Glycogenesis, Glycogenolysis and Glycolysis

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Introduction

Glucose is the main source of energy for almost all the cells in our body. A large amount of energy is released upon the oxidative metabolism of glucose in living cells. This energy is used to phosphorylate ADP to ATP, the energy currency of the cell. 

Glucose can also be stored in living bodies for later use. Plants store glucose in the form of starch while animals store it in the form of glycogen. Glycogen is found in almost all the animal cells, is abundantly present in the liver as well as skeletal muscles of animals. 

In this article, we will discuss three main processes concerning glycogen;

  1. The synthesis of glycogen from glucose, glycogenesis
  2. The breakdown of glycogen to release glucose, glycogenolysis
  3. The breakdown of glucose into pyruvic acid, glycolysis

Glycogenesis

The process of glycogen synthesis from glucose residues is called glycogenesis. Before studying the steps involved in its synthesis, it is important to first understand the general structure of glycogen. 

Structure

Glycogen is a branched polymer of alpha-glucose. The glucose molecules are linked together via alpha 1-4 glycosidic linkages in the linear chains while the residue at the branch points are linked via alpha 1-6 glycosidic linkages. The glycogen molecule shows extensive branching, with one branch point occurring after every 8 to 12 glucose residues in the linear chain. It has a protein at its core, called the glycogenin protein. The glycogen molecule appears as branches of tree emerging from the glycogenin core. 

Synthesis

Glycogen is synthesized from the molecules of alpha D-glucose. The process takes place in the cytoplasm and uses energy in the form of ATP as well as UTP. It involves the following steps.

Synthesis of Glucose-1-Phosphate

First of all, the molecules of glucose are phosphorylated to form glucose-6-phosphate. This reaction is catalyzed by glucokinase enzymes. The phosphate is provided by the ATP molecules. 

These glucose-6-phosphate molecules are later converted to glucose-1-phosphate via phosphoglucomutase enzyme. During this conversion, glucose-1,6-bisphosphate is also generated that is an obligatory intermediate of the reaction. 

Synthesis of UDP-glucose

All the glucose residues found in glycogen are provided by UDP-glucose. The UDP-glucose molecules are synthesized from glucose-1-phosphate and UTP via UDP-glucose phosphorylase enzyme. 

A molecule of pyrophosphate (PPi) is also produced during this process. This pyrophosphate is hydrolyzed to release two inorganic phosphates along with energy. This exergonic reaction makes sure that the UDP-glucose synthesis reaction always proceeds in the forward direction. 

Glycogen Synthase Enzyme

Once the UDP-glucose molecules are formed, they are utilized by the glycogen synthase enzyme to form a linear chain of alpha D-glucose. An important feature of this enzyme is that it can only elongate already existing chains of glycogen. It cannot begin the synthesis of a new chain starting from the first residue. A primer is always needed by the glycogen synthase enzyme to begin its process.

However, if some pre-existing chains of glycogen are present in the cell, the glycogen synthase enzyme can use these fragments as a primer and continue its process of making glycogen. 

Synthesis of Primer

In the case when glycogen fragments are not present, a protein called glycogenin serves as a primer. The hydroxyl group present in the side-chain of a tyrosine residue in glycogenin acts as the acceptor of the first glucosyl residue from UDP-glucose. The reaction is called autoglucosylation as it is catalyzed by the glycogenin itself. The protein keeps adding few more glucosyl residues via alpha 1-4 glycosidic linkages until a short chain is formed. This short-chain of glucose residues then serves as a primer for glycogen synthase enzyme. 

Elongation of Chain

Once the primer has been formed, it can be acted upon by the glycogen synthase enzyme. This enzyme elongates the glycogen chain by adding new glucosyl residues to the non-reducing end of the chain. The glucose residues are provided by UDP-glucose molecules. the non-reducing end of the chain is the one having free anomeric carbon, carbon of the aldehydic functional group. During the process of chain elongation, the hydroxyl group at the fourth carbon of the new glycosyl residue reacts with the aldehydic group of the residue present at the non-reducing end, forming an alpha 1-4 glycosidic bond. 

During this process, a molecule of UDP is released with each glucosyl residue added to the chain. This UDP is converted back to UTP by nucleoside diphosphate kinase, using ATP as a source of energy as well as the provider of inorganic phosphate. 

Branching 

The linear chain alpha 1-4 glucosyl residues formed by the glycogen synthase enzyme resembles the amylase starch found in plants. On the other hand, glycogen is a highly branched polymer of alpha 1-4 glucosyl residues. 

