Class 5 glycogen metabolism
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Glycogen is a highly branched polymer of glucose that serves as a readily mobilized form of energy storage. It is synthesized from glucose through glycogenesis and broken down through glycogenolysis to release glucose-1-phosphate. Glycogen is stored primarily in the liver and muscle cells. Glycogenesis involves the activation of glucose, initiation using glycogenin, elongation by adding glucose units via glycogen synthase, and branching. Glycogenolysis breaks down glycogen through phosphorylation by glycogen phosphorylase and the action of debranching enzyme and phosphoglucomutase. Deficiencies in the enzymes involved in glycogen metabolism can cause glycogen storage diseases.
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Class 5 glycogen metabolism
- 1. Glycogen metabolism What is glycogen ? Glycogenesis Glycogenolysis Glycogen storage disorders
- 2. What is Glycogen • Large, highly branched polymer of glucose • Mainly contain α - 1—4 glycosidic bonds in straight chain and α - 1 –6 glycosidic bonds at branch points • Readily mobilized form of glucose • Broken down when energy is needed.
- 3. Glycogen storage • Animal polysaccharide synthesized when • glucose is excess • Stored in liver and muscle • Liver store more glycogen than muscle , but as muscle mass is greater than liver about ¾ of total • body glycogen is present in muscle. • Extra cellular glycogen is very small
- 4. Why glycogen is stored? • Buffer to maintain blood glucose level • Provide glucose to brain - except in starvation • In muscle required for strenuous activity • Glycogen release glucose which can provide energy in absence of oxygen • Liver glycogen can export glucose and maintain blood glucose level in fasting states
- 5. Glycogenesis • Synthesis of glycogen from glucose • Occurs in muscle and liver • Steps 1. Activation of glucose 2. Initiation 3. Elongation 4. Branching of glycogen
- 6. Activation of GlucoseGlucose Glucose -1-phosphate UDP- Glucose ATP ADP Glucokinase Hexokinase UTP PPi 2Pi UDPG pyro phosphorylase Spontaneous hydrolysis of phosphate bond Provides reaction energy Only energy cost in glycogen synthesis Glucose -6-phosphate Phosphoglucomutase
- 7. Initiation of Glycogenesis • Glucose unit is transferred from UDP-Glucose to glycogen primer called glycogenin • Glycogenin – • dimeric protein, 37kd • Protein-carbohydrate complex • Glycosidic bond is formed between C1 of glucose and hydroxyl group of tyrosine • UDP is released OH O-UDPOH UDP OOH Glycogen synthase Glycogenin Glycogenin + Glucose
- 8. 1 2 Addition of new glucose on non reducing end
- 9. Elongation • New glucosyl units are added to the Non-reducing terminal of glycogen • Active Glucosyl unit UDP-Glucose is transferred to the hydoxyl group of C—4 forming α - 1—4 glycosidic link • Reaction is catalyzed by glycogen synthase • Glycogen synthase is Key regulatory enzyme in glycogen synthesis. OOOOOO GlucoseGlucoseGlucoseGlucose
- 10. Elongation • Addition of new glucosyl unit in straight chain continue till 11- 12 glucose grow in chain • Branching enzyme is required to form the branch • Branching enzyme : Amylo 1—4 -- 1—6 transglucosidase • Branching enzyme transfer 6-8 glucose units on 6th carbon to form α - 1 –6 branch
- 11. OOOOOO Branching is important as more number of glucose units Can be added simultaneously Similarly Glycogen phosphorylation can release more glucose Branching
- 12. 1—4 glycosidic bonds 1—6 glycosidic bonds Glycogen Non reducing ends
- 15. Glycogenolysis • Break down of glycogen • Takes place in Liver and muscle cytosol • Divided in to three phase – 1. Release of G-1-P from glycogen – 2. Remodeling of limit dextrin – 3. Conversion of G-1-P to Glucose -6 – Phosphate • Two major enzymes required • 1. Glycogen phosphorylase • 2. Glycogen debranching enzyme
