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.