The next step in the glycogenesis is the process of making branching so that a highly branched molecule is formed. This is carried out by a separate enzyme called branching enzyme. 

The branching enzyme is called amylo-alpha(1-4) to alpha(1-6) transglucosidase. A branch is made in two steps:

  • In the first step, the branching enzyme removes a short-chain of six to eight glucosyl residues from the non-reducing end of the linear chain by breaking an alpha 1-4 glycosidic linkage. 
  • In the next step, the branching enzyme inserts this short linear branch at a non-reducing residue of the chain via an alpha 1-6 glycosidic bond. The first residue at the branch point is attached via an alpha 1-6 glycosidic bond while the rest of residues in the chain have the same alpha 1-4 glycosidic linkages. 

Once the branch has been formed, both the chains can be further elongated by the glycogen synthase enzyme. In addition, more branches can also be added by the branching enzyme. 

The ultimate result is the formation of a large molecule having extensive tree-like branches with one branch occurring every eight to twelve residues in the chain. 

The glycogenin protein that was used to make the primer remains a part of the molecule and forming the core of glycogen granules found in the cells.

Glycogenolysis

The process of breakdown of glycogen to yield glucose residues is called glycogenolysis. Glycogen acts as a source of glucose providing it when the body needs it. The process of glycogenolysis takes place in the skeletal muscles as well as in the liver. However, the complete breakdown of glycogen to glucose molecules takes place only in the liver so that it can be used by other cells of the body.

Before diving into the details of glycogenolysis, let us first discuss the site of glycogen storage and its role in the body. 

Glycogen Storage

Glycogen is present in almost all the cells of the human body. However, its major stores are skeletal muscles and liver. In an average human being, 400 grams of glycogen are present in the skeletal muscles while the liver contains only 100 grams of glycogen in the well-fed state. This glycogen makes around 10% of the total weight of the liver. 

Glycogen is stored in the cells in the form of granules present in the cytoplasm. 

The glycogen stores in the liver fluctuate with the body needs. In the well-fed state, the amount of glycogen in the liver increases while it decreases during fasting. On the other hand, glycogen stores of the skeletal muscles are not affected by fasting. They only fluctuates when fasting continues for weeks or months. 

Degradation Process

The degradation of glycogen makes the stored glucose available to be used by the cells for obtaining energy. The degradation process uses a separate set of cytosolic enzymes. The major product of glycogen degradation is glucose-1-phosphate released by breaking the alpha 1-4 linkages. In addition, glucose-6-phosphate is also obtained when alpha 1-6 bonds are broken. 

The degradation of glycogen involves the following steps.

Shortening of Chains

The first step in glycogen degradation is the shortening of linear chains. This is carried out by glycogen phosphorylase enzyme. The process begins from the non-reducing end of the chain. Thus, the glucose residue that is last to be added is the first one to be removed. 

The glycogen phosphorylase enzyme cleaves the alpha 1-4 glycosidic linkages in the presence of inorganic phosphate and generates glucose-1-phosphate molecules. This enzyme requires pyridoxal phosphate as a co-enzyme. 

The process of breaking alpha 1-4 linkages continues until only four glucose residues are left in the chain before a branch point. The glycogen phosphorylase enzyme cannot proceed any further. The branching point has be removed for its cation to continue. 

Removal of Branches

This process is carried out by a  debranching enzyme. It is a bifunctional enzyme having two activities. Thus, branches are also removed in two steps;

  • The first step involves the glucantransferase activity of the debranching enzyme. It removes the terminal three out of four glucose residues from the branch and inserts it into a non-reducing end of another chain. Thus, it involves the breaking of an alpha 1-4 glycosidic as well as the making of another one. 
  • The second step involves the alpha 1-6 glucosidase activity of the debranching enzyme. It cleaves the alpha 1-6 glycosidic bond at the branch point and removes the glucose residue in the form of glucose-6-phosphate. 

The new linear chain is available for degradation by the glycogen phosphorylase enzyme until the next branch point is reached. The process continues as long as the entire glycogen molecule is broken down into glucose-1-phosphate and glucose-6-phosphate residues.

Conversion of Glucose-1-phosphate to Glucose-6-phosphate

Recall that the major breakdown product of glycogen is glucose-1-phosphate. It cannot be used in the metabolic process unless it is converted into glucose-6-phosphate. This process is carried out by the phosphoglucomutase enzyme present in the cytosol. This enzyme reposition the phosphate from carbon number 1 to carbon number 6 via a glucose-1,6-bisphosphate intermediate. 

