Professor of Biochemistry Glycogen metabolism Dr.Saidunnisa Professor of Biochemistry Glycogen 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: Define glycogenesis and glycogenolysis. Explain the mechanism of glycogenesis and glycogenolysis. Describe the various mechanisms regulating glycogenesis and glycogenolysis. Name the enzyme deficiency in Glycogen storage disorders (von Gierke's disease) (McArdle's disease). 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 Form LIVER: 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 Activation of glucose Glycogen synthase Branching enzyme

Activation of glucose UDPG + Pyrophosphate Glucose-1-P + UTP UDPG Pyrophosphorylase UDPG + Pyrophosphate

Mechanism of reaction Activation 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 Metabolism Allosteric: Hormonal: Glucagon and epinephrine Covalent: Phosphorylation and dephosphorylation

Allosteric regulation

Hormonal Signaling through G-Proteins

Glycogen regulation- Covalent modification Glycogenolysis: In Glycogenolysis: Example: Glycogen phosphorylase is a rate limiting enzyme. It is regulated by Phosphorylation (active) and dephosphorylation(inactive) mechanism. Glucagon and Epinephrine 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 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.