The Ultimate Guide to Glycogenolysis | Everything You Need to Know

Demystifying Glycogenolysis: Your Complete Resource for Self-Study and Healthcare Professional Exams/Tests and Research Papers

    Glycogenolysis, the breakdown of glycogen into glucose, is a vital process in our body that plays a crucial role in energy production. It is a topic that is often tested on healthcare professional exams and entrance tests like MBBS-I, BS Nursing, Paramedics, BS Nutrition, BS Biochemistry, and NEET, among others. Understanding the mechanism of glycogen breakdown is essential for students pursuing careers in healthcare and medicine. However, it can be a challenging subject to grasp due to its complexity.

    This article aims to provide a complete resource for self-study and healthcare professional exams and research papers. We will cover the major sub-topics related to glycogenolysis, including its definition and overview, steps involved in the process, regulation, and clinical significance. The article is written in a simple and understandable way to ensure guaranteed success in exams/tests.

    Whether you are a healthcare professional, a student preparing for an exam, or just someone who wants to understand the body mechanism of glycogen breakdown, this article is for you. By the end of this article, you will have a comprehensive understanding of glycogenolysis, and you'll be equipped with the knowledge you need to succeed in your exams and tests.

Notes on Glycogenolysis for Professionals
From the Biochemistry Library of H.E.S (Health, Education, and Skills)

Glycogenolysis Definition and Overview

The breakdown of glycogen up to glucose is known as glycogenolysis.

• It occurs in the cytosol of liver cells.
• In the liver, glycogen forms blood glucose which is either used for energy or converted into glucose-6-phosphate, which can be further metabolized through the glycolytic pathway or used for synthesizing other compounds, such as nucleotides.
• In muscles, glycogen provides energy (ATPs) through glycolysis.

Importance of Glycogenolysis in the human body

    Here are some key reasons why glycogenolysis is essential for the human body:

1. Regulation of blood glucose levels: Glycogenolysis helps to maintain blood glucose levels within a narrow range. When blood glucose levels drop, the body can quickly break down stored glycogen to release glucose into the bloodstream, preventing hypoglycemia (low blood sugar), which can lead to weakness, dizziness, and even fainting.
2. Energy production: Glycogenolysis is an important energy source for the body's cells. During exercise or other forms of physical activity, the body can rapidly break down glycogen to release glucose and provide energy to the muscles.
3. Brain function: The brain relies almost entirely on glucose as a source of energy. Glycogenolysis ensures that there is a steady supply of glucose available to the brain, even when blood glucose levels are low.
4. Hormonal regulation: Glycogenolysis is regulated by several hormones, including glucagon and adrenaline, which help to stimulate the breakdown of glycogen and release glucose into the bloodstream. These hormones play a crucial role in maintaining blood glucose levels during periods of fasting or stress.

Steps in Glycogenolysis

1. Activation of glycogen phosphorylase | Shortening of Glycogen chain

• The first step of glycogenolysis is the activation of an enzyme called glycogen phosphorylase.
• Glycogen phosphorylase is activated by a hormone called glucagon, which is released by the pancreas in response to low blood glucose levels. 
• By simple phosphorolysis, glycogen phosphorylase cleaves α-1,4 linkage between glycosyl residues and releases glucose 1-phosphate until four glucosyl units are left on each chain before a branch point.  
• The resulting structure with four glucosyl units in each branch is called a limit dextrin.
• Glycogen phosphorylase cannot degrade limit dextrin any further.

Removal of Branches 

• Branches are removed by the Debranching enzyme.
• Debranching enzyme is a group of two enzymes i.e glucosyl (4:4) transferase (oligo (1,4:1,4)-glucosidase.
• Glucosyl (4:4) transferase removes the outer three of the four remaining glucosyl residues in the limit dextrins and transfers them to the non-reducing end of another chain, lengthening it accordingly. Thus the α-1,4 linkage is broken and the α-1,4 linkage is made.
• Amylo-α-(1,6) glucosidase removes the remaining one glucosyl residue from the limit dextrins.    

2. Conversion of glucose-1-phosphate to glucose-6-phosphate

• The glucose-1-phosphate that is released from the glycogen molecule is then converted to glucose-6-phosphate by an enzyme called phosphoglucomutase. 
• This conversion is important because glucose-6-phosphate can be used for energy production or stored as glycogen.

3. Conversion of glucose-6-phosphate to glucose

• The final step of glycogenolysis is the conversion of glucose-6-phosphate to glucose. 
• This conversion is catalyzed by an enzyme called glucose-6-phosphatase, which is found primarily in the liver and kidney. This is the reason that muscles cannot synthesize glucose from glycogen (so muscles have no role in maintaining blood glucose levels). 
• The resulting glucose molecule can then be released into the bloodstream and used by the body's cells for energy production.

Regulation of Glycogen Synthesis (Glycogenesis) and Glycogen Degradation (Glycogenolysis)

1. Allosteric Regulation

• Increased levels of energy and increased availability of substrate will increase glycogen synthesis.
• Decreased levels of energy and decreased availability of substrate will decrease glycogen synthesis.

A. Regulation in the well-fed state

    Increased glucose →increased concentration of glucose 6-phosphate →activation of glycogen synthase and inhibition of glycogen phosphorylase → glycogen synthesis (glycogenesis).

B. Regulation during the fasting state

    Decreased glucose → decreased concentration of glucose 6-phosphate →activation of glycogen phosphorylase and inhibition of glycogen synthase → glycogen degradation (glycogenolysis).

C. Activation of Glycogen (Degradation in muscles by Ca++ and AMP)

• Effect of Ca++: Muscle contraction requires energy, which is supplied by glycogen in the form of ATP. 

    Muscle contraction → nerve impulse generated →cell membrane gets depolarized → Ca++ binds with calmodulin →activates glycogen phosphorylase →glycogenolysis starts.

• Effect of AMP: Decreased Oxygen in muscles during strenuous exercise →decreased ATP concentration →increased AMP concentration →AMP binds with an inactive form of glycogen phosphorylase 'b' →glycogen phosphorylase 'b' activated to glycogen phosphorylase 'a' →glycogenolysis starts.

2. Hormonal Regulation

• Hormonal control of glucose metabolism (glycogenesis, glycogenolysis, gluconeogenesis etc) is mainly through altering the concentration of cAMP (Cyclic AMP).
• cAMP acts as a second messenger for insulin, glucagon, and epinephrine to regulate carbohydrate metabolic processes.
• Insulin decreases cAMP → ↓ cAMP concentration activates glycogenesis (in the liver and muscles) i.e. insulin decreases glucose concentration.
• Glucagon increases cAMP → ↑ cAMP concentration activates glycogenolysis (in the liver) i.e. glucagon increases glucose concentration.
• Epinephrine increases cAMP →↑ cAMP concentration activates glycogenolysis (in the liver and muscles) i.e. epinephrine increases glucose concentration.
• ↓ insulin, ↑ glucagon, and ↑ epinephrine → activates adenylate cyclase → conversion of ATP into cAMP →↑ concentration of cAMP → activates protein kinase.
• Protein kinase activates phosphorylase kinase →activation of glycogen phosphorylase → initiation of glycogenolysis and inhibition of glycogenesis.
• Protein kinase inactivates glycogen synthase →inhibition of glycogenesis and activation of glycogenolysis.
• The overall effect is increased glycogenolysis and decreased glycogenesis.
• On the contrary, when ↑ insulin is increased and ↓ glucagon, and ↓ epinephrine, the overall effect will be reversed i.e. increased glycogenesis and decreased glycogenolysis.