Dr.Saidunnisa

Professor of BiochemistryGlycogen metabolism

Case-1

An infant was brought into the emergency room after her parents witnessed severe hypoglycemia that causes lethargy, seizures, and brain damage.

After a thorough work up a GSD is suspected and found liver is loaded with glycogen.

A biopsy of the liver demonstrates a deficiency of enzyme glucose - 6 phosphatase.

A diagnosis of Von- Grieks disease was made.

Case-2

A 30 year old male presents with severe muscle cramps and pain while exercising.

He is found to have muscle glycogen phosphorylase deficiency( Mc Ardles disease).

Objectives

At the end of the session student shall be able to:1. Define glycogenesis and glycogenolysis. 2. Explain the mechanism of glycogenesis and

glycogenolysis. 3. Describe the various mechanisms regulating

glycogenesis and glycogenolysis. 4. Name the enzyme deficiency in Glycogen storage

disorders (von Gierke's disease) (McArdle's disease).5. Apply the above knowledge in explaining why

glycogen storage disease type I (von Gierke's disease) can lead to severe hypoglycemia but type V (McArdle's disease) does not cause hypoglycemia.

Glycogen Structure

Linkages all a; 1->4 chains and 1->6 branches

Branches every 8-12 residues has compact, structure and high number of non-reducing ends

Non reducing ends of glycogen

Most Glycogen is Stored in Liver and Muscle

Liver - 10gm/100gm tissue

Muscle – 1-2gm/100gm (Total quantity of muscle glycogen is more than liver glycogen because of larger muscle mass)

Glycogen plays different roles in liver and muscle Liver supplies

tissues with Glucose from glycogen during fasting.

After food blood glucose increase which causes glycogen deposition in liver.

In muscle, conversion of glycogen to Glucose is important during muscle contraction.

Glycogenolysis

Break down of glycogen to glucose.

Two major enzymes participate in all glycogen degradation: (Glycogenolysis) Break down of glycogen to glucose.

All the enzymes are cytoplasmic

Glycogen phosphorylase and

Glycogen debranching enzyme

Glycogenolysis

Ratio of: glucose-1-phosphate to free glucose is 8:1

Glycogen Debranching is bifunctional Enzyme

The Debranching Enzyme accomplishes this using two different enzyme activities on the same polypeptide,

-1,4 Glucan transferase and

-1,6 Glucosidase

To Complete Glycogen Degradation, Need to Convert Glc-1-P to Useful FormLIVER:

Phosphoglucomutase Glucose-6-Phosphatase

Glc-1-P ------------------------> Glc-6-P --------------> Glucose

To Complete Glycogen Degradation, Need to Convert Glc-1-P to Useful Form

In muscle, glycogen is degraded to provide an immediate energy source. Therefore, Glc-6-P is needed for entry into glycolysis.

Molecules left after complete phosphorylase digestion of glycogen are Limit Dextrin's

Non-reducing ends

Reducing end

Remember!

Liver contains glucose 6-phosphatase.

Muscle does not have this enzyme. WHY?

The liver releases glucose to the blood and liver regulates blood glucose levels.

The muscle retains glucose 6-phosphate to be use for energy.

Glycogenesis

Synthesis of glycogen from glucose is glycogenesis.

Takes place in muscle and liver cell cytoplasm.

Requires ATP, UTP and glucose.

Two major enzymes participate in glycogen synthesis:

Glycogen synthase

and

Branching enzyme

Steps in Glycogenesis

1. Activation of glucose2. Glycogen synthase3. Branching enzyme

Activation of glucose

Glucose-1-P + UTP

UDPG Pyrophosphorylase

UDPG + Pyrophosphate

Mechanism of reactionActivation of glucose (only for understanding)

Every glycogen particle has a Glycogenin buried inside

What is Glycogenin?

Glycogen primer (A small fragment of pre-existing glycogen must act as a primer) is essential to initiate glycogenesis.

Glycogenin is a primer having 7 glucose units accepts glucose from UDPGlu.

Glycogen synthase transfers glucose from UDPG to primer to form 1,4 glycosidic linkages till the chain is lengthened to 12-13 glucose residues.

The branching of glycogen

Branching enzyme will transfers 6-8 glucose units from one chain to another site with formation of branching α-1,6 linkage.

Newly created branch further glucose units are added by α-1,4 linkage by glycogen synthase .

GLYCOGENESIS AND GLYCOGENOLYSIS PATHWAY

Regulation of Glycogen MetabolismAllosteric: Hormonal: Glucagon and epinephrine

Covalent: Phosphorylation and dephosphorylation

Allosteric regulation

Hormonal Signaling through G-Proteins

Glycogen regulation-Covalent modification

In Glycogenolysis: Example:• Glycogen phosphorylase is a rate

limiting enzyme. • It is regulated by Phosphorylation

(active) and dephosphorylation(inactive) mechanism.

• Glucagon and Epinephrine

Glycogenolysis:

In Glycogenesis: Example:• Glycogen synthase is a rate limiting

enzyme. • It is regulated by Phosphorylation

(inactive) and dephosphorylation(active) mechanism.

• Insulin

Regulation by covalent modification (phosphorylation):

The hormones glucagon and epinephrine activate G-protein coupled receptors to trigger cAMP cascades. Both hormones are produced in

response to low blood sugar. Glucagon, which is synthesized by a-

cells of the pancreas, activates cAMP formation in liver.

Epinephrine activates cAMP formation in muscle.

Glycogen storage disease

Disease Type Enzyme Deficiency

Organ Location

Von Gierke disease

1 Glucose -6 phosphotase

Liver

Mc Ardles V Glycogen phosphorylase

Muscle

A Take Home Lesson!

Glucagon = starved state; stimulates glycogen breakdown, inhibits glycogen synthesis.

High blood glucose levels = fed state; insulin stimulates glycogen synthesis and inhibits glycogen breakdown.