Glycogen Metabolism Notes

Glycogen Metabolism

Learning Objectives

Synthesis of Uridine diphosphate-glucose.
Glycogen synthase.
Glycogenin.
Branching enzyme.
Regulation of glycogen metabolism.
Hormonal Control of Glycogen Metabolism.
Regulation of protein phosphatase 1 in muscle and liver.
Glycogen storage diseases.

Glycogen Synthesis

Glycogen synthesis uses UDP-glucose to extend the glycogen chain.
Glycogen is synthesized and degraded by different pathways.
Glycogen degradation yields glucose 1-phosphate.
Uridine diphosphate-glucose (UDP-glucose) is the glucose donor in glycogen synthesis.

UDP-Glucose

UDP-Glucose is an activated form of Glucose.
UDP-Glucose is synthesized from glucose 1-phosphate and the nucleotide uridine triphosphate (UTP).
The reaction is catalyzed by glucose 1-phosphate uridylyltransferase.
The reaction is subsequently rendered irreversible by the hydrolysis of pyrophosphate.

Glycogen Synthase

Glycogen synthase catalyzes the transfer of glucose from UDP-glucose to a C-4 terminal residue of a growing glycogen chain to form an α-1,4-glycosidic bond.

Glycogenin

The primer is synthesized by glycogenin.
Glycogenin generates an oligosaccharide of at least 8 glucose molecules.
Glycogen synthase then extends this primer.
Glycogen synthase requires an oligosaccharide primer α-1,6 linkage.

Branching Enzyme

A branching enzyme forms alpha-1,6 linkages.
Glycogen synthase can only synthesize α-1,4- linkages.
A branching enzyme generates branches by cleaving an α-1,4-linkage and taking a block of approximately seven glucoses and forming a α-1,6-linkage.
The block must contain the nonreducing terminus and comes from a chain at least 11 residues long.
Glycogen synthase can then extend the branched polymer.
Branching is important for the solubility of Glycogen granules.

Regulation of Glycogen Metabolism

Glycogen synthesis is inhibited by the same cAMP triggered signaling pathways that stimulate glycogen breakdown.
Phosphorylation of glycogen synthase by protein kinase A inhibits glycogen synthesis.
Glycogen synthase kinase also phosphorylates and inhibits glycogen synthase.
Protein phosphatase 1 (PP1) shifts glycogen metabolism from the degradation mode to the synthesis mode.

Regulation of Protein Phosphatase 1 in Muscle

Protein phosphatase 1 consists of a catalytic subunit (PP1) and regulatory subunits (GL in liver and GM in muscle).
In muscle, phosphorylation of GM leads to dissociation of PP1, which decreases the enzyme’s activity.
An inhibitor, when phosphorylated, binds to PP1, resulting in further inhibition.

Insulin and Glycogen Synthesis

Insulin stimulates glycogen synthesis by inactivating glycogen synthase kinase.
PP1 subsequently dephosphorylates glycogen synthase, generating the active a form of the synthase.
Insulin stimulates glycogen synthesis by activating a signal transduction pathway that results in the phosphorylation and inactivation of glycogen synthase kinase.

Glycogen Metabolism in the Liver

Glycogen metabolism in the liver regulates the blood glucose concentration.
Glycogen degradation in the liver is inhibited and glycogen synthesis is stimulated by high blood-glucose levels.

Glucose Regulation of Liver-Glycogen Metabolism

Glucose binds to glycogen phosphorylase a (R-state) and inhibits it (T-state).
T-state glycogen phosphorylase dissociates from PP1, leading to its activation.
Free PP1 dephosphorylates glycogen phosphorylase a and glycogen synthase b, which inactivates glycogen breakdown and activates glycogen synthesis.

Hormonal Control of Glycogen Metabolism

Muscle cell regulation involves epinephrine binding to β-Adrenoreceptors, leading to cAMP production and glycogen degradation, while insulin promotes glycogen synthesis via the GLUT4 glucose transporter.
Liver cell regulation involves glucagon binding to glucagon receptors and epinephrine binding to β-Adrenoreceptors, both leading to cAMP production and glycogen degradation, while insulin promotes glycogen synthesis via the GLUT2 glucose transporter. Calcium ions (Ca2+) also play a role in liver cell regulation.

