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Glycogen Metabolism

Glycogen Metabolism. ASSOC. PROF. DR. CEMİLE KOCA ANKARA ATATÜRK TRAINING AND RESEARCH HOSPITAL. Blood glucose can be obtained from three primary sources: T he diet Gluconeogenesis D egradation of glycogen. Glycogenesis and Glycogenolysis.

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Glycogen Metabolism

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  1. GlycogenMetabolism ASSOC. PROF. DR.CEMİLE KOCA ANKARA ATATÜRK TRAINING AND RESEARCH HOSPITAL

  2. Blood glucose can be obtained from three primary sources: • The diet • Gluconeogenesis • Degradation of glycogen

  3. Glycogenesis and Glycogenolysis • Glycogenesis – formation of glycogen when glucose supplies exceed cellular need for ATP synthesis • Glycogenolysis – breakdown of glycogen in response to low blood glucose Figure 24.12

  4. Glycogen a highlybranched polymerof D-glucose • Chainshave glycosidiclinks • a(14) linkages • a(16) linked branches every 8-14 residues Up to 50,000 or so residues total • Highlybranched which leads to : • More soluble • Increase rate of degradation • Increase rate of synthesis

  5. Structure of Glycogen

  6. Glycogen is the readily mobilized andmajor storage of glucose in animals • Glycogen is principally stored in the cytosol granules of - • Liver • Muscle Glycogen is present in virtually every cell in the body but it is especially abundant in liver and skeletal muscle

  7. In liver : 10% of the fresh weight in the well-fed adult liver (100g) After 12-18 hrs of fasting almost depleted In skeletal muscle : 1-2 % of fresh weight of resting muscle ( 400 g) Depleted after prolonged vigorous exercise Moderately decreased by prolonged fasting (weeks) Stores of Glycogen

  8. Liver glycogen stores are partially depleted, even during short fasts

  9. Glycogen Function • In liver – The synthesis and breakdown of glycogen is regulated to maintain blood glucose levels • In muscle - The synthesis and breakdown of glycogen is regulated to meet the energy requirements of the muscle cell • In humans, total energy stored in glycogen – 900 kcal • total energy in fats – 141 000 kcal

  10. Glycogen Is Synthesized and Degraded by Different Pathways • Glycogen breakdown and synthesis are reciprocally regulated

  11. Glycogen Synthesis Glucose units are activated for transfer by formation of sugar nucleotides

  12. cytosol Glycogenesis It requiresATP&UTP Building blocks: UDP-GLUCOSE Glycogen Synthesis starts with the activation of glucose-1-P to UDP-glucose Initiation of synthesis 1. Elongation of pre-existing glycogen fragment OR 2. The use of a protein glycogen primer (glycogenin)

  13. Glycogenesis: formation of glycogen • 1. formation of new glycogen particleor • 2. enlargement of existing glycogen particle UDP-glucose pyrophosphorylase Glycogen synthase (ELONGATION) (for a1-4 linkages) Branching enzyme (BRANCHING) [amylo-(1-4 1-6) transglycosylase] amylo-α(1→4) → α(1→6)-transglucosidase (for a1-6 linkages) and Glycogeninare required for the formation of glycogen

  14. Glycogen Synthesis

  15. 1. Formation of Glucose-6-Phosphate • D-Glucose + ATP  D-Glucose-6-phosphate + ADP • a) glucokinase(hexokinase IV in liver) or • b) hexokinase (in muscle) 2. Formation of Glucose-1-Phosphate D-Glucose-6-phosphate is isomerized by • phosphoglucomutase • glucose-6-phosphate  glucose-1-phosphate

  16. UDP-Glucose UTP activates glucose-1-P to form UDP-glucose and pyrophosphate (PPi) UDP glucose is the activated form of glucose Like Acetyl CoA is the activated form of acetate

  17. Formation of UDP-glucose UDP-glucosepyrophosphorylase Although the reaction is reversible acts like irreversible because pyrophosphate is removed by inorganic pyrophosphatase as soon as it was generated

  18. Every glycogen particle has a glycogenin (a protein) buried inside

  19. Glycogenin serves as primer for synthesis of new glycogen particles • Glycogenin (a protein) forms the core of a glycogen particle • First C-1 of the glucosyl moietyof UDP-glucose is linked to a tyrosine -OH

  20. After glucosylated Tyr residue formation ; The C-1 of another UDP-glucose molecule is now attacked by the C-4 hydroxyl group of the terminal glucose this sequence repeats to form a nascent glycogen molecule of eight glucose residues attached by (1→4) glycosidic linkages.

  21. Glycogen Synthesis • Glycogen synthase can enlarge existing glycogen particles • But it cannot synthesize new glycogen particle • it need nonreducing ends from existing glycogen as primer GlycogenSynthase enzymethenadds to the nonreducing end

  22. Enlargement of existing glycogen particleGlycogen synthase catalyzes α-1,4 linkages A primer of at least 4 units are required via glycogenin Glycogen synthase transfers glucosyl units from UDP-glucose to C-4 hydroxyl at a nonreducing end of a glycogen strand

  23. Glycogen synthase enzyme • Glycogen synthase is the keyregulatory enzyme in the glycogen synthesis • The enzyme is regulated by covalent modification; phosphorylation

  24. Branching enzyme forms α-1,6 linkages:Remodeling The enzyme breaks the α-1,4 link and forms a α-1,6 link A large number of terminal residues are now available for glycogen phosphorylase; degradation Branching increases the solubility of glycogenandthe rate of glycogen synthesis and degradation