- 16. Glycogen moleculeNon reducing ends
- 17. (Glycogen ) n (Glycogen ) n—1 Pi Glycogen phosphorylase Glucose -1-P 1—4 glycosidic bonds 1—6 glycosidic bonds Glucose -1-P Action of Glycogen phosphorylase
- 18. Phase 1 Phosphorolysis • Glycogen phosphorylase , A key enzyme in glycogen breakdown • Action: • Phosphorylates glucose on non- reducing end of glycogen branch • Release glucose -1- Phosphate • Limitation: • Enzyme has limitation as it reaches the point 3-4 glucose remained in chain • This forms limit glycogen
- 19. Action of debranching enzyme • Shifts a block of three glucosyl unit from outer branch to other • Exposes α 1—6 linkage • α 1—6 Glucosidase or debranching enzyme hydrolyses α 1—6 bond and releases free glucose
- 20. Action of debranching enzyme • Exposed α 1—6 linkage • α 1—6 Glucosidase or debranching enzyme hydrolyses α 1—6 bond and releases free glucose Free Glucose
- 21. Action of phospho-gluco-mutase enzyme • Free glucose is phosphorylated • Glucose -1-Phosphate is converted to Glucose -6- Phosphate Glucose -1- P Glucose -6- P Phosphoglucomutase Free Glucose Glucokinase
- 22. Energetics of glycogenesis and glycogenolysis • One ATP for incorporating one Glucose 6 p in glycogen • 90% of glycogen molecules are released as G-1-P which is converted to G-6-P without any energy • Glucose released from branch need one ATP to form Glucose -6-P
- 24. Glycogen storage diseases • Group of inherited disorders characterized by deficient mobilization of glycogen or deposition of abnormal type or quantity of glycogen in tissues. • Leads to liver damage or muscle weakness. Some GSD resulting in early death. • Though there are more than 10 type six are classical type
- 25. Glycogen storage diseases Disease type Enzyme defect Tissue involved Clinical manifestations Type I Von Gierke’s disease Glucose 6 phaophatase Autosomal recessive Liver and mucosal cell Glycogen accumulates in liver & renal cell, Hypoglycemia, lipidemia, Ketoacidosis , Fatty liver , early death
- 26. Glycogen storage diseases Disease type Enzyme defect Tissue involved Clinical manifestations Type II Pompe’s disease Lysosomal Acid maltase Autosomal recessive Heart, liver Smooth and skeletal muscle Glycogen accumulates lysosome, muscle hypotonia, death due to heart failure by 2yrs age , Muscle dystrophy
- 27. Glycogen storage diseases Disease type Enzyme defect Tissue involved Clinical manifestations Type III Cori’s disease Limit dextrinosis Debranching enzyme Autosomal recessive Liver , Heart and Muscle Abnormal Glycogen accumulates Hepatomegaly, hypoglycemia, Progressive myopathy, acidosis Survive - adult life
- 28. Glycogen storage diseases Disease type Enzyme defect Tissue involved Clinical manifestations Type IV Andersen’s disease Amylopectin osis Branching enzyme Liver , Abnormal Glycogen deposited, without branch Hepatomegaly, splenogegaly, hypoglycemia, Progressive cirhosis of liver , Survive - < 4 yrs
- 29. Glycogen storage diseases Disease type Enzyme defect Tissue involved Clinical manifestations Type V McArdle’s disease Muscle phosphorylase Autosomal recessive Muscle Poor exercise tolerance, cramps, muscle glycogen abormally high, Blood lactate low
- 30. Glycogen storage diseases Disease type Enzyme defect Tissue involved Clinical manifestations Type VI Her’s disease Liver phosphorylase Liver Glycogen accumulation normal, Splenomegaly, mild hypoglycemia with acidosis ,
- 31. Glycogen storage diseases Disease type Enzyme defect Tissue involved Clinical manifestations Von Gierkes G6P L,H,M Pompe’s AM L,H,M, Cori’s DB L,H,M Andersen’s B L McArdle’s Mplyase M Hwe’s LPlyase L
- 32. Role of Insulin
- 34. Regulation of glycogen Phosphorylase
- 35. In short role of cAMP
- 36. Thank you