SU

Glycogenolysis Notes

Glycogenolysis: Breaking Down Glycogen into Glucose

Introduction

  • Glycogenolysis is the process of breaking down glycogen into glucose. It is the opposite of glycogenesis.
  • It's crucial to understand glycogenesis before diving into glycogenolysis.

Definition of Glycogenolysis

  • Glycogenolysis: "Lysis" means cutting, so it's the cutting of glycogen to form glucose.

Location of Glycogenolysis

  • Primarily occurs in the liver and muscles.
  • Can occur in other tissues but is most significant in the liver and muscles.
  • Muscle glycogenolysis has limitations, which will be discussed.

Reason for Glycogenolysis

  • Occurs when blood glucose levels are low (hypoglycemia).
  • Hypoglycemia: Low blood glucose levels (below the normal range of 70-130 mg/dL).
  • Glycogenolysis helps increase blood glucose levels by breaking down glycogen into glucose and releasing it into the blood.

When Glycogenolysis Occurs

  • During the fasting state (post-absorptive state) when you haven't eaten in a while.
  • During starvation when you are not eating food.

Hormones Involved

  • Main hormones: Glucagon, epinephrine, and norepinephrine.
  • Other hormones: Growth hormone and thyroid hormone can also be involved.

The Process of Glycogenolysis

Starting Point

  • Begins with the glycogen polymer attached to a base molecule called glycogenin.

Key Enzyme: Glycogen Phosphorylase

  • This enzyme cuts alpha-1,4 glycosidic bonds in glycogen.
  • Alpha-1,4 glycosidic bonds: Bonds between the one carbon of one glucose molecule and the four carbon of another glucose molecule.
  • Glycogen phosphorylase carries phosphates in a "satchel."
  • It grabs a phosphate and flings it at the alpha-1,4 glycosidic bond, breaking the bond.
  • This process adds the phosphate onto the one carbon of the released glucose molecule, forming glucose-1-phosphate.

Glucose-1-Phosphate Formation

  • The enzyme continues to break alpha-1,4 glycosidic bonds and add phosphates, forming multiple glucose-1-phosphate molecules.

Restriction Point

  • Glycogen phosphorylase stops when it reaches four glucose molecules away from an alpha-1,6 glycosidic bond (branch point).
  • Alpha-1,6 glycosidic bond: bond coming off the six carbon of a glucose and linking to the one carbon of another glucose.

Debranching Enzyme

  • Comes into play when glycogen phosphorylase stops.
  • Has two activities:
    • Alpha-1,4-Glucosidase activity: cuts the alpha-1,4 glycosidic bond between the glucose bound with the alpha-1,6 glycosidic bond and the glucose right after it so it can transfer three glucose molecules onto the elongating chain.
    • Alpha-1,6-Glucosidase activity: breaks the alpha-1,6 glycosidic bond, releasing a free glucose molecule.

Debranching Enzyme Mechanism:

  • The debranching enzyme transfers three glucose molecules from the branch to another longer chain.
  • Then, it cleaves the alpha-1,6-glycosidic bond, releasing a single, free glucose molecule.

Glycogen Phosphorylase after Debranching

  • After the debranching enzyme acts, glycogen phosphorylase can continue breaking alpha-1,4 glycosidic bonds until it encounters another branch point.
  • For every five glucose-1-phosphates produced, a very small amount of free glucose is produced.

Pyridoxal Phosphate

  • Glycogen phosphorylase has pyridoxal phosphate earrings, which are important for the transfer of phosphates onto glucose molecules.
  • Pyridoxal phosphate is a derivative of vitamin B6.

Fate of Glucose and Glucose-1-Phosphate

Fate of Free Glucose

  • Free glucose can exit the cell and enter the bloodstream, increasing blood glucose levels.
  • However, the amount of free glucose released is insignificant compared to glucose-1-phosphate.

Fate of Glucose-1-Phosphate

  • Glucose-1-phosphate is converted to glucose-6-phosphate by the enzyme phosphoglucomutase.
  • Phosphoglucomutase is a reversible enzyme.

Conversion to Glucose-6-Phosphate

  • The phosphate is shifted from the one carbon to the six carbon, resulting in glucose-6-phosphate.
  • Glucose-6-phosphate cannot be directly transported out of the cell.

Role of Glucose-6-Phosphatase

  • Glucose-6-phosphatase is an enzyme found in the liver, kidneys (specifically the proximal convoluted tubule), and parts of the GI tract (particularly the duodenum).
  • It is not found in muscles.
  • Glucose-6-phosphatase removes the phosphate from glucose-6-phosphate, forming free glucose.

Glucose-6-Phosphatase Mechanism

  • Glucose-6-phosphate is transported into the endoplasmic reticulum (ER) via the T1 GLUT transporter.
  • Glucose-6-phosphatase acts on glucose-6-phosphate, removing the phosphate group.
  • Free glucose is then transported out of the ER via the T2 GLUT transporter and diffuses out into the blood.

Importance for Blood Glucose

  • The liver is the primary organ where this process occurs, contributing to the regulation of blood glucose levels.

Muscle Limitations

  • Muscles can perform glycogenolysis but lack glucose-6-phosphatase.
  • Therefore, muscles cannot release free glucose into the blood.
  • Glucose-6-phosphate gets stuck in the muscles.
  • Indirect mechanisms, such as the Cori cycle and glucose-alanine cycle (discussed in gluconeogenesis), are used to get glucose from muscles into the blood.

Summary

  • Glycogenolysis is the breakdown of glycogen into glucose.
  • Key enzymes are glycogen phosphorylase and debranching enzyme.
  • The liver plays a crucial role in regulating blood glucose levels through glycogenolysis, while muscles have limitations due to the absence of glucose-6-phosphatase.