Glycogen Synthesis and degradation, significance, regulation, and disorders.

Glycogen is a storage polysaccharide with glucose as its monomeric unit. It is a highly-branched storage form of glucose that can be rapidly utilized as a quick source of energy when required.

Glycogen Structure

• Contains a core protein, glycogenin.
• Main chain, made of glucose molecules connected to each other by ɑ-1,4-glycosidic bonds.
• Branches made of glucose molecules connected to the main chain by  ɑ-1,6-glycosidic bonds separated by 8-12 glycosyl units. Branching allows for rapid addition and removal of glucose (synthesis and degradation).
• The main chain consists of a reducing end, where the anomeric carbon is not linked to another glycosyl residue and is attached to the core protein glycogenin by a covalent bond to its tyrosine residue (-OH).

Glycogen structure with core protein - glycogenin.

Bonds between glucose unit. Main chain: ɑ-1,4-glycosidic bonds. Branches: ɑ-1,6-glycosidic bonds.

Glycogen storage

Glycogen is stored in glycogen granules in the cytoplasm of liver cells and muscle cells mostly. Muscle uses its glycogen as a source for ATP synthesis during strenuous exercise for muscle contraction. On the other hand, liver glycogen is used to maintain adequate blood glucose levels during early stages of fasting. Note that liver glycogen cannot maintain blood glucose levels for more than 24 hours.  

Glycogenesis

Synthesis of glycogen occurs in a well-fed state. This is when we would expect liver glycogen to increase. Glycogen is synthesized from glucose molecules, specifically ɑ-D-glucose and requires ATP.

Glycogen Synthesis: Initiation

A pre-existing glycogen molecule or the protein “glycogenin” serves as the primer. Glycogenin is self-glucosylating, attaches glucose from UDP-glucose (Uridine diphosphate glucose) to its tyrosine residue. This then serves as a template for glycogen synthase. In fact, the glucose of UDP-glucose is the source of all glucosyl residues used in glycogen synthesis.

How do we form UDP-glucose?

Glucose 6-phosphate is the precursor of glycolysis, the pentose phosphate pathway, and pathways for the synthesis of other sugars.  In the pathway for glycogen synthesis, glucose 6- phosphate is converted to glucose 1-phosphate by phosphoglucomutase, a reversible reaction.

• UDP glucose is synthesized from glucose 1-P and UTP by UDP-glucose pyrophosphorylase.
• PPi (pyrophosphate) is also produced.
• PPi → 2 Pi by pyrophosphatase This drives both reactions in the forward direction
• The high-energy phosphate bond found in UTP provides the energy for the formation of the bond in UDP-G.

Formation of UDP-Glucose.

Glycogen Synthesis: Elongation

Glycogen Synthesis with glycogen synthase enzyme.

After glycogenin creates glycogen’s template, elongation takes place by glycogen synthase, which utilizes glucose from UDP-glucose and adds glucose units to the non-reducing ends of the chain. It can only form ɑ-1,4-glycosidic bonds which is why it can only elongate the chain, but cannot create branches. The branches (ɑ-1,6-glycosidic bonds) are created by a branching enzyme, amylo-(1,4→1,6)--transglycosylase. It transfers about 7 glucosyl residues from the non-reducing end to a branch at an adjacent branch point.

• Note that the UDP from UDP-glucose, after glucose is added to the glycogen chain, is converted back to UTP by nucleoside diphosphate kinase. UTP is then reutilized in the conversion of Glucose 1-phosphate to UDP-glucose.

Glycogen Synthesis: glycogen synthase vs. branching enzyme.

Glycogen Degradation

The degradation of glycogen occurs quickly, as enzymes can act on the non-reducing ends of many branches at the same time. Two enzymes are involved, glycogen phosphorylase and a debranching enzyme.

Function of Glycogen Debranching enzyme.

The degradation of glycogen is mediated by a phosphorylase enzyme, glycogen phosphorylase, which breaks the bonds between glucose molecules using a phosphate ion as a nucleophile. It acts on the glucose molecules of the chain itself and the branches.The phosphate is added to the anomeric carbon of a glycosyl residue, releasing it (glucose-1-phosphate) from the chain. Note that glycogen phosphorylase cannot act on the first 4 glucose units from a branch point, as their structure doesn’t allow for a fit in the catalytic site of the enzyme. This is where the debrancher enzyme comes into play. It has two functions, it acts as a transferase which removes three glucose units and attaches them by an ɑ-1,4-glycosidic bond to the main chain. Its second function allows for the release of the last glucose unit at the branch point due to its amylo-1,6-glucosidase activity.

Regulation of Glycogen Metabolism in the Liver and Muscle

Liver glycogen stores are regulated by insulin/glucagon ratios and blood glucose levels because liver glycogen principally serves the blood’s glucose levels.

• When fasting, high glucagon and low insulin promote an increase in glycogen degradation and decrease in glycogen synthesis
• After a carbohydrate meal, low glucagon, high insulin, and high glucose in the blood as well as low cAMP in the tissue promotes an increase in glycogen synthesis and decrease in glycogen degradation.
• During exercise and stress high epinephrine in the blood,l and high tissue cAMP, AMP and Ca+2 promotes an increase in glycogen degradation and decrease in glycogen synthesis

Skeletal muscle glycogen is used for the synthesis of ATP, which is why its levels rely heavily on AMP concentrations and Ca+2.

• During exercise, high AMP levels in the tissue, high blood epinephrine, and high Ca+2-calmodulin in the tissue alongside high cAMP promote increased glycogen degradation and decrease glycogen synthesis.

• Note that all of these factors affect the enzymes glycogen synthase (synthesis) and glycogen phosphorylase (degradation)

Inborn errors of glycogen metabolism

These are termed glycogen storage diseases which result from deficiencies in the enzymes involved in glycogen synthesis.

Resources

Related Articles

• Glycogen
• Glycogen metabolism

Literature

• Abali. Lippincott Illustrated Reviews: Biochemistry. Wolters Kluwer, 2021.
• Lieberman, Michael, and Alisa Peet. Marks’ Essentials of Medical Biochemistry: A Clinical Approach. Wolters Kluwer, 2015.