7 glycogen metabolism

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  • 1. Glycogen Metabolism
  • 2.  Glycogenesis and glycogenolysis occur in the cytoplasm of cells
  • 3. Glycogenesis &Glycogenolysis Step 2 UDP-glucose pyrophosphorylase Step 3 P~Pi Step 4 Glycogen synthase Branching enzyme
  • 4. Glycogen Structure
  • 5. Activation of Glucose UTPGlucose
  • 6. Activationof Glucose
  • 7.  Glycogen synthase enzyme catalyses the transfer of glucose units of UDPG to a pre–existing glycogen molecule or primer C1 of UDPG forms a glycosidic bond with C4 of a terminal glucose residue of glycogen, liberating UDP When the chain has been lengthened to between 8 and 12 glucose residues, the branching enzyme transfers a part of the 1,4–chain to a neighboring chain to form a 1,6–linkage, thus establishing a branching point in the molecule
  • 8. Glycogen Synthase Enzyme & Branching Enzyme
  • 9. Glycogen primer synthase Glycogenin (Glycogen primer)autocatalysis
  • 10. Glycogen primer Glycogen primer synthase
  • 11. Regulation of Glycogenesis Glycogen synthase is the key enzyme of glycogenesis It is present in two inter-convertible forms:  Synthase D, inactive (Dependent), phosphorylated  It is dependent on the presence of G6P  Synthase I, active (Independent), which is dephosphorylated and independent on the presence of glucose 6–phosphate Synthase I is converted to the inactive synthase D by phosphorylation by protein kinase enzyme, with ATP as phosphate donor The protein kinase only acts in the presence of cAMP
  • 12. Glycogenesis Stimulated after carbohydrate meal, due to increased insulin Glycogen synthase activated allosterically by Glucose–6–phosphate & ATP Inhibited during fasting, due to increased secretion of adrenaline & glucagon Inhibited also by thyroxin
  • 13. cylic AMP) is trained by having 3,5–Cyclic AMP (cAMP ) NH2 ith ester linkages N of the same ribose. None of these N Nd), convertingMP is highly H2 O 5 C 4 H H 1 O H 3 2 H cAMP to P O OHkes it an excellent O O-al.P with Chime.
  • 14. The conversion of ATP to cyclic AMP releases pyrophosphate Adrenaline &/or Glucagon + (P~Pi( 3′,5′-cAMP
  • 15. Insulin Decomposes cAMP Insulin + 3′-
  • 16. Activation of cAMP-dependent protein kinase A (PKA) Glucagon activates its cell-surface receptor This activation is coupled to the activation of a receptor-coupled G–protein (GTP–binding and hydrolyzing protein) G–protein is composed of 3 subunits (, , ) Upon activation the alpha subunit dissociates and binds to and activates adenylate cyclase Adenylate cyclase then converts ATP to cAMP
  • 17.
  • 18. Activation of cAMP-dependent protein kinase A (PKA) PKA is cAMP-dependent protein kinase PKA is composed of 2 catalytic & 2 regulatory subunits The cAMP binds to the regulatory subunits of PKA leading to dissociation of the catalytic subunits, so the catalytic subunits become active The dissociated catalytic subunits phosphorylate numerous substrate using ATP as phosphate donor
  • 19. Activation of Protein kinase A C cAMP C R R C C R R2 Catalytic & 2 Regulatory subunits
  • 20.
