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Cellular Biochemistry and Metabolism ( CLS 333 )

Cellular Biochemistry and Metabolism ( CLS 333 ). Dr. Samah Kotb Nasr Eldeen. Glycogen Synthesis. Glycogenesis. Glycogen is synthesized via uridine diphosphate glucose (UDP – glucose). Synthesis: Glycogen n + UDP-glucose → glycogen n+1 + UDP .

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Cellular Biochemistry and Metabolism ( CLS 333 )

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  1. Cellular Biochemistry and Metabolism(CLS 333 ) Dr. Samah Kotb Nasr Eldeen

  2. Glycogen Synthesis

  3. Glycogenesis • Glycogen is synthesized via uridine diphosphate glucose (UDP – glucose). • Synthesis: Glycogen n+ UDP-glucose → glycogenn+1+ UDP. • Degradation: glycogenn+ Pi → Glycogenn-1 + glucose 1-phosphate. Glycogen synthesis and degradation utilize separate pathways.

  4. Luis Leloir Nobel Prize in Chemistry, 1970 “ for his discovery of sugar nucleotides and their role in the biosynthesis of carbohydrates”

  5. Glycogen Synthesis • Glucose units are activated for transfer by formation of sugar nucleotides • Other examples of activation are acetyl-CoA and biotin. • Leloir showed in the 1950s that glycogen synthesis depends on sugar nucleotides. • UDP-glucose pyrophosphorylase • A phosphoanhydride exchange driven by pyrophosphate hydrolysis

  6. Glycogen Synthase • forms α-(1→4) glycosidic bonds in glycogen • Glycogenin (a protein) forms the core of a glycogen particle • Glycogen synthase transfers glucosyl units from UDP-glucose to C-4 hydroxyl • at a non reducing end of a glycogen strand

  7. UDP glucose is the activated form of glucose. Acetyl CoA is the activated form of acetate. AA-tRNA is the activated form of amino acids.

  8. UDP-glucose pyrophosphorylase Glucose 1-phosphate + UTP  UDP-glucose + PPi. ppi + H2O → 2Pi. Glucose 1-phosphate + UTP + H2O → UDP-glucose + 2Pi. Although the reaction is reversible the hydrolysis of the pyrophosphate pushes it to the right.

  9. Glycogen synthase catalyzes α-1,4 linkages A primer of a least 4 units are required via glycogenin. Glucose is added to the non-reducing end. UDP

  10. Control of Glycogen Metabolism • Highly regulated process involving reciprocal control of glycogen • phosphorylase and glycogen synthase • Glycogen phosphorylaseallosterically activated by AMP and inhibited byATP, glucose-6-P • Glycogen synthase is stimulated by glucose-6-P • Both enzymes are regulated by covalent modification - phosphorylation

  11. Regulation of Glycogen Synthase Glycogen synthase is the regulatory enzyme in the synthesis of glycogen. • When the enzyme is phosphorylated, it is inactivated. • Active “a” form to inactive phosphorylated “b” form. • Notice that phosphorylation has the opposite effect on glycogen phosphorylase; phosphorylation activates. The enzyme is regulated by covalent modification and phosphorylation.

  12. Glycogen synthesis Glucose 6-P→ glucose 1-P. glucose 1-P + UTP→UDP-glucose + PPi. PPi+ H2O→ 2 Pi. UDP-glucose + glycogenn→ glycogenn+1. UDP + ATP → UTP + ADP. Glucose 6-P + ATP + glycogenn + H2O → glycogenn+1 + ADP + 2Pi. Only one ATP is used to store one glucose residue in glycogen.

  13. Hormonal Regulation • Glucagon and epinephrine • Glucagon and epinephrine stimulate glycogen breakdown - opposite effect of insulin • Glucagon is also secreted by pancreas • Glucagon acts in liver and adipose tissue only • Epinephrine (adrenaline) is released from adrenal glands • Epinephrine acts on liver and muscles • The phosphorylase cascade amplifies the signal.

  14. epinephrine and glucagon: the difference • Both are glycogenolytic but for differentreasons • Epinephrine is the fight or flight hormone – rapidly mobilizes large amounts ofenergy. • Glucagon is for long-term maintenanceof steady-state levels of glucose in theblood • – activates glycogen breakdown • – activates liver gluconeogenesis

  15. Glycogen synthesis and breakdown are reciprocally regulated Red=inactive forms, green = active forms. Inactive Active Protein phosphatase 1 (PP1) regulates glycogen metabolism.

  16. Protein Phosphatase 1 • PP1 dephosphorylates phosphorylase kinase and phosphorylase a, thus inactivating glycogenolysis. • PP1 also dephosphorylates glycogen synthase b, thus activating glycogen synthesis.

  17. PP1 dephosphorylates phosphorylase kinase and phosphorylase a thus inactivating glycogenolysis.

  18. PP1 dephosphorylates glycogen synthase b thus activating glycogen synthesis

  19. When blood glucose levels are high, insulin activates protein phosphatase 1 which stimulates glycogen synthesis. • This is accomplished through a complex highly regulated signal transduction pathway. • Remember: Glycogen metabolism in liver regulates blood glucose levels.

  20. Blood glucose levels rise after ingestion of carbohydrates, leading to glycogen synthesis. Inactivation of phosphorylase and an activation of glycogen synthase. Liver

  21. Glucogon = starved state; stimulates glycogen breakdown, inhibits glycogen synthesis. • High blood glucose levels = fed state; insulin stimulates glycogen synthesis and inhibits glycogen breakdown.

  22. Insulin is a Peptide Hormone Glycogen synthesis and degradation • Insulin is secreted from the pancreas(to liver) in response to an increase inblood glucose • Insulin stimulates glycogen synthesisand inhibits glycogen breakdown • Note that the portal vein is the only vein in the body that feeds an organ • Note the other effects of insulin

  23. Thank you

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