Glycogen Storage Diseases

Inherited disorders that affect glycogen metabolism (10 different types).
Glycogen is produced abnormally either in quantity or quality.
Studies of the genetic defects have helped to understand the complexity of glycogen metabolism.
Glycogen storage diseases that affect the liver generally produce hepatomegaly (enlarged liver) and hypoglycemia (low blood sugar).
Glycogen storage diseases that affect the muscles result in muscle cramps and weakness.
Both types may cause cardiovascular and renal disturbances.

Type I: von Gierke’s disease

Glucose-6-phosphatase deficiency.
Glucose-6-phosphatase catalyzes the final step leading to the release of glucose into the blood stream by the liver.
Deficiency results in an increase of intracellular G6P and large accumulation of glycogen in liver and kidney.
Inability to increase blood glucose concentration in response to the hormones glucagon and epinephrine.
Severe hepatomegaly and hypoglycemia and failure to thrive.
Treatment involves controlled carbohydrate intake and liver transplantation.

Type II: Pompe’s disease

α-1-4-Glucosidase deficiency.
Most devastating of the glycogen storage diseases.
Large accumulation of glycogen with normal structure in the lysosomes of all cells usually cause death by cardiorespiratory failure before the age of one.
α-1-4-Glucosidase is not involved in the main pathway and provides an alternative pathway by hydrolyzing maltose to glucose in lysosomes.
Physiological relevance unknown.

Type IV: Andersen’s disease

Alpha-(1,4->1,6)-transglycosylase deficiency.
One of the most severe glycogen storage diseases.
Victims rarely survive the age of four years due to liver dysfunction.
Liver glycogen is present in normal concentration, but it contains long unbranched chains with reduced solubility.
Liver dysfunction may be caused by foreign body immune reaction to the abnormal glycogen.

Type V: McArdle’s disease

Muscle phosphorylase deficiency.
Symptoms are painful muscle cramps on exertion.
Symptoms typically do not appear until early adulthood.
Can be prevented by avoiding strenuous exercise.
Condition affects glycogen metabolism in muscle but not in liver, which contains normal amounts of different phosphorylase isoforms.

Overview of Glycogen Storage Diseases (I-VIII)

Type	Defective enzyme	Organ affected	Glycogen in the affected organ	Clinical features
I	Glucose 6-phosphatase	Liver and kidney	Increased amount; normal structure	Massive enlargement of the liver. Failure to thrive. Severe hypoglycemia, ketosis, hyperuricemia, hyperlipemia.
II	α-1,4-Glucosidase (lysosomal)	All organs	Massive increase in amount; normal structure	Cardiorespiratory failure causes death, usually before age 2.
III	α-1,6-glucosidase (debranching enzyme)	Muscle and liver	Increased amount; short outer branches	Like type I, but milder course.
IV	Branching enzyme (α-1,4 -> α-1,6)	Liver and spleen	Normal amount; very long outer branches	Progressive cirrhosis of the liver. Liver failure causes death, usually before age 2.
V	Phosphorylase	Muscle	Moderately increased amount; normal structure	Limited ability to perform strenuous exercise because of painful muscle cramps. Otherwise patient is normal and well developed.
VI	Phosphorylase	Liver	Increased amount	Like type 1, but milder course.
VII	Phosphofructokinase	Muscle	Increased amount; normal structure	Like type V.
VIII	Phosphorylase kinase	Liver	Increased amount; normal structure	Mild liver enlargement. Mild hypoglycemia.

Glycogen Degradation

Learning Objectives

Glycogen phosphorylase.
Glycogen remodelling.
Phosphoglucomutase.
Regulation of glycogen degradation in liver and muscle.
Phosphorylase kinase.
The signalling cascade for glycogen breakdown.
Hormonal control of glycogen breakdown.

