Glycogen Metabolism Lecture Notes PDF

Glycogen metabolism Professor Shivananda Nayak Objectives At the end of this topic the student should be able to: Describe the breakdown and the synthesis of glycogen. Explain how the glycogen metabolism is regulated. Describe the biochemical basis, signs symptoms of glycogen storage diseases. an...

Glycogen metabolism Professor Shivananda Nayak Objectives At the end of this topic the student should be able to: Describe the breakdown and the synthesis of glycogen. Explain how the glycogen metabolism is regulated. Describe the biochemical basis, signs symptoms of glycogen storage diseases. and DR S NAYAK 2 Glycogen metabolism     Glycogen is the storage from of glucose in animals Stored in liver (6-8%) and muscle (1-2%) Helps to maintain the blood glucose levels between meals Glycogen stores increase in a well-fed state depleted during fasting  Muscle glycogen serves as a fuel reserve for the supply of ATP during muscle contraction In homopolysaccharide, glucose molecules held together by - 1,4 linkages. Branch with -1, 6 linkage. Glucokinase in liver and hexokinase in muscle which converts glucose to glucose–6 phosphate DR S NAYAK 3 Glycogenesis  Synthesis of glycogen from glucose which occurs in liver and muscle  Storage from in liver and muscle  After the meal excess glucose is converted into glycogen  UDPG is the carrier of glucose  Glucose from UDPG is attached at the nonreducing end of glucose molecules of glycogen primer DR S NAYAK 4 ATP ADP Glucose Phosphoglucomutase Glucose 6-P Glu 1-P Hexokinase Glucokinase UDPG pyrophosphorylase UTP PPi Uridine diphosphate glucose (UDPG) Glycogen synthase Glycogen primer UDP Glycogen (1, 4 glucosyl units) n (1, 4 and 1,6 Branching enzyme Glucosyl units) n (Amylo-1, 4-1,6- transglucosidase) (Glucosyl -4,6 transferase) DR S NAYAK 5 Glycogenesis DR S NAYAK 6  In the absence of glycogen primer, GLYCOGENIN (protein) can accept glucose from UDPG. The initial glucose is attached to the OH group of tyrosine residue of glycogenin. The enzyme glycogen initiator synthase transfers the first molecule of glucose to glycogenin. Later glycogenin itself takes up a few glucose residues to form a fragment of primer  Branching enzyme (Amylo 1,4 –1,6 transglucosidase transfers 6 glucose residues portion from one chain to a neighbouring chain to form a -1,6 – linkage DR S NAYAK 7 Glycogenolysis      Breakdown of glycogen to glucose Occurs in liver and muscle End product of liver glycogenolysis is glucose Muscle glycogenolysis is lactate (strenuous exercise) Muscle and brain does not contain glu-6-phosphatase Phosphorylase Glycogen Pi Glu-1-P Phosphoglucomutase H2O Pi Glu –6-P Glu-6-Phosphatase Glucose DR S NAYAK 8  Phosphorylase phosphorolytically splits -1,4 glucoside bonds from the outermost chains of glycogen until 4 residues remain on either side of – 1.6 branch point [limit dextrin]   1.4 glucan transferase transfers 3 glucose residue portion from one side chain to the other exposing -1,6 branch points  Amylo 1, 6 glucosidase splits the 1,6 linkages  Acid maltase or -1,4-glucosidase (lysosomal enzyme) degrades small quantity of glycogen. The significance of this pathway is not clear v Muscle glycogenolysis Glycogen  Glu-1-P  Glu-6-P   glycolysis  lactate DR S NAYAK 9 Glycogenolysis DR S NAYAK 10 Regulation of glycogenesis and glycogenolysis · The glycogen synthase and phosphorylase exist in active and inactive forms · The dephosphorylated form of glycogen synthase is active · Phosphorylated form of phosphorylase is active The activation of phosphorylase depends on high cAMP level. At the same time high cAMP level inactivates glycogen synthase Glycogen synthase b Phosphorylase a H2O Protein phosphatase Pi Glycogen synthase a Phosphorylase b (Glycogenesis ON) (Glycogenolysis OFF) DR S NAYAK 11 Allosteric regulation In a well fed state Glu–6– P level is high which activates glycogen synthase · On the other hand glu-6-p and ATP allosterically inhibit phosphorylase · Free glucose also act as inhibitor to phosphorylase Glucose –6 –P ATP Liver glucose Muscle AMP _ _ _ + Glycogen Phosphorylase + Ca2+ Glycogen Glu-1-Phosphate Glycogen Synthase + Glucose-6-phosphate DR S NAYAK 12 Adrenaline (Liver and muscle) Glucagon + (Liver only) Adenylate Cyclase Adenylate Cyclase ATP cAMP PPi Protein Kinase Protein Kinase ATP ADP ATP ADP Phosphorylase Phosphorylase Glycogen Glycogen Kinase kinase Synthase (a) synthase (b) Phosphorylase (b) Phosphorylase (a) 2ATP 2ADP Glycogen Glucose-1-P Pi cAMP 51 AMP Glycogenesis ON + Phosphodiesterase Insulin DR S NAYAK 13 GLYCOGEN STORAGE DISEASES Genetic diseases [may be inherited] Deposition of abnormal type or increased quantity of glycogen in the tissues Diseases Type I. Von Gierke’s disease Type II. Pompe’s disease Type III. Limit dextrinosis [Coris disease] TypeIV. Amylo pectinosis or Andersons disease Defect and Features Glucose – 6 – phosphatase [liver] Accumulation of glycogen in liver Hypoglycaemia and ketosis Lysosomal -1, 4 – glucosidase Glycogen accumulates in lysosomes, in all tissues (including muscles) Muscle weakness and diminished muscle tone, enlarged liver and heart Debranching enzyme [amylo -1,6- glucosidase Accumulation of polysaccharide [limit dextrin] liver, heart, & muscle Branching enzyme (glucosyl 4-6 transferase) Accumulation of polysaccharide with few branch points. Cirrhosis of liver DR S NAYAK 14 Muscle glycogen phosphorylase Glycogen accumulates in the muscle Diminished tolerance to exercise Liver glycogen Phosphorylase Liver enlarged Von Gierke’s Disease Type V McArdles disease Type VI. Hers disease 1. Fasting hypoglycemia 2. Lactic acidemia: Glucose is not synthesized from lactate produced in muscle and liver. Lactate level increases and pH decreases 3. Hyperlipidemia: Block in gluconeogenesis leads to mobilisation fat to meet energy requirement. So This increases free plasma FA & ketone bodies. 4. Hyperuricemia: Accumulated glucose -6-p diverted to HMP pathway, leading to increased synthesis of ribose and nucleotides, this enhances metabolism of purine nucleotides and to uric acid later 5. Massive liver enlargement leads to cirrhosis 6. Children fail to grow Given small quantity of food at frequent intervals DR S NAYAK 15 REF: ESSENTIALS OF BIOCHEMISTRY: DR S NAYAK 16