\) is independent of \(t .\) h. Choose a value of \(t\) between 5 and 15 and find the optimum value of \(g_{\mathrm{c}}\). How does this compare with the \(g_{e}\) found in liver glycogen (see Egg.15-2)? (Hint: You may find it useful to use a spreadsheet program.)
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