Glycogen metabolism in muscle and liver

Question 1

What is glycogen?

Answer 1

Glycogen is the polysaccharide storage form of glucose in the body. It serves as an energy reserve and is stored in granules, predominantly in the liver and muscle.

Question 2

What is the role of liver glycogen?

Answer 2

Liver glycogen is utilized to maintain plasma glucose levels between meals through the process of glycogenolysis, where glycogen is broken down into glucose.

Question 3

What is the role of muscle glycogen?

Answer 3

Muscle glycogen is required to sustain muscle contraction during physical activity.

Question 4

How is glycogen formed?

Answer 4

Glycogen is formed from dietary glucose through the process of glycogenesis.

Question 5

What is the structure of glycogen?

Answer 5

Glycogen is a highly branched polysaccharide of glucose. It consists of glucose molecules linked by α1→4 glycosidic bonds, with an α1→6 branch occurring every 8-14 glucose residues.

Question 6

Why is the branching structure of glycogen important?

Answer 6

The branching structure of glycogen is important because it provides a large number of ends where enzymes such as phosphorylase and glycogen synthase can act. This allows for rapid breakdown and re-synthesis of glycogen.

Question 7

What percentage of the weight of the liver does glycogen constitute in the fed state?

Answer 7

In the fed state, glycogen constitutes approximately 10% of the weight of the liver.

Question 8

What percentage of the weight of muscle does glycogen constitute in the fed state?

Answer 8

In the fed state, glycogen constitutes approximately 2% of the weight of muscle.

Question 9

Which tissues store more glycogen, muscle or liver?

Answer 9

More glycogen is stored in muscle compared to the liver.

Question 10

Why does the liver require de novo synthesis of glycogen via gluconeogenesis?

Answer 10

The liver contains less glycogen than is required to sustain glucose metabolism for 24 hours. Therefore, it requires de novo synthesis of glycogen through the process of gluconeogenesis.

Question 11

What type of linkages are used to form glycogen?

Answer 11

Glycogen is formed through the use of α-1,4 and α-1,6 linkages of α-D-glucose.

Question 12

What is the process of glycogen breakdown called?

Answer 12

The process of glycogen breakdown is often referred to as mobilization.

Question 13

What are the breakdown products of glycogen in the liver and muscle?

Answer 13

During glycogen breakdown, glycogen is converted to glucose-1-phosphate in both the liver and muscle. This glucose-1-phosphate can then be further metabolized to meet the different needs of each tissue.

Question 14

How does muscle mobilize glycogen?

Answer 14

Muscle mobilizes glycogen to fuel its own energy requirements through glycolysis, which supports muscle contraction.

Question 15

How does the liver convert glycogen to glucose?

Answer 15

The liver converts glycogen to glucose between meals for export to other tissues. It expresses the enzyme glucose 6-phosphatase, which allows it to convert glucose-6-phosphate back to glucose. Muscle does not express this enzyme.

Question 16

How do glycogen stores in the liver change throughout the day?

Answer 16

After a meal, glycogen stores in the liver rise in response to an increase in blood glucose. Between meals, glycogen stores in the liver fall as glucose is released from liver glycogen to stabilize the concentration of glucose in the blood. Overnight, glycogen stores in the liver are mobilized to help maintain blood glucose concentration.

Question 17

What is the relationship between blood glucose and liver glycogen stores?

Answer 17

Throughout the day, the level of liver glycogen stores and blood glucose concentration are closely related. After a meal, liver glycogen stores increase as blood glucose rises. Between meals, liver glycogen stores decrease as glucose is released into the bloodstream to maintain blood glucose levels.

Question 18

How are the (α1→4) linkages in glycogen broken?

Answer 18

The (α1→4) linkages in glycogen are broken by phosphorolysis, catalyzed by the enzyme glycogen phosphorylase. This process removes single glucose units from the non-reducing ends of glycogen, forming glucose-1-phosphate.

Question 19

What happens when glycogen phosphorylase reaches an α1→6 branch point?

Answer 19

When glycogen phosphorylase reaches an α1→6 branch point, it stops four residues away from the branch point. At this point, a debranching enzyme transfers a block of three glucose residues from the branch point to the non-reducing end of the glycogen chain.

Question 20

What is the role of the debranching enzyme in glycogen breakdown?

Answer 20

The debranching enzyme plays a role in glycogen breakdown by cleaving the α1→6 linkage at the branch points. This cleavage is performed by the α-1,6-glucosidase activity of the debranching enzyme. It releases the glucose unit as a free glucose molecule, not as glucose-1-phosphate.

Question 21

What is the difference between glycogen phosphorylase and the debranching enzyme?

Answer 21

Glycogen phosphorylase breaks the (α1→4) linkages in glycogen, while the debranching enzyme cleaves the α1→6 linkages at the branch points. Glycogen phosphorylase produces glucose-1-phosphate, whereas the debranching enzyme produces free glucose by hydrolysis.

