1. Professor of Biochemistry Glycogen metabolism
Dr.Saidunnisa
Professor of Biochemistry
Glycogen metabolism

2. 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.

3. 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).

4. 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.

5. 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

6. Non reducing ends of glycogen

7. 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)

8. 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.

9. Glycogenolysis
Break down of glycogen to glucose.

10. 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

11. Glycogenolysis
Ratio of:
glucose-1-phosphate to free glucose is 8:1

12. 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

13. 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

14. 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.

15. Molecules left after complete phosphorylase digestion of glycogen are Limit Dextrin's
Non-reducing ends
Reducing end

16. 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.

17. Glycogenesis Synthesis of glycogen from glucose is glycogenesis.
Takes place in muscle and liver cell cytoplasm.
Requires ATP, UTP and glucose.

18. Two major enzymes participate in glycogen synthesis:
Glycogen synthase
and
Branching enzyme

19. Steps in Glycogenesis
Activation of glucose
Glycogen synthase
Branching enzyme

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

21. Mechanism of reaction Activation of glucose (only for understanding)

22. Every glycogen particle has a Glycogenin buried inside

23. 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.

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

25. 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 .

26. GLYCOGENESIS AND GLYCOGENOLYSIS PATHWAY

27. Regulation of Glycogen Metabolism
Allosteric:
Hormonal: Glucagon and epinephrine
Covalent: Phosphorylation and dephosphorylation

28. Allosteric regulation

29. Hormonal Signaling through G-Proteins

30. 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

31. 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.

32. Glycogen storage disease
Type
Enzyme Deficiency
Organ Location
Von Gierke disease 1
Glucose -6 phosphotase
Liver
Mc Ardles V
Glycogen phosphorylase
Muscle

33. 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.