  • 21. Structural formulas of four common intracellular Second messengerscAMP cGMP DAG IP3
  • 22. Regulation of Glycogen Synthesis Briefly, glycogen synthase I (active form) when phosphorylated, becomes much less active and requires glucose–6–phosphate to restore its activity PKA also phosphorylates glycogen synthase directly
  • 23. Regulation of Glycogen Synthesis Glycogen synthase is directly phosphorylated by:  Protein kinase A (PKA), which activated by cAMP  Protein kinase C (PKC) or Calmodulin–dependent protein kinase, which activated by Ca2+ ions or DAG DAG is formed by receptor–mediated hydrolysis of membrane phosphatidylinositol disphosphate (PIP2)
  • 24. • Phosphorylation of Glycogen Synthase leads to: 1. Decreased affinity of synthase for UDP–glucose 2. Decreased affinity of synthase for glucose–6– phosphate 3. Increased affinity of synthase for ATP and Pi
  • 25. Glycogenolysis It is the breakdown of glycogen into glucose in liver or into lactic acid in muscles In liver, glycogenolysis maintains the blood glucose level during fasting for less then 18 hours In muscles, glycogenolysis followed by glycolysis supply the contracting muscle with energy during muscular exercise Site: Cytoplasm of cells
  • 26. Glycogen Catabolism (Breakdown)• Glycogen Phosphorylase catalyzes phosphorolytic cleavage of the  (1 4) glycosidic linkages of glycogen, releasing glucose-1-phosphate Glycogen (n) + Pi  glycogen (n-1) + glucose-1-phosphate
  • 27. Glycogenolysis1. Glycogen phosphorylase acts at the 1,4–glycosidic linkages yielding glucose–1–P. It stops when there are only four glucose units away from a branch point2. Glucan transferase transfers a trisaccharide unit from one side to the other, thus exposing the 1,6–linkage (branch point)3. Debranching enzyme acts on the 1,6–linkage to liberate a free glucose residue
  • 28. Glycogenolysis
  • 29. GlycogenolysisPhosphoglucomutase (Absent in Muscles)
  • 30. Regulation of Glycogenolysis Phosphorylase is the key enzyme of glycogenolysis There are 2 types of phosphorylase enzyme  Active form: phosphorylase a, which is phosphorylated, so known as phospho- phosphorylase  Inactive form: phosphorylase b, which is dephosphorylated, so known as dephospho- phosphorylase
  • 31. Regulation of Glycogenolysis Phosphorylase b is converted to phosphorylase a by the enzyme phosphorylase b kinase, with ATP as phosphate donor Phosphorylase b kinase is activated by the enzyme protein kinase which requires cAMP for its activity cAMP is increased by glucagon (in liver) and adrenaline (in liver and muscle)
  • 32. Regulation of Glycogenolysis Glycogen phosphorylase is also regulated by allosteric effectors:  Activation by AMP is seen only in muscle cells under extreme conditions of anoxia and ATP depletion  G6P inhibits glycogen phosphorylase by binding to the AMP allosteric site, to ensure that glycogen is not wasted if the cells have sufficient energy
  • 33. Regulation of Glycogenolysis Activation of glycogen degradation during muscle contraction by calcium Rapid need of ATP increases nerve impulses, leading to membrane depolarization, which promote Ca release from the sarcoplasmic reticulum into the sarcoplasm of muscle cells
  • 34. Regulation of Glycogenolysis Calcium binds to calmodulin (subunit of phosphorylase kinase) So Calcium ions activate phosphorylase kinase even in the absence of the enzyme phosphorylase kinase This allows neuromuscular stimulation by acetylcholine leading to increased glycogenolysis in the absence of receptor stimulation
  • 35. Regulation of Glycogen Phosphorylase
  • 36. Regulation of Glycogen Phosphorylase Glycogen phosphorylase is activated by: • cAMP • AMP, allosterically • Ca2+ • Phospholipase C (PLC) Glycogen phosphorylase is inhibited by: • G–6–P • F–1–P, allosterically
  • 37. Differences Between Liver & Muscle Glycogen Liver Glycogen Muscle Glycogen Tissue Weight 1 – 1.5 Kg 30 Kg Glycogen 100 g 300 g Amount Glycogen 10 % 1% Conc. Blood Glucose & Source Blood Glucose only Gluconeogenesis Hydrolysis Blood Glucose Blood Lactate Product Energy Used by all tissues Used by muscles only produced Maintenance of Blood Source of Energy for Function Glucose muscles only
  • 38. Factors Affecting Liver & Muscle Glycogen Liver Muscle Glycogen Glycogen Diet Increases greatly Less Marked IncreaseFasting Depletion Little effectMuscular Little effect DepletionExercise
  • 39. Hormonal Regulation of Liver & Muscle Glycogen Liver Muscle Glycogen Glycogen Insulin Glycogenesis Glycogenesis Little increase due toGlucocorticoids Gluconeogenesis hyperglycemia Growth Little increase due to Gluconeogenesis Hormone hyperglycemia Thyroxine Glycogenolysis Glycogenolysis Glucagon Glycogenolysis No Effect Adrenaline Glycogenolysis Glycogenolysis
  • 40. Glycogen Storage Diseases (GSD)• Glycogen storage diseases are inborn errors of glycogen metabolism (genetic diseases)• It is characterized by the storage of abnormal amounts of glycogen in the body• There are five different types of these diseases depending on the enzyme missing
  • 41. Glycogen Storage Diseases (GSD)• All people who are born with GSD are unable to properly metabolize or break down glycogen• People with GSD have the ability to use sugar stored as glycogen, but are unable to use the stores to provide the body with energy during fasting or exercise
  • 42. Thanks