Glycogen Degradation Overview

The liver breaks down glycogen and releases glucose to the blood to provide energy for the brain and red blood cells.
Muscle glycogen stores are mobilized to provide energy for muscle contraction.
Glucose units are joined by α-1,4 and α-1,6 glycosidic bonds.

Glycogen Breakdown to Glucose 6-Phosphate

Glycogen is converted to Glucose 1-phosphate by Glycogen phosphorylase.
Glucose 1-phosphate is converted to Glucose 6-phosphate by Phosphoglucomutase.
In the liver, Glucose 6-phosphate is converted to Glucose by Glucose 6-phosphatase.
In muscle, Glucose 6-phosphate enters Glycolysis.

Glycogen Phosphorylase

Glycogen phosphorylase degrades glycogen from the nonreducing ends of the glycogen molecule.
The phosphorylase catalyzes a phosphorolysis reaction that yields glucose 1-phosphate.
Problem: Glycogen phosphorylase cannot cleave near branch points and can only cleave α- 1,4-glycosidic bonds.

Glycogen Remodelling

A transferase shifts a small oligosaccharide near the branch point to a nearby chain, thereby making the glucose moieties accessible to the phosphorylase.
A debranching enzyme (α-1,6- glucosidase) then cleaves the α-1,6 bond at the branch point, releasing a free glucose.

Phosphoglucomutase

Phosphoglucomutase forms glucose 6-phosphate from glucose 1-phosphate with the use of a glucose 1, 6-bisphosphate intermediate.
A phosphoryl group is transferred from the enzyme to the substrate, and a different phosphoryl group is transferred back to restore the enzyme to its initial state.
Glucose 6-phosphatase generates free glucose from glucose 6-phosphate in liver.
The free glucose is released into the blood for use by other tissues such as the brain and red blood cells.

Regulation of Glycogen Degradation

The key regulatory enzyme for glycogen degradation is glycogen phosphorylase (dimer).
Phosphorylase exists in two forms: a less active b form and a more active a form.
The a form differs from the b form in that a serine residue is phosphorylated.

Glycogen Phosphorylase Forms

Both the a form and the b form display R/T equilibrium.
In the b form, the T state is favoured while in the a form, the R state is favoured.
In the T state, the active site is partly blocked by a regulatory structure. The active site is unobstructed in the R state.

Allosteric Regulation of Liver Phosphorylase

A key role of the liver is to maintain adequate blood levels of glucose.
As a result, the default state of liver phosphorylase is the active a form in the R state.
Glucose is a negative regulator of liver phosphorylase, facilitating the transition from the R state to the T state.
The binding of glucose inactivates the enzyme. Thus, glycogen is not mobilized when glucose is already abundant.

Allosteric Regulation of Muscle Phosphorylase

Muscle phosphorylase is regulated by the intracellular energy level.
In muscle, the default form of the phosphorylase is the inactive b form in the T state.
When energy is needed, as signalled by an increase in the concentration of AMP, the phosphorylase binds AMP, which stabilizes the R state.
The T state of the phosphorylase is stabilized by ATP and glucose 6-phosphate.

Epinephrine and Glucagon

Muscular activity, excitement (fear) result in release of epinephrine (adrenaline; a catecholamine) from the adrenal medulla.
Glucagon, a polypeptide hormone, is secreted by the alpha-cells of the pancreas, when blood sugar levels are low.

Signalling Cascade for Glycogen Breakdown

Epinephrine binds to the β adrenergic receptor in muscle.
Glucagon bind to the glucagon receptor in the liver.

Hormonal Control of Glycogen Breakdown

In the liver, low glucose levels during fasting stimulate glucagon release from the pancreas, leading to glycogen breakdown and glucose release into the blood.
In muscle cells, epinephrine released from the adrenal medulla during exercise stimulates glycogen breakdown, providing glucose-6-phosphate for glycolysis, the citric acid cycle, and oxidative phosphorylation. Lactate is also produced.