Question 22

What can glucose 1-phosphate be converted to?

Answer 22

Glucose 1-phosphate can be reversibly converted to glucose 6-phosphate by the enzyme phosphoglucomutase.

Question 23

What happens to glucose 6-phosphate in skeletal muscle and liver?

Answer 23

In skeletal muscle, glucose 6-phosphate can enter glycolysis. In the liver, glucose 6-phosphate can be released into the blood when blood glucose levels drop. This process requires the enzyme glucose 6-phosphatase, which is present in the liver and kidney but not in other tissues including muscle. The conversion of glucose 6-phosphate to glucose occurs in the endoplasmic reticulum (ER) within liver cells.

Question 24

What is the high-energy form of glucose?

Answer 24

Glycogen is formed from UDP-glucose, which is the high-energy form of glucose.

Question 25

What enzyme adds glucose units to the glycogen chain during glycogen synthesis?

Answer 25

Glycogen synthase is the enzyme that adds glucose units to the glycogen chain in an α1→4 linkage using UDP-glucose.

Question 26

What is the energetically equivalent process to ATP consumption during glycogen synthesis?

Answer 26

The consumption of UTP during glycogen synthesis is energetically equivalent to ATP consumption. In other words, the process of glycogen synthesis requires an input of energy.

Question 27

What is the role of glycogenin in glycogen synthesis?

Answer 27

Glycogenin is a protein that carries out the priming function in glycogen synthesis. It allows glycogen synthase to add glucose units to a pre-existing chain of more than four glucosyl residues. Glycogenin accepts the first glucosyl residue from UDP-glucose and attaches it to the amino acid tyrosine within the protein.

Question 28

How are the remaining glucose units added during glycogen synthesis?

Answer 28

The remaining glucose units are added in an α1→4 linkage from UDP-glucose to the growing chain. Glycogen synthase catalyzes this process.

Question 29

How are branches introduced in glycogen?

Answer 29

Glycogen synthase can extend the glycogen chain in α1→4 linkages but cannot create branches. The branching enzyme transfers a block of seven glucose residues from a growing chain to create a new branch with an α1→6 linkage. It ensures that the new branch does not form within four residues of a pre-existing branch.

Question 30

What are the two forms of glucose involved in glycogen metabolism?

Answer 30

The two forms of glucose involved in glycogen metabolism are glucose 1-phosphate and glucose 6-phosphate.

Question 31

Why is glycogen considered a good energy store?

Answer 31

Glycogen is considered a good energy store because it can be mobilized rapidly. The enzymes phosphorylase and glycogen synthase, which are involved in glycogen breakdown and synthesis, are highly sensitive to regulation by hormones, stress, and muscle contraction. The branched structure of glycogen provides numerous ends where the polymer can be added to or broken down.

Question 32

What is a drawback of glycogen as an energy store?

Answer 32

One drawback of glycogen as an energy store is that glucose is hydrophilic and associates with water, increasing the overall weight and bulk of glycogen.

Question 33

Summarize the process of glycogen synthesis and breakdown.

Answer 33

Glycogen synthesis involves the initiation of glycogen synthesis by glycogenin, glycogen synthase linking glucose molecules via α1→4 linkages to create linear chains, and branching enzyme creating α1→6 linkages to form branches in the glycogen structure. Glycogen breakdown involves glycogen phosphorylase cleaving α1→4 linkages by phosphorolysis to yield glucose 1-phosphate and the debranching enzyme cleaving α1→6 linkages by hydrolysis to yield free glucose. Glucose 1-phosphate is converted to glucose 6-phosphate by phosphoglucomutase, and in the liver, glucose 6-phosphate is converted to free glucose by glucose 6-phosphatase for export. In muscle, glucose 6-phosphate enters glycolysis to provide energy.

Question 34

What conditions accelerate glycogen mobilization and activation of glycogen synthesis?

Answer 34

Glycogen mobilization is greatly accelerated in the liver during starvation when glucose is needed for glycolysis by the brain and red blood cells. In muscle, glycogen mobilization is accelerated during vigorous exercise to fuel glycolysis. Glycogen synthesis is activated to replenish liver glycogen stores after feeding or muscle glycogen stores when exercise ceases. Insulin promotes glycogen synthesis.

Question 35

Is the pathway for glycogen synthesis a simple reversal of glycogen breakdown?

Answer 35

No, the pathway for glycogen synthesis is not a simple reversal of glycogen breakdown. It requires energy input and is not a direct reversal process.

Question 36

What is the role of AMP in the allosteric regulation of glycogen phosphorylase?

Answer 36

AMP, which is present when ATP is depleted during muscle contraction, activates glycogen phosphorylase. It serves as a signal of low energy levels.

Question 37

What are the inhibitory signals for glycogen phosphorylase?

Answer 37

ATP and glucose 6-phosphate, which both compete with AMP binding, inhibit glycogen phosphorylase. These molecules are signs of high energy levels.

