CH 25: Glycogen Synthesis

Chapter 25: Glycogen Synthesis Overview

• Glycogen is a polysaccharide that serves as a form of energy storage in animals and fungi.

• This chapter explores the pathways involved in glycogen synthesis and degradation, the enzymes responsible, and the regulatory mechanisms governing these processes.

25.1 Glycogen Synthesis and Degradation Pathways

• Key Learning Objectives:

  • Understand the steps and enzymes involved in glycogen synthesis.

  • Explain the regulation of glycogen synthesis.

• High Glucose Concentrations:

  • Glycogen synthesis occurs primarily under conditions of high glucose availability (fed state).

• Activated Form of Glucose:

  • UDP-glucose (uridine diphosphate-glucose) is the main monomer used to extend glycogen chains and is synthesized by the enzyme UDP-glucose pyrophosphorylase.

  • The hydrolysis of pyrophosphate makes the forward reaction of UDP-glucose synthesis more favorable.

Enzymes of Glycogen Synthesis

• Phosphoglucomutase:

  • Converts glucose-1-phosphate to glucose-6-phosphate.

• UDP-glucose Pyrophosphorylase:

  • Produces UDP-glucose from glucose-1-phosphate and UTP.

• Glycogen Synthase:

  • Transfers glucose from UDP-glucose to the growing glycogen chain, forming an α-1,4-glycosidic bond.

  • Requires a minimum primer (at least 4 glucose units) synthesized by glycogenin.

• Glycogen Branching Enzyme:

  • Forms α-1,6 linkages, crucial for increasing the solubility and availability of glycogen.

  • Cleaves α-1,4 linkages and transfers a block of seven glucose units to create branches.

Regulation of Glycogen Synthase

• Two Forms of Glycogen Synthase:

  • b form: Phosphorylated and inactive.

  • a form: Dephosphorylated and active.

• Allosteric Regulation:

  • Glucose-6-phosphate is a potent allosteric activator of glycogen synthase b, enhancing its activity without affecting glycogen synthase a.

Glycogen as Energy Storage

• Glycogen is an efficient way to store glucose, requiring only 2 ATP equivalents to incorporate glucose into glycogen, while oxidation of glycogen-derived glucose yields 31 ATP molecules due to the initial investment.

25.2 Reciprocal Regulation of Glycogen Synthesis and Breakdown

• Preventing Simultaneous Processes:

  • Glucagon and epinephrine stimulate glycogen breakdown (glycogenolysis) while inhibiting glycogen synthesis (glycogenesis).

• Switching Metabolic Modes:

  • Protein Phosphatase 1 (PP1) reverses kinase actions, enabling the switch from glycogenolysis to glycogenesis by dephosphorylating active enzymes.

Insulin's Role in Glycogen Synthesis

• Post-exercise Recovery:

  • Carbohydrate-rich foods increase blood glucose, activating glycogen synthesis after exercise.

• Mechanism of Insulin Action:

  • Increases expression of GLUT4 transporter, enhancing glucose uptake.

  • Insulin inactivates glycogen synthase kinase, which keeps glycogen synthase phosphorylated and inactive; thus, more glycogen is synthesized as glycogen synthase is activated.

Liver and Blood-Glucose Regulation

• Glycogen Metabolism in the Liver:

  • The liver adjusts glycogen metabolism based on blood glucose levels, with the action of PP1 being critical for transition to glycogenesis when glucose is abundant.

Clinical Insight: Diabetes Mellitus

• Characterization of Diabetes:

  • Diabetes results from insulin insufficiency or glucagon excess, leading to high blood glucose levels and inefficient fuel utilization.

  • Type 1: Insulin is not produced; Type 2: Insulin resistance occurs despite production.

• Lack of Glycogen Regulation:

  • Impaired insulin signaling affects glycogen synthesis regulation, contributing to elevated blood glucose levels.

1. What enzymes are involved in glycogen synthesis?

   • Phosphoglucomutase: Converts glucose-1-phosphate to glucose-6-phosphate.

   • UDP-glucose Pyrophosphorylase: Produces UDP-glucose from glucose-1-phosphate and UTP.

   • Glycogen Synthase: Transfers glucose from UDP-glucose to the growing glycogen chain, forming an α-1,4-glycosidic bond and requires a minimum primer (at least 4 glucose units) synthesized by glycogenin.

