METABOLISM OF GLYCOGEN

1. METABOLISM OF GLYCOGEN Dr. S.Chakravarty MD

2. Points to be covered- • Introduction • Biomedical importance • Glycogen Synthesis- Glycogenesis • Regulation of glycogenesis • Glycogen Breakdown- Glycogenolysis • Regulation of glycogenolysis • Reciprocal regulation of Glycogen Metabolism • Glycogen Storage Diseases

3. INTRODUCTION • Glycogen - storage form of glucose - stored in the liver and the skeletal muscles - energy reserve. • A homopolysaccharide - linear chain of  (1→4) linked glucosyl residues with branches joined by  (1→6) linkages.

4. Glycogen in liver (6-8%) is higher than that in the muscles (1-2%). • Liver glycogen - first line of defense against declining blood glucose levels especially between meals.

5. Maintenance of blood glucose during various states

6. Biomedical Importance: • In health, liver glycogen maintain blood glucose level particularly between meals whereas muscle glycogen is a readily available source of glucose in the exercising muscles. • Deficient mobilization and abnormal accumulation of glycogen leads to certain disorders called as GLYCOGEN STORAGE diseases which can lead to muscular weakness and even death in the affected individual.

7. REM-Glucose 6-phosphatase is absent in muscle-so NO contribution to plasma glucose level by muscle glycogen-only locally available glucose 6-P for glycolysis and HMP shunt

8. GLYCOGEN SYNTHESIS(GLYCOGENESIS): • Glycogen - synthesized from glucose. • Site : Liver, • Skeletal Muscles • Subcellular site: cytosol • Steps: 1.Synthesis of UDP-Glucose 2.Synthesis of Primer to initiate Glycogen synthesis 3.Elongation of chain 4.Formation of branches in Glycogen

9. 1. Synthesis of UDP-Glucose Glucose ATP ADP Glucokinase Hexokinase Glucose-6-phosphate Phosphoglucomutase Glucose-1-phosphate UTP PPi UDP-Glucose pyrophosphorylase UDP- Glucose Pyrophosphate - is hydrolyzed to inorganic phosphate by Pyrophosphatase and thus ensures the IRREVERSIBILITY of this reaction.

10. 2.Synthesis of PRIMER to initiate Glycogen synthesis: • Primer is a preexisting  (1→4) glucosyl chain with Glycogenin which will accept the glucosylresidues donated by UDPG. • Normally a fragment of glycogen serves as a primer. • When glycogen stores are depleted, a specific protein known as GLYCOGENIN provides the site at which the primer is built. Tyrosyl-OH + UDPG Tyrosyl-o-glucose + UDP UDPG + glycogen primer UDP + Glycogen (n residue) (n+1residues)

11. 3. Elongation of the chain: UDP Glucose Glycogen synthase + UDP

12. 4. Formation of Branches in Glycogen: • The branch points - created by the action of BRANCHING enzyme. Also called as glucosyl 4:6 transferase OR amylo [14] [1-6]transglucosidase • When the the chain is minimum 11 glucose residues long , branching enzyme removes a block of 6-8 glucosyl units from the non reducing end of the chain and attaches it via an  (1→6) linkage to a glucose residue of the same or other chain. Branching enzyme New branch point created ( (1→6) linkage )

13. Regulation of glycogenesis: • Rate limiting enzyme - GLYCOGEN SYNTHASE • Regulated by- • Allosteric regulation: +ve modifiers- Glucose-6-phosphate • in the liver and muscles. • 2. Covalent modification: By phosphorylation & dephosphorylation • Protein Kinase • Glycogen synthase Glycogen synthase • (Dephosphorylated) (Phosphorylated) • (active)Protein phosphatase(Inactive)

14. Glucagon/Epinephrine Insulin + Adenylate cyclase Phosphodiesterase 5’AMP ATP cAMP Inactive protein kinase Active protein kinase Protein Kinase Glycogen synthase Glycogen synthase (Dephosphorylated) (Phosphorylated) (active)Protein phosphatase(Inactive) + Glycogenesis stimulated Glycogenesis inhibited Hormonal regulation

15. GLYCOGEN BREAKDOWN (GLYCOGENOLYSIS) • The principal enzyme of glycogenolysis - GLYCOGEN PHOSPHORYLASE. Glycogen + Pi Glycogen + Glucose – 1-P ( n residues) (n-1 residues) Phosphorylase • glucosyl 4:4 transferase activity transfers the 3 of the 4 glucosyl units and involves cleaving of an  (1→4)linkage at one site and formation of new  (1→4)bond elsewhere. • The key enzyme for removing branch points is the debranching enzyme -  (1→6) glucosidase activity – free glucose released.

16. Glycogenolysis: + Phosphorylase GlucanTransferase Debranching enzyme (Glucosidase or 1,6 glycosidase) Glucose molecules are removed sequentially by PHOSPHORYLASE until approximately 4 glucose remain on either side of a 16branch point Glucantransferase removes a trisaccharide from one branch to the other. Glucosidase removes the remaining glucose

18. Regulation of Glycogenolysis: • The rate limiting enzyme of glycogenolysis is glycogen phosphorylase which is regulated by- • Allosteric regulation - +ve modifiers- AMP • -ve modifiers- ATP in liver and muscles • Glucose in liver • Glucose-6-phosphate in muscles • 2.Covalent modification-Phosphorylated form is active. • Phosphorylase kinase • Glycogen phosphorylase Glycogen phosphorylase • (dephosphorylated) (phosphorylated) • (inactive) Protein phosphatase(active) • 3.Ca ions- activates phosphorylase kinase

19. Glucagon/Epinephrine Insulin + Adenylate cyclase Phosphodiesterase 5’AMP ATP cAMP Inactive protein kinase Active protein kinase Phosphorylase Kinase Glycogen phosphorylase Glycogen phosphorylase (Dephosphorylated) (Phosphorylated) (Inactive) Protein phosphatase (active) + Glycogenolysis stimulated Hormonal regulation

20. Reciprocal regulation

21. Regulation of Glycogenolysis in muscle:

22. Glucose loading in Sports!! • i.v glucose loading( CARBO-LOADING ) for 1-2 days prior to sports event has been extensively used by athletes to build up stores of glycogen to enhance performance later on during the contest.

23. Glycogen storage diseases Abnormalities in metabolism of glycogen leads to a group of disorders called Glycogen storage diseases. Types- Hepatic (I III,IV,VI,andVIII) Myopathic(V and VII) General features – Hypoglycemia , poor exercise tolerance , lactic acidosis Muscle weakness in myopathic forms Hepatic fibrosis and hepatomegaly(due to accumulation of glycogen in liver)

24. Von-Gierke’s disease • Glucose 6 phosphatase deficiency • Hypoglycemia not responding even to i.v glucagon/epinephrine . • Lactic acidosis – Impairment of gluconeogenesis. • Accumulation of G6P inhibits conversion of lactate to pyruvate. The lactic acid level rises during fasting as glucose falls. In people with GSD I, it may not fall entirely to normal even when normal glucose levels are restored. • Hepatomegaly – progressing to cirrhosis • Hyperuricemia ?? ---- increased glucose 6 P  increased influx into HMP shunt increased Ribose 5P INCREASED DENOVO BIOSYNTHESIS OF Nucleic acids.

25. After a meal, blood glucose enters cells and is stored as glycogen, particularly in the liver. Which of the following is the donor of new glucose molecules in glycogen? • UDP-glucose-1-phosphate • UDP-glucose • UDP-glucose-6-phosphate • Glucose-6-phosphate • Glucose-1-phosphate

26. Thank you