Glycogen, an energy reservoir in animals, is a highly branched molecule or polysaccharide. It is present in the liver and skeletal muscles. When there is lack of glucose in blood, glycogen serves as an immediate source of glucose. The breakdown of glycogen is termed glycogenolysis.
An increase in cAMP (cyclic adenosine monophosphate) in the cell induces glycogenolysis. Hormones like glucagon and insulin help regulate glycogenolysis. Glycogenesis, the formation of glycogen, and glycogenolysis (the breakdown of glycogen) go hand in hand.
Phosphorylase kinase and glycogen phosphorylase are vital regulatory enzymes for glycogenolysis. These occur mainly in the liver, muscle cells, and brain.
Table of Contents
Enzymes Involved in Glycogenolysis
Various enzymes are involved in glycogenolysis. These include glycogen phosphorylase, debranching enzyme, phosphoglucomutase, and glucose-6-phosphatase.
- Glycogen phosphorylase: This enzyme removes a single glucose-1-phosphate from the glycogen chain. It has restrictions and cannot remove glucose-1-phosphate after reaching a certain length.
- Debranching enzyme: This enzyme has three sub-sections. First, it removes the α-1,4-glycosidic bond of 3-4 glucose molecules from the previous branch. Then, it transfers the glucose molecules to another branch. Finally, it breaks the α-1,6-glycosidic bond and releases a free glucose molecule.
- Phosphoglucomutase: The glucose-1-phosphate conversion to glucose-6-phosphate occurs due to the presence of this enzyme. This is the final step in muscle cells. However, in liver cells, the glucose-6-phosphate changes into glucose molecules.
- Glucose-6-phosphatase: This enzyme is present in liver, kidney, and gastrointestinal cells. As glycogenolysis occurs in the liver, glucose-6-phosphate released after debranching and isomerization needs to change into glucose for removal from the cell. Glucose-6-phosphatase is the enzyme that dephosphorylates glucose-6-phosphate, releasing the glucose molecule.
Steps of Glycogenolysis
Glycogenolysis is a tightly regulated metabolic process that has several steps. It occurs in the cytoplasm of the liver and muscle cells. The starting of glycogenolysis is activating the enzyme glycogen phosphorylase, followed by its activity, then debranching enzyme activity and releasing a glucose molecule. The following are the steps of glycogenolysis:
Activating Glycogen Phosphorylase
The hormones like glucagon and epinephrine activate phosphorylase kinase a (PKA) through a signaling cascade, i.e., it triggers the increase of cAMP. The cAMP activates the inactivated phosphorylase kinase, phosphorylase kinase b, to phosphorylase kinase a (the activated form). The activated phosphorylase kinase then phosphorylates glycogen phosphorylase, activating the enzyme.
Glycogen Phosphorylase activity for releasing Glucose-1-phosphate
Glycogen phosphorylase breaks down the α-1,4-glycosidic bond in glucose residues of glycogen and adds or phosphorylates the separated glucose molecule. This phosphorylation produces glucose-1-phosphate. It acts on several glucose residues in the glycogen molecule. However, once the chain divides and almost four residues of glucose remain, it stops acting in this branch.
Debranching Enzyme Activity for Release of Glucose
Once the chain has four glucose residues, the debranching enzymes act on the chain. This enzyme has a group of enzymes, including α-1,4-glucosidase, amylo-1,4→1,6 transglycosylase, and α-1,6-glucosidase. The α-1,4-glucosidase breaks down the α-1,4-glycosidic bond from the last glucose residue of the chain. The amyloid-1,4→1,6 transglycosylase transfers the 3 remaining glucose residues to a different branch. The α-1,6-glucosidase breaks the α-1,6-glycosidic bond, releasing free glucose molecules. This free glucose molecule transfers from the liver cells into the blood to maintain glucose levels.
Conversion of Glucose-1-phosphate
We know cells cannot utilize glucose-1-phosphate molecules. So, the phosphoglucomutase enzyme converts the glucose-1-phosphate molecule into the glucose-6-molecule. This step is the end of glycogenolysis if it occurs inside muscle cells because muscle cells lack the enzyme glucose-6-phosphatase. The glucose-6-phosphate then enters the ER (endoplasmic reticulum) of liver cells through GLUT (glucose transporters).
Removal of Phosphate to Release Glucose
The enzyme glucose-6-phosphatase dephosphorylates glucose-6-phosphate, releasing a glucose molecule into the cytosol. This glucose molecule further helps maintain blood glucose levels.
