10-10-11 Glycogen Metabolism

1. 10-10-11 Glycogen Metabolism • Glycogen metabolism is carefully regulated so that sufficient glucose is available for the body’s energy needs. • Insulin, glucagon and epinephrine control glycogenesis and glycogenolysis.

3. Glycogen Breakdown • Glycogen phosphorylase removes glucose units from the nonreducing end until four are left approaching a branch point. The glucose is produced as glucose-1-P. • G-1-P is isomerized to G-6-P. • Note: this saves one ATP molecule when glucose from glycogen goes through glycolysis! A net of three ATP are produced. • When the four glucose units next to a branch remain, another enzyme is needed.

4. The phosphorylase reaction

6. Glycogen Breakdown • When four glucose units remain, two additional enzymes are required • Transferase removes three (“limit branch”) of the four units and transfers them to the end of another chain. • The glucose 1,6 bond is cleaved by a-1,6-glucosidase. Glucose is the product, not phosphorylated glucose.

7. Transferase and a-1,6-glucosidase are required for the complete breakdown of glycogen

9. The phosphoglucomutase reaction Liver contains glucose-6-phosphatase (also used for gluconeogenesis)

10. Regulation of glycogen breakdown Glycogen phosphorylase is regulated by: 1. Allosteric interactions – signal the energy state of the cell 2. Reversible phosphorylation – in response to hormones such as insulin, glucagon, epinephrine 3. Regulation differs in muscle and liver

11. Muscle phosphorylase is regulated by the intracellular energy charge Muscle phosphorylase exists in two forms: 1. phosphorylase a (usually active) 2. phosphorylase b(usually inactive) phosphorylase b exists primarily in the inactive T state, active only when bound to AMP which stabilizes the active R state 3. ATP inhibits stimulation by AMP by competing for AMP binding; thus energy charge regulates muscle phosphorylase b

13. active inactive Inactive muscle phosphorylase bis converted to active phosphorylase aby hormone- regulated phosphorylation

14. Liver phosphorylase produces glucose for use by other tissues when blood glucose is low Liver phosphorylase ais inhibited by glucose

16. Phosphorylase kinase converts inactive phosphorylase b to active phosphorylase a Phosphorylase kinase is activated by calcium ions and phosphorylation; responsive to hormonally regulated Protein Kinase A (phosphorylation) and muscle contraction (calcium) Protein Kinase A phosphorylates phosphorylase kinase which phosphorylates phosphorylase activating glycogen breakdown.

18. Epinephrine and glucagon signal the need for glycogen breakdown Hormonal signals activate G-proteins that initiate glycogen breakdown Epinephrine primarily targets muscle (anticipated or actual muscle activity) Glucagon primarily targets liver (low blood sugar)

20. The regulatory cascade for glycogen breakdown

21. Glycogen Synthesis • Synthesis of glycogen, the storage form of glucose, occurs after a meal • Requires a set of three reactions (1 and 2 are preparatory and 3 is for chain elongation): • 1. Synthesis of glucose-1-phosphate • (G-1-P) from glucose-6-phosphate by phosphoglucomutase • 2. Synthesis of UDP-glucose from G-1-P by UDP-glucose phosphorylase

22. Glycogenesis – synthesis of G-1-P Phosphogluco- mutase • Final product via 1,6-bisphosphate hexokinase ATP, Mg2+

23. Glycogenesis – synthesis of UDP-G • Pyrophosphate hydrolyzes UDP glucose- phosphorylase UDP-G

24. Glycogen Synthesis • 3. Synthesis of Glycogen from UDP- glucose requires two enzymes: • i. Glycogen synthase grows chain • ii. Branching enzyme (amylo- a(1,41,6)-glucosyl transferase) creates a(1,6) linkages for branches

26. Increase breakdown Decrease synthesis Coordinate control of glycogen metabolism

27. Speeding glycogen synthesis

28. Slowing glycogen synthesis

29. Insulin stimulates glycogen synthesis by activating glycogen synthase kinase Glycogen synthase kinase maintains glycogen synthase in its inactive phosphorylated form

30. Insulin induces glycogen synthesis

34. Hexokinase = tissues nonallosteric vs [glucose] (with respect to glucose) high glucose affinity inhibited by G6P Glucokinase = liver “allosteric” vs [glucose] (with respect to glucose) low glucose affinity not inhibited by G6P Therefore, glucokinase activity increases rapidly at high [glucose] = ~6mM, liver takes up glucose At low [glucose], liver does not compete, tissues take up glucose in proportion to their needs The liver acts as a blood glucose buffer

36. Glycogen metabolism in the liver regulates blood-glucose levels Two signals stimulate glycogen synthesis: 1. insulin 2. high blood glucose concentrations Liver phosphorylase a is the glucose sensor inliver cells