  25. Btranching enzyme amylo-α(1→4) → α(1→6)-transglucosidase

  26. Branching by glycogen-branching enzyme • Once 11 residues are built up, 6-7 are transferred to a branchGlycogen-branching enzyme transfer of a terminal fragment of 6 or 7 glucose redisues from the nonreducing end of a glycogen branch having at least 11 residues to the C-6 hydroxyl group of a glucose residue at a more interior position of the same or another glycogen chain

  27. Mature Glycogen • Built around glycogenin core • Multiple non-reducing ends accessible to glycogen phosphorylase

  28. Glycogen Degradation

  29. GlycogenolysisGlycogenolysis Is Not the Reverse of Glycogenesis, But Is a Separate Pathway break down of glycogen to glucose • consists of threesteps: • the release of glucose 1-phosphate from glycogen • the remodeling of the glycogen substrate to permitfurther degradation • the conversion of glucose 1-phosphate into glucose 6-phosphate for further metabolism

  30. Glucose 6-phosphate has 3 fates

  31. Glycogen Degradation • Glycogen Phosphorylase • Hydrolyzes glucose units from glycogen • Produces glucose-1-P Glycogen + Pi <-> glycogen + G1P (n residues) (n-1 residues) • Glycogen debranching • Debranching enzyme complex • Glucan transferase • Alpha-1,6-glucosidase Shortening of chains Removal of branches

  32. Shortening of chains Glycogen Phosphorylase catalyzes the rate-limiting step in glycogenolysis Requires Pyridoxal-5’-phosphate(PLP) as coenzyme cleaves the α(1→4) glycosidic bonds between the glucosyl residues at the nonreducing ends Use Pi to form glucose-1-phosphate ( glucose-6-P) simple phosphorolysis until four glucosyl units awayfroma branch point (structure is limit dextrin)

  33. Molecules left after complete phosphorylase digestion of glycogen areLimit Dextrins Non-reducing ends Reducing end

  34. Removal of branches • First, oligoα(1→4)→α(1→4)-glucan transferase removes the outer three of the four glucosyl residues attached at a branch. • It next transfers them to the nonreducing end of another chain, lengthening it accordingly • Thus, an α(1→4) bond is broken and an α(1→4) bond is made, and the enzyme functions as a 4:4 transferase Next, the remaining single glucose residue attached in an α(1→6) linkage is removed hydrolytically by amylo-α(1→6)-glucosidaseactivity, releasing free glucose

  35. Removal of branches • debranching enzyme • Debranching enzyme transfer the  as whole from the branch to the main chain, then it will use its (a16) glucosidase activity to hydrolyze the  from glycogen for glycogen phosphorylase

  36. Conversion of glucose 1-phosphate to glucose 6-phosphate • Finally, phophoglucomutase converts glucose-1-phosphate to glucose-6-phosphate that can then enter glycolysis (muscle) • In liver (and kidney), the glucose-6-phosphate is converted to glucose by glucose-6-phosphatase for release to the blood

  37. Glucose 6-phosphatase • Glucose 6-phosphatase converted T1 transported G-6-P to glucose and Pi • Then glucose and Pi are transported to cytosol by T2 and T3, and glucose leave the hepatocyte by GLUT2 transporter

  38. Regulation of Glycogen Synthesis and Degradation

  39. Regulation of Glycogen Synthesis and Degradation Synthesis & degradation of glycogen are tightly regulated on two levels: • glycogen synthase and glycogen phosphorylase are allosterically controlled • the pathways of glycogen synthesis and degradation are hormonally regulated

  40. In the liver: • glycogen synthesis accelerates during periods when the body has been well fed • glycogen degradation accelerates during periods of fasting InSkeletalMuscles: • Glycogendegradationoccursduringactiveexercise • Glycogensynthesisbeginswhenthemuscle is at rest

  41. Allosteric regulation of glycogen synthesis and degradation I: In the well-fed state, glycogen synthase is allosterically activated by glucose 6-phosphate when it is present in elevated concentrations • In contrast, glycogen phosphorylaseis allosterically inhibited by glucose 6-phosphate, as well as by ATP, a high-energy signal in the cell • In liver, glucose serves as the key allosteric inhibitor of glycogen phosphorylase

  42. Regulation of Glycogen Metabolism in muscle1. Allosteric Regulation

  43. Allosteric regulation of glycogen synthesis and degradation • II. Activation of glycogen degradation in muscle by calcium: • During muscle contraction, there is a rapid and urgent need for energy in the form of ATP • energy is supplied by degradation and metabolism of the muscle's store of glycogen • 1. Increase of calcium during muscle contraction • 2. Formation of Ca2+ -calmodulin complex • 3. Activation of Ca2+ -dependent enzymes, • e.g., glycogen phosphorylase

  44. Allosteric regulation of glycogen synthesis and degradation III: Activation of glycogen degradation in muscle by AMP: Muscle glycogen phosphorylase is active in the presence of the high AMP concentrations that occur in the muscle under extreme conditions of anoxia and ATP depletion AMP binds to the inactive form of glycogen phosphorylase, causing its activation without phosphorylation

  45. Hormonal control-Reverse Regulation of Phosphorylase and Synthase • Glycogen synthase (a and b form) • Glycogen phosphorylase (a and b form) • Protein Kinases (PKA,PKC..) • Phosphorylase kinase (a and b form) • Protein Phosphatases (PP1) • cAMP • G proteins • Insulin,glucagon, and epinephrine • The same kinase phosphorylates both phosphorylase and synthase

  46. Reciprocal Regulation • Glucagon and Insulin • Triggered by blood glucose levels • Glucagon acts like epinephrine (via cAMP) to promote glycogen breakdown, and it inhibits glycolysis while stimulating gluconeogenesis and glucose release (liver) • Insulin promotes glucose uptake and storage/consumption Insulin-stimulated processes . Glucagon-stimulated processes

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