Conversion of Glucose-6-phosphate to Glucose

The glucose-6-phosphate molecules formed in the above reaction can be utilized in various processes within the cell. However, they cannot cross the cell membrane and thus, cannot be released into the blood. 

In the hepatocytes, glucose-6-phosphate molecules are transferred into the endoplasmic reticulum via a translocase enzyme. Here, they are cleaved by glucose-6-phosphatase enzyme to form glucose molecules. These glucose molecules are then released into the blood. 

It should be noted that this process only occurs in the liver. Skeletal muscles lack this enzyme and thus cannot release glucose into the blood. 

Degradation in Lysosome

A small amount of glycogen is also degraded by the lysosomal enzymes in hepatocytes as well as the skeletal muscles. This process is carried out by glucosidase enzyme, a lysosomal enzyme that releases free glucose residues by breaking the alpha 1-4 glycosidic linkages.

Although the importance of this lysosomal degradation is unknown, the absence of this pathway results in one of the several glycogen storage diseases discussed at the end of this article. 

Glycolysis

This is the process of obtaining energy from glucose molecules. The process takes place in the cytosol. It is an oxygen-independent process and can occur in aerobic as well as non-aerobic conditions.  

The process of glycolysis involves ten reactions that can be divided into two phases;

  1. Energy investment phase, energy is used in the form of ATP to make phosphorylated intermediates
  2. Energy generation phase, two molecules of ATP are formed via substrate-level phosphorylation.

A detail of both these phases is discussed below. 

Energy Investment Phase

This phase comprises the first five reactions of glycolysis. Energy is used in this phase in the form of ATP. The reactions occurring during this phase are as follows.

  1. Phosphorylation of Glucose

The first step in glycolysis is the conversion of glucose to glucose-6-phosphate. This process uses energy in the form of ATP. The reaction is catalyzed by hexokinase enzyme. 

Hexokinase causes the phosphorylation of any hexose sugar using ATP as an energy source as well as the source of inorganic phosphate. Hexokinase involves four isoenzyme, three of which have similar properties while the fourth is entirely different. 

The I-III isozymes cause phosphorylation of glucose in most of the tissues. These isozymes have broad substrate specificity and can phosphorylase any hexose even at low concentrations. They have high Km and low Vmax, meaning that they cannot cause phosphorylation of a large concentration of sugars. 

The isozyme hexokinase IV is specific only for glucose. It has a very high Km and high Vmax. It means that this enzyme is activated only at the high concentrations of glucose. However, due to high Vmax, it can cause phosphorylation of a large amount of glucose without becoming saturated.

The phosphorylated form of glucose cannot pass through the cellular membranes. Thus, the significance of this step is that it sequesters a large amount of glucose in the cell. The glucose molecules become trapped in the cytoplasm. 

It is an irreversible and regulated step of glycolysis. 

  1. Isomerization of Glucose

In the second reaction, glucose-6-phosphate is converted to its isomer, fructose-6-phosphate. This reaction is catalyzed by phosphoglucose isomerase enzyme. It is a reversible reaction. 

  1. Phosphorylation of Fructose-6-phosphate

In the third reaction, fructose-6-phosphate is phosphorylated to form fructose-1,6-bisphosphate. Another molecule of ATP is used in this process. The reaction is catalyzed by phosphofructokinase-1 (PFK-1). It is the regulated and the rate-limiting step of glycolysis. It is also the committed step. After this step, the product (fructose-1,6-bisphosphate) can only be processed through glycolysis. It cannot undergo any other process. 

  1. Cleavage of Fructose-1,6-bisphosphate

It is a reversible step and involves the breakdown of fructose-1,6-bisphosphate into two molecules, glyceraldehyde-3-phosphate and dihydroxyacetone phosphate. The enzyme involved in this process is called aldolase. 

  1. Isomerization of Dihydroxyacetone phosphate

Dihydroxyacetone phosphate formed in the previous reaction must be converted into glyceraldehyde-3-phosphate for further processing in glycolysis. This isomerization is a reversible process that is carried out by triose phosphate isomerase enzyme. 

With this step, the energy investment phase of glycolysis ends. 

Energy Generation Phase

The final product of the energy investment phase are the two molecules of glyceraldehyde-3-phosphate. Each of these molecules goes through another series of five reactions to liberate energy. The five reactions of th8is phase are as follows. 