Question 38

How is glycogen synthase allosterically regulated?

Answer 38

Glycogen synthase is allosterically activated by glucose 6-phosphate. This activation occurs when glucose 6-phosphate is plentiful, indicating a high level of the substrate for glycogen synthesis.

Question 39

What is the effect of allosteric regulation on glycogen breakdown and synthesis in muscle?

Answer 39

In muscle, allosteric control of glycogen phosphorylase is mainly influenced by the energy status (ATP and AMP) and substrate availability (glucose 6-phosphate). AMP activates glycogen phosphorylase, while ATP and glucose 6-phosphate inhibit it. Glycogen synthase is activated by glucose 6-phosphate, promoting glycogen synthesis.

Question 40

What is the role of covalent modification in the regulation of glycogen metabolism?

Answer 40

Covalent modification plays a role in the regulation of glycogen metabolism by the addition and removal of a phosphate group. This modification is reversible and is catalyzed by protein kinases (phosphorylation) and protein phosphatases (dephosphorylation).

Question 41

What is the process of phosphorylation in glycogen metabolism?

Answer 41

Phosphorylation involves the addition of a phosphate group to a protein. In glycogen metabolism, phosphorylation of key enzymes, such as glycogen phosphorylase, is mediated by protein kinases. This modification can activate or deactivate the enzyme, depending on the specific context.

Question 42

How is glycogen phosphorylase activated by cAMP-dependent phosphorylation?

Answer 42

External stimuli, such as the hormones glucagon (in the liver) or adrenaline (in muscle), can activate adenylyl cyclase, which converts ATP into cyclic adenosine monophosphate (cAMP). cAMP acts as a cellular signaling molecule and activates proteins downstream in the signaling pathway. In the case of glycogen phosphorylase, cAMP-dependent phosphorylation leads to the phosphorylation of a serine hydroxyl on the enzyme, promoting its transition to the active state. The phosphorylated enzyme is less sensitive to allosteric inhibitors, allowing it to be active even in the presence of high levels of cellular ATP and glucose 6-phosphate.

Question 43

What is the effect of the cAMP cascade on glycogen synthase?

Answer 43

The induction of the cAMP cascade has the opposite effect on glycogen synthase compared to glycogen phosphorylase. Phosphorylation of glycogen synthase converts the enzyme to its less active “b” conformation. As a result, glycogen synthesis is inhibited when protein kinases are activated.

Question 44

What is the reciprocal regulation of phosphorylase and glycogen synthase?

Answer 44

The reciprocal regulation of phosphorylase and glycogen synthase determines whether glycogen breakdown or glycogen synthesis is favored. Activation of phosphorylase favors glycogen breakdown, while activation of glycogen synthase favors glycogen synthesis.

Question 45

What are glycogen storage diseases (GSDs)?

Answer 45

Glycogen storage diseases (GSDs) are disorders caused by mutations in genes encoding enzymes involved in glycogen metabolism. The clinical manifestations of GSDs vary depending on the specific enzyme affected and its relative expression in the affected tissues. Liver GSDs commonly present with fasting hypoglycemia and hepatomegaly (enlarged liver), while muscle GSDs can present with exercise intolerance and rhabdomyolysis (muscle cell death and release of cell contents) or fixed muscle weakness without rhabdomyolysis.

Question 46

What is Glucose-6-Phosphatase Deficiency (Von Gierke)?

Answer 46

Glucose-6-Phosphatase Deficiency, also known as Von Gierke disease, is a genetic disorder caused by a mutation that impairs the hydrolase activity of the enzyme glucose-6-phosphatase. This enzyme is responsible for removing the phosphate group from glucose 6-phosphate, the final step in gluconeogenesis. The deficiency leads to reduced availability of “free glucose” and impaired glucose homeostasis.

Question 47

What are the clinical manifestations of Glucose-6-Phosphatase Deficiency?

Answer 47

Glucose-6-Phosphatase Deficiency presents with fasting hypoglycemia, lactic acidosis, hyperuricemia (elevated levels of uric acid), and hypertriglyceridemia (elevated lipids in the bloodstream). The mutation in the enzyme leads to increased flux of metabolites through the pentose phosphate pathway, glycolysis, and lipogenesis.

Question 48

What are the treatment approaches for Glucose-6-Phosphatase Deficiency?

Answer 48

The treatment aims to maintain normal blood glucose levels and avoid hypoglycemia. Nutritional approaches involve frequent feeding, including the use of nasogastric and gastrostomy tubes, and the use of Glycosade, a cornstarch polymer of glucose, to help maintain blood glucose levels overnight. Control of hyperuricemia can be achieved through diet or the use of allopurinol. Hyperlipidemia may improve with diet and/or the use of statins. In severe cases, liver transplantation has shown favorable outcomes. Gene therapy is also being explored as a potential treatment option.