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8 glycogen metabolism (6)

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  • 1. Glycogen MetabolismGlycogenolysis: catabolism of glycogenGlycogenesis: anabolism or biosynthesis of glycogen•Glycogen represent a stored form of glucose and energy that is quickly mobilized by hormones.• Total glucose in body fluids has an energy content of ~ 40 kcal•Total body glycogen has an energy content of ~ 600 kcal.•Stored in liver (5-6%) by weight and muscle (1-2%) by weight.•Since muscle mass is >> liver mass, quantity of muscle glycogen is greater.•Stored in the cytosol in the form of glycogen granules which contain the enzyme that catalyzed glycogenolysis, glycogenesis, plus regulatory enzymes.
  • 2. Structure of Two Outer Branches of a Glycogen Particle 4 1 4
  • 3. The C-1 aldehyde in the open-chain form of glucose reacts with the C-5 hydroxylgroup to form an intramolecular hemiacetal resulting in a 6-membered pyranosering. Reducing Group 1 Reducing end 1 6 2 δ- 3 δ+ 1 4 5 6 Reducing End: contains a free keto- or aldehyde group in the straight chain representation of the sugar.
  • 4. GlycogenolysisGlycogen phosphorylase: an α-1,4 glycosidic bond linking 2 glucoseresidues by inorganic phosphate removing the terminal glucoseresidues as glucose 1-phosphate. 1 4•Phosphorylase stops when it reaches a residue that is 4 positions away from a branch point.•A glycogen molecule that has been degraded by phosphorylase to the limit caused by the branches is called a phosphorylase-limit dextrin.
  • 5. •α-1,6 glycosidic linkages at the branch points are not degraded by phosphorylase.•When phosphorylase reaches a point 4 residues away from a branch point it stops.
  • 6. Further degradation occurs via the action of debranching enzyme.Debranching enzyme is bifunctional (it catalyzes 2 different reactions).(1) A transferase activity in which a block of 3 glycosyl residues aretransferred from one outer branch to the other.The result is a longer amylose chain with only one glucosyl remainingin α-1,6 glycosidic linkage in the other chain. Debranching Enzyme
  • 7. The remaining α-1,6 linkage is hydrolyzed by the second enzymaticactivity of debranching enzyme, namely its α-1,6-glucosidase activitywherein an α-1,6 glycosidic bond between two residues is hydrolyzed. Debranching Enzyme Debranching Enzyme ***Thus, the sum of the transferase and the glucosidase activities of debranchingenzyme convert a branched structure into a linear one.Net Result: mainly glucose 1-phosphate + some glucose (from the branch points).
  • 8. Phosphoglucomutase: converts glucose 1-phosphate to glucose6-phosphate via shifting a phosphoryl group. The glucose 6-phosphate can then enter the metabolic mainstream.
  • 9. The Fate of Glucose 6-PhosphateTissues which have glucose 6-phosphatasecan generate free glucose.Liver, kidneys, intestineHAVE THE ENZYMEThe resulting free glucose is then transporter muscle liver braininto the bloodstream thereby providing a kidney adiposesupply of glucose where needed. tissue intesineMuscle, brain,adipose tissue,DO NOT HAVE THE ENZYMEThus glucose is effectively trapped within thesecells where it is used as a fuel to generate ATPvia Glycolysis and the Citric Acid Cycle.
  • 10. Regulation of Glycogen PhosphorylaseRegulated by both allosteric effectors and by reversible phosphorylation.In skeletal muscle the phosphorylase exists in 2 interconvertible forms:Phosphorylase a: usually active formPhosphorylase b: usually (but not always) inactive form.
  • 11. Phosphorylase b can be allosterically activated by AMP.ATP and glucose 6-phosphate can prevent this activation.Thus, the b form is usually inactive (because ATP and glucose 6-phosphate are plentiful).The b form is active only when the energy charge of the cell is very low. Allosteric Regulation by (in response to epinephrine regulation phosphorylation in muscle cells) The a form is active regardless of the cell’s energy charge. At rest, most of the enzyme exists in the b form. During exercise, elevated AMP activates the b form.
  • 12. In the liver, allosteric regulation differs in two respects:First, AMP does not activate the liver phosphorylase b.Second, liver phosphorylase a is deactivated by glucose.Thus when blood glucose is sufficiently high to supply othertissues, and glycogen breakdown is not needed, phosphorylase ais inhibited.Glycogen phosphorylase a acts as a glucose sensor in liver,slowing glycogen breakdown when blood glucose is high.