Regulation of Glycogenolysis
Both hormonal and allosteric regulation of glycogenolysis can occur. Glucagon, epinephrine, and norepinephrine regulate glycogenolysis hormonally. Phosphorylase kinase allosterically controls glycogenolysis. The following are the regulatory mechanisms of glycogenolysis:
Enzymatic Regulation
The enzyme glycogen phosphorylase is the most critical enzyme for beginning glycogenolysis. Its regulation is based on the phosphorylation and dephosphorylation reactions. Hormones like glucagon and epinephrine trigger the phosphorylation of this enzyme. Likewise, the protein phosphatase (PP1) enzyme controls the dephosphorylation of the enzyme. The activation of glycogen phosphorylase is the primary regulatory step of glycogenolysis. In muscle cells, calcium ions activate glycogen phosphorylase. During muscle contraction, an increase in intracellular calcium levels triggers the activation of glycogenolysis, which provides energy for muscle contraction.
The enzyme involved in glycogenesis, glycogen synthase, also contributes to the regulatory mechanism of glycogenolysis. This enzyme is inhibited due to phosphorylation, which is mediated by protein kinase a (PKA). Inhibition of glycogen synthase promotes glycogenolysis.
Hormonal Regulation
The hormones glucagon, epinephrine, and cortisol are responsible for the regulation of glycogenolysis. Glucagon promotes glycogenolysis as it is released during fasting when the glucose level in the blood is low or the condition called hypoglycemia.
Likewise, epinephrine or adrenaline, released during times of stress and physical activity, promotes glycogenolysis. This aids in providing a rapid source of glucose for energy. In a similar manner, cortisol, released in response to stress, promotes glycogenolysis.
In contrast, the hormone insulin inhibits glycogenolysis and promotes glycogenesis. It is released as a response to high blood glucose levels and encourages glycogen formation by utilizing the glucose molecule.
Availability of Substrate
Glucose-6-phosphate, an intermediate substrate during glycogenolysis, also regulates glycogenolysis. The higher the concentration of glucose-6-phosphate in the cell, the slower the glycogenolysis rate.
Clinical Significance
Glycogenolysis is significant for the regulation of blood glucose levels. Likewise, muscle cells can provide immediate glucose-6-phosphate, essential for muscle contraction. Various inheritable metabolic disorders like glycogen storage disease can impair glycogenolysis.
Blood Glucose Regulation
Glycogenolysis plays a critical role in regulating blood glucose levels. During increased energy demand (like exercise) or fasting, glycogen in the liver and muscles is broken down into glucose via glycogenolysis to maintain normal blood glucose levels.
Hypoglycemia
Dysregulation of glycogenolysis can lead to hypoglycemia (low blood sugar). Conditions such as glycogen storage diseases (e.g., Von Gierke disease) can impair glycogenolysis, resulting in hypoglycemia, muscle weakness, and other metabolic abnormalities.
Diabetes Mellitus
In diabetes mellitus, glycogenolysis and overall glucose metabolism are dysregulated. During type 1 diabetes, where insulin is deficient, glycogenolysis and gluconeogenesis (formation of glucose from non-carbohydrate sources) are increased, contributing to hyperglycemia. In type 2 diabetes, resistance to insulin leads to impaired glycogen synthesis and increased glycogenolysis.
Exercise Physiology
During exercise, glycogenolysis in muscle cells provides a rapid source of glucose for energy production. Understanding the regulation of glycogenolysis is essential in sports medicine and exercise physiology to optimize energy utilization and performance.
Liver Function
The liver plays a central role in glycogenolysis, and impaired liver function can affect glycogen metabolism. Liver diseases like cirrhosis can lead to glycogen storage and glycogenolysis alterations, impacting overall energy metabolism and glucose homeostasis.
Pharmacological Interventions
Drugs that modulate glycogenolysis or glycogen metabolism are used in clinical settings. For example, medications that stimulate glycogenolysis (such as glucagon) are used in emergency management of severe hypoglycemia. Drugs that affect insulin signaling and glycogen synthesis are also used in diabetes management.
Metabolic Disorders
Various metabolic disorders, including glycogen storage diseases (GSDs), are characterized by defects in glycogenolysis or glycogen synthesis enzymes. These disorders can lead to abnormal glycogen accumulation or depletion, causing various symptoms affecting different organs and tissues.
References
- Paredes-Flores MA, Rahimi N, Mohiuddin SS. Biochemistry, Glycogenolysis. [Updated 2024 Jan 9]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK554417/
- Komoda, T., & Matsunaga, T. (2015). Metabolic pathways in the human body. Biochemistry for Medical Professionals, 25–63. https://doi.org/10.1016/b978-0-12-801918-4.00004-9
- Nelson, D., Lehninger, A., Cox, M., & Nelson, D. (2005). Lecture notebook for Lehninger principles of biochemistry, fourth edition (pp. 601-612). W.H. Freeman.
- Regulation of glycogenesis and glycogenolysis – biochemistry. pharmacy180.com. (n.d.). https://www.pharmacy180.com/article/regulation-of-glycogenesis-and-glycogenolysis-1886/