  1. Oxidation of Glyceraldehyde-3-phosphate

It is a reversible reaction during which a molecule of glyceraldehyde-3-phosphate is oxidized by using NAD+ that gets reduced to NADH2. An inorganic phosphate is also incorporated into the glyceraldehyde molecule forming 1,3-bisphosphoglycerate. This reaction is catalyzed by glyceraldehyde-3-phosphate dehydrogenase enzyme. 

  1. Synthesis of 3-Phosphoglycerate

In this reversible reaction, 1,3-bisphosphoglycerate is converted to 3-phosphoglycerate producing a molecule of ATP. The energy released by the high energy phosphate bond in 1,3-bisphosphoglycerate is utilized to phosphorylate ADP to ATP. It is called substrate-level phosphorylation of ATP.

This reaction is catalyzed by phosphoglycerate kinase enzyme. This enzyme functions in a physiologically reverse manner. 

  1. Transfer of Phosphate group

This step involves the transfer of phosphate group from 3rd position to 2nd position, resulting in the formation of 2-phosphoglycerate. The reaction is catalyzed by phosphoglycerate mutase enzyme.  

  1. Dehydration of 2-phosphoglycerate 

In this step, 2-phosphoglycerate is dehydrated to form phosphoenolpyruvate (PEP). The reaction is catalyzed by enolase enzyme. The resulting compound has a high energy enol phosphate which is used to phosphorylate ADP in the next step. 

  1.   Synthesis of Pyruvate

It is an irreversible reaction that involves the conversion of PEP to pyruvate by pyruvate kinase enzyme. It is another regulated step of glycolysis. The energy released during this step is used to phosphorylate ADP to ATP, another substrate-level phosphorylation in glycolysis. 

Products of Glycolysis

The final products of glycolysis are the two molecules of pyruvic acid or pyruvate.  The fate of these pyruvate molecules depends on the oxidation state of the tissue. In the presence of oxygen, pyruvate is processed via the citric acid cycle. However, in anaerobic conditions, pyruvate is converted to lactate via lactate dehydrogenase enzyme. 

Energetics of Glycolysis

Recall that glycolysis is the process of obtaining energy from glucose molecules in the presence or absence of oxygen. Two molecules of ATP are used in the first phase of glycolysis. In return, four ATP molecules are formed in the second phase from one glucose molecules. In addition, two NADH2 molecules are also formed.

So, the net result of glycolysis is two ATP molecules, two NADH2 molecules and two pyruvate molecules from one glucose residue. 

Summary

Glycogen is the glucose storage molecule found in animals only. The glycogen metabolism in the animals includes glycogenesis, glycogenolysis and glycolysis. 

Glycogenesis is the synthesis of glycogen from glucose residues. The following are the important point that should be kept in mind.

  • All the glucose residues in glycogen are provided by UDP-glucose which is made for glucose-1-phosphate and UTP.
  • The chain elongation is carried out by glycogen synthase enzyme that requires a primer, to begin with. 
  • The primer is made on glycogenin protein that forms the core of glycogen granules. 
  • Branches are present after every 8 to 12 residues that are introduced by a special enzyme called branching enzyme.
  • Energy is provided for this process in the form of ATP and UTP.

The glycogen thus formed is broken down to release glucose during fasting by the process of glycogenolysis. It involves the following;

  • Glucose residues are removed from the linear chain by glycogen phosphorylase in the form of glucose-1-phosphate. 
  • The breakdown starts from the non-reducing end of the chain. 
  • The branches are removed by the debranching enzyme.
  • The branch points are removed in the form of glucose-6-phosphate. 
  • Glucose-6-phosphate can be converted to glucose and released into the blood only by the hepatocytes.
  • Degradation also takes place in lysosomes to some extent.

Once the glucose molecules are released into the blood, they are utilized by the cells for obtaining energy. Glycolysis is the process that generates energy by breaking down glucose molecules in the presence or absence of oxygen. The following are some important points regarding glycolysis;

  • One glucose molecule gives two ATP and two NADH2 molecules at the end of glycolysis. 
  • The first five reactions are energy investment phase while the next five are energy generation phase. 
  • One glucose molecule is broken down into two pyruvate molecules. 
  • The further processing of pyruvate depends on the availability of oxygen. 

References

  1. Denise R. Ferrier, Lippincott Illustrated Reviews, Biochemistry, Ed. 6th
  2. Rodwell, Kennelly, Harper’s Illustrated Biochemistry, Ed. 30th
  3. https://en.wikipedia.org/wiki/File:Glycogenesis.png
  4. https://en.wikipedia.org/wiki/File:Glycolysis_metabolic_pathway_3_annotated.svg
  5. https://en.wikipedia.org/wiki/File:Glycogen.svg