  • 13. Superimposed on this regulation, is the fact that phosphorylase kinase can be regulated by reversible phosphorylation and by Ca2+.Phosphorylase kinase is activated byphosphorylation via protein kinase A (PKA). Activated by phosphorylationPKA is turned on by cAMP.Thus hormones such as glucagon and Inactivated byepinephrine induce the breakdown of dephosphorylation.glycogen in liver and muscle by activatingthe cAMP cascade. Activated by phosphorylationPhosphorylase kinase is also activated byCa2+.The enzyme phosphoprotein phosphatasedephosphorylates and inactivates Inactivated byboth phosphorylase kinase and dephosphorylation.phosphorylase converting them from thea to the b forms.cAMP decreases the activity of thephosphatase.Insulin increases the phosphatase activity.
  • 14. or Glucagon b aThis cascade of reactions results in a tremendous amplification of a hormonalsignal which stimulates liver glycogenolysis in order to increase blood glucose.For example: 10-9 M epinephrine can result in blood glucose concentration of5 mM, for ~ 3 million fold amplification.
  • 15. GlycogenesisGlycogen synthesis occurs in virtually all animal tissues, but is mostprominent in the liver and skeletal muscle.1) The first reaction is catalyzed by hexokinase (or glucokinase in liver): D-Glucose + ATP D-glucose 6-phosphate + ADP2) The second reaction is catalyzed by phosphoglucomutase: Glucose 6 phosphate glucose 1-phosphate
  • 16. 3) UDP-glucose pyrophosphorylase catalyzes the formation ofUDP-glucose which will serve as a glucose donor in subsequentreactions.Thus, UDP glucose can be considered as an activated form of glucose.Glucose 1-phosphate + UTP UDP-glucose + PPi Glucose donor PPi is rapidly hydrolyzed to 2 Pi driving the above reaction to completion.
  • 17. 4) Glycogen synthase catalyzes the transfer of glucose from UDP-glucose to a growing chain. Glucosyl units are added to the non-reducing terminal residue of glycogen (i.e., at the C-4 terminus) to form an α-1,4-glycosidic bond. Nonreducing end 4 1 1 4•The reaction requires at least 4 residues of glucose as a primer.•Thus a tetrasaccharide primer is elongated by one residue.•This process is repeated many times to form a long, unbranched glycogen molecule.
  • 18. 5) Glycogen synthase requires a primer. This priming function is carriedout by glycogenin, a 37 kDa protein to which the first glucose residue isattached.Glycogenin acts as a catalyst for synthesis of the nascent glycogenmolecule by attaching a glucose to the hydroxyl group of a specifictyrosine residue within its structure.Glycogenin then autocatalyzes the addition of up to 8 glucose units inα-1,4 glycosidic linkages with UDP-glucose being the glucose donor.Glycogen synthase then takes over.
  • 19. 6) Branching enzyme forms the α-1,6 linkages that make glycogen abranched polymer.Transfers a terminal fragment, 6-7 glucosyl residues in number, fromthe non-reducing end of a glycogen branch having at least 11 residues,to the C-6 hydroxyl group of a glucose residue of the same or anotherglycogen chain at a more interior point, thereby creating a branch. 1 2 3 4 5 6 7 8 9 10 11 1 6Branching: increases the solubility of glycogen (by increasing the numberof hydroxyl groups); ANDincreases the rate of glycogen synthesis and degradation by creating a largenumber of terminal residues at which the appropriate enzymes can act.
  • 20. Hormonal Control of Glycogenesis The activity of glycogen synthase is regulated by BOTH covalent modification and allosterically.The active a form of glycogen synthaseis converted to the inactive b formby phosphorylation via a variety ofkinases.The synthase is reactivated bydephosphorylation by phosphoprotein Phosphorylationphosphatase. inactivates. ActiveHence the phosphatase accelerates Inactiveglycogen synthesis.Finally, the inactive b form can be Dephosphorylation activates.allosterically activated by glucose6-phosphate.
  • 21. Cooridinated Regulation of Glycogen Synthesis/ Breakdown Low blood glucose: glucagon, insulin, PKA, phosphorylase kinase glycogen phosphorylase glycogen synthase glycogen breakdown, synthesis High blood glucose: insulin, glucagon, phosphoprotein phosphatase phosphorylase kinase Epinephrine has an effect similar to glycogen phosphorylase that of glucagon. glycogen synthase glycogen breakdown, glycogen synthesis
  • 22. Glycogen Storage DiseasesResult from a defect in an enzyme required for either synthesis ordegradation.In general:•affected organs either contain more glycogen or have abnormally structured glycogen;•liver is usually the tissue most affected; heart and muscle can also be affected;•abnormally structured glycogen due to defects in either debranching enzyme or branching enzyme;•depending on the disease type, prognosis varies from poor to easily manageable;•most of the defective enzymes are involved in glycogenolysis.
  • 23. Know types I – V, defective enzyme and effect on glycogen.