Glycogenolysis and Glycogen storage diseases

1. Introduction

• Glycogen is the storage form of glucose.
• The degradation of stored glycogen in the liver and muscles to form glucose is called as glycogenolysis.
• All the required enzymes for the process are present in cytosol.
• Glycogen is a polysaccharide which is composed of many monomeric units of glucose held together by α-1,4- and α-1,6-glycosidic bonds as shown in the following figure. Hence, it is degraded by breaking these two bonds.

2. Steps in Glycogenolysis

The process basically includes 3 steps as follows:

Step 1: Action of glycogen phosphorylase

The enzyme glycogen phosphorylase breaks α-1,4- glycosidic bond until 4 glucose residues remain on either side of branching point. The formed product is called limit dextrin.

Step 2: Action of debranching enzymes

The enzyme glycosyl transferase removes fragment of glucose residues attached at a branch and transfer them to another chain. Then, another enzyme amylo-glucosidase breaks the α-1,6- bond.

Step 3: Formation of glucose 6-phosphate and glucose

Glucose 1-phosphate is produced by action of glycogen phosphorylase. Glucose 1-phosphate gets then gets converted into Glucose 6-phosphate by phosphoglucomutase. Then, glucose 6-phosphatase cleaves it into glucose.

3. Importance of Glycogen

• As such, fat is fuel reserve of the body.
• However, utilization of glycogen is preferred because:
• It can be rapidly metabolized.
• It can generate energy even in the absence of O_2.
• The brain depends upon glucose only for energy.

4. Glycogen storage diseases

• The metabolic defects concerned with the glycogen synthesis and degradation are called as glycogen storage diseases.
• The cause of these diseases is the defect in the enzymes involved in the synthesis or metabolism of glycogen.
• These diseases may either be generalized (affecting all the tissues of the body) or tissue-specific (affecting a particular organ or a tissue).
• A summary of all these disorders has been represented in the following table.

Type	Enzyme affected	Organ affected	Characteristic features
Type I (von Gierke’s)	Glucose 6-phosphatase	Liver, kidney	Glycogen accumulates in hepatocytes and renal cell è Enlarged liver, kidney failure
Type II (Pompe’s)	Lysosomal glucosidase (Debranching enzyme)	Skeletal and cardiac muscles	Glycogen accumulates in lysosomes in almost all the tissues (especially heart and liver) è death at an early age
Type III (Cori’s or Forbes’s)	Debranching enzyme	Liver, skeletal and cardiac muscle	Branched chain glycogen accumulates; Enlarged liver in infants
Type IV (Andersen’s)	Branching enzyme (Glucosyl 4-6 transferase)	Liver, skeletal muscle	Glycogen with only few branches accumulates; Enlarged liver and spleen
Type V (McArdle’s)	Muscle phosphorylase	Skeletal muscle	Muscle glycogen stores very high; not available during exercise; patients cannot perform strenuous exercise è suffer from muscle cramps
Type VI (Hers’s)	Liver phosphorylase	Liver	Liver glycogen cannot form glucose; Enlarged liver
Type VII (Tarui’s)	Phosphofructo-kinase	Skeletal muscles, erythrocytes	Muscle cramps due to exercise; hemolysis