   • Glycogen Branching Enzyme: Forms α-1,6 linkages, crucial for increasing the solubility and availability of glycogen by cleaving α-1,4 linkages and transferring a block of seven glucose units to create branches.

2. What are the functions of the enzymes involved in glycogen synthesis?

   • Phosphoglucomutase: Interconversion of glucose-1-phosphate and glucose-6-phosphate.

   • UDP-glucose Pyrophosphorylase: Synthesis of UDP-glucose, activating glucose for incorporation into glycogen.

   • Glycogen Synthase: Main enzyme responsible for elongating the glycogen chain by adding glucose monomers.

   • Glycogen Branching Enzyme: Creates branches in glycogen chains, enhancing solubility and accessibility of stored glucose.

3. What is the key regulatory enzyme of glycogen synthesis?

   • Glycogen Synthase is the key regulatory enzyme, with two forms: b form (phosphorylated and inactive) and a form (dephosphorylated and active).

4. How is the key regulatory enzyme of glycogen synthesis allosterically regulated?

   • Glycogen Synthase is allosterically regulated by glucose-6-phosphate, which activates the b form of glycogen synthase, enhancing its activity without affecting the a form.

5. Explain how glycogen synthesis and glycogen breakdown are reciprocally regulated.

   • Glycogen synthesis and breakdown are regulated by hormones such as glucagon and epinephrine. These hormones stimulate glycogen breakdown (glycogenolysis) while inhibiting glycogen synthesis (glycogenesis). Protein Phosphatase 1 (PP1) plays a critical role in switching from the breakdown to the synthesis by dephosphorylating active enzymes.

6. How do hormonal signals regulate glycogen metabolism?

   • Insulin promotes glycogen synthesis by increasing the expression of GLUT4 transporter, enhancing glucose uptake, and inactivating glycogen synthase kinase, thus activating glycogen synthase. Glucagon and epinephrine stimulate glycogen breakdown, promoting glycogenolysis.

7. What is the role of protein phosphatase 1 (PP1) in glycogen metabolism?

   • PP1 reverses the action of kinases, enabling the switch from glycogenolysis to glycogenesis by dephosphorylating enzymes, thus promoting glycogen synthesis when glucose is available.

8. How does PP1 differ in muscle versus liver?

   • PP1 is regulated differently in muscle and liver tissues. In muscle, PP1 activation is more dependent on local signaling molecules, while in the liver, it is influenced by the overall hormonal signals related to blood glucose levels.

9. Describe how insulin signaling promotes glycogen synthesis.

   • Insulin signaling enhances glycogen synthesis by increasing GLUT4 expression, allowing for better glucose uptake, and inactivating glycogen synthase kinase, thereby promoting the active form of glycogen synthase and leading to increased glycogen synthesis.

10. What is the effect of insulin on glycogen synthase kinase?

    • Insulin inactivates glycogen synthase kinase, preventing it from phosphorylating glycogen synthase, thereby allowing glycogen synthase to remain active and promote glycogen synthesis.

11. What is the mechanism by which the liver acts as a sensor of high blood glucose?

    • The liver senses high blood glucose levels through insulin signaling pathways, leading to increased glycogen synthesis via the activation of glycogen synthase and inhibition of glycogen breakdown.

12. Describe how blood glucose levels regulate liver-glycogen metabolism.

    • High blood glucose levels stimulate insulin secretion, which in turn promotes glycogen synthesis in the liver. Conversely, low blood glucose levels trigger the release of glucagon, promoting glycogenolysis.

13. Why is there a lag when switching from glycogen degradation to glycogen synthesis?

    • There is a lag in switching metabolic pathways due to the need for phosphorylation state changes and the involvement of signaling molecules that take time to restore previous conditions as well as the requirement for PP1 activity.

14. What is the biochemical basis of diabetes mellitus?

    • Diabetes mellitus is characterized by insulin insufficiency or glucagon excess, leading to elevated blood glucose levels. Type 1 diabetes involves lack of insulin production, while Type 2 involves insulin resistance despite production.

15. What are the biochemical defects leading to glycogen storage diseases?

    • Glycogen storage diseases are caused by deficiencies in enzymes involved in glycogen metabolism, leading to abnormal accumulation of glycogen in various tissues and affecting glucose availability.