Glycogen metabolism


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Glycogen Metabolism- Detailed description with clinical significance

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Glycogen metabolism

  1. 1. Biochemistry for Medics Biochemistry For Medics 8/12/2012 1
  2. 2. Glycogen is a readily mobilized storageform of glucose.It is a very large, branched polymer ofglucose residues that can be broken down toyield glucose molecules when energy isneeded.Most of the glucose residues in glycogenare linked by α-1,4-glycosidic bonds.Branches at about every tenth residue arecreated by α-1,6-glycosidic bonds. Biochemistry For Medics 8/12/2012 2
  3. 3. Biochemistry For Medics 8/12/2012 3
  4. 4. Glycogen is present in the cytosol in the formof granules ranging in diameter from 10 to 40nm.It has a molecular mass of 10 7 Da and consistsof polysaccharide chains, each containing about13 glucose residues.The chains are either branched or unbranchedand are arranged in 12 concentric layers.The branched chains (each has two branches)are found in the inner layers and the unbranchedchains in the outer layer. (G, Glycogenin, theprimer molecule for glycogen synthesis.) Biochemistry For Medics 8/12/2012 4
  5. 5. The highly branched structure of glycogen provides a large number of sites for glycogenolysis, permitting rapid release of glucose 1-phosphate for muscle activity.Glycogenin Biochemistry For Medics 8/12/2012 5
  6. 6. It is stored mainly in liver andmuscleThe liver content of glycogen isgreater than that of muscle,Since the muscle mass of the body isconsiderably greater than that of theliver, about three-quarters of totalbody glycogen is in muscle Biochemistry For Medics 8/12/2012 6
  7. 7. Percentage of Tissue Weight Body Content Tissue WeightLiver glycogen 1.8 kg 90 g 5.0Muscle 0.7 35 kg 245 gglycogenExtracellular 0.1 10 L 10 gglucose Biochemistry For Medics 8/12/2012 7
  8. 8. Glycogen serves as a buffer to maintainblood-glucose levels.Glucose is virtually the only fuel used by thebrain, except during prolonged starvation.The glucose from glycogen is readilymobilized and is therefore a good source ofenergy for sudden, strenuous activity.Unlike fatty acids, the released glucose canprovide energy in the absence of oxygen andcan thus supply energy for anaerobic activity. Biochemistry For Medics 8/12/2012 8
  9. 9.  Glycogenesis is the synthesis of glycogenfrom glucose. Glycogenesis mainly occurs in muscle andliver. Muscle glycogen provides a readilyavailable source of glucose for glycolysiswithin the muscle itself. Liver glycogen functions to store andexport glucose to maintain blood glucosebetween meals. Biochemistry For Medics 8/12/2012 9
  10. 10. Biochemistry For Medics 8/12/2012 10
  11. 11. oAlanine and lactate transported from muscle are used for glucose production in liver by gluconeogenesis. oGlucose is poured in blood to maintain homeostasis.Biochemistry For Medics 8/12/2012 11
  12. 12. 1) Activation of Glucose2) Initiation3) Elongation4) Glycogen branching Biochemistry For Medics 8/12/2012 12
  13. 13. Synthesis of glycogen from glucose iscarried out by the enzyme glycogensynthase.This enzyme utilizes UDP-glucose as onesubstrate and the non-reducing end ofglycogen as another. UDP-glucose, the glucose donor in thebiosynthesis of glycogen, is an activatedform of glucose. Biochemistry For Medics 8/12/2012 13
  14. 14. UDP-glucose is formed from glucose-1-phosphate:Spontaneous hydrolysis of the ~P bond in PPi(P~P) drives the overall reaction.Cleavage of PPi is the only energy cost forglycogen synthesis (one ~P bond per glucoseresidue). Biochemistry For Medics 8/12/2012 14
  15. 15. As in glycolysis, glucose isphosphorylated to glucose 6-phosphate, catalyzed by hexokinase inmuscle and glucokinase in liver.Glucose 6-phosphate is isomerized toglucose 1-phosphate byPhosphoglucomutase.Glucose 1-phosphate reacts withuridine triphosphate (UTP) to formthe active nucleotide uridinediphosphate glucose (UDPGlc) andpyrophosphate. The reaction iscatalyzed by UDPGlc pyrophosphorylase. Biochemistry For Medics 8/12/2012 15
  16. 16. Glycogen synthase can addglucosyl residues only if thepolysaccharide chain alreadycontains more than fourresidues.Thus, glycogen synthesisrequires a primer.This priming function is carriedout by glycogenin,A protein composed of twoidentical 37-kd subunits, eachbearing an oligosaccharide ofalpha-1,4-glucose units. Biochemistry For Medics 8/12/2012 16
  17. 17. A glycosidic bond is formed between the anomeric C1 of the glucose moiety derived from UDP-glucose and the hydroxyl oxygen of a tyrosine side- chain of Glycogenin. UDP is released as a product.Each subunit of glycogenin catalyzes the addition of eight glucose units to itspartner in the glycogenin dimer. At this point, glycogen synthase takes over toextend the glycogen molecule. Biochemistry For Medics 8/12/2012 17
  18. 18. New glucosyl units are added to the nonreducingterminal residues of glycogen.The activated glucosyl unit of UDP glucose is transferredto the hydroxyl group at a C-4 terminus of glycogen toform an α-1,4-glycosidic linkage.Inelongation, UDP is displaced by the terminal hydroxylgroup of the growing glycogen molecule.This reaction is catalyzed by glycogen synthase, the keyregulatory enzyme in glycogen synthesis. Biochemistry For Medics 8/12/2012 18
  19. 19. Both synthesis & breakdown of glycogen are spontaneous.If both pathways were active simultaneously in a cell, there would bea "futile cycle" with cleavage of one ~P bond per cycle (in formingUDP-glucose).To prevent this both pathways are reciprocallyregulated Glycogen Synthesis UTP UDP + 2 Pi glycogen(n) + glucose-1-P glycogen(n + 1) Glycogen Phosphorylase Pi Biochemistry For Medics 8/12/2012 19
  20. 20. Glycogen synthase catalyzes only the synthesis ofα-1,4 linkages.Another enzyme is required to form the α-1,6linkages that make glycogen a branched polymer.Branching occurs after a number of glucosylresidues are joined in α-1,4 linkage by glycogensynthase.A branch is created by the breaking of an α-1,4 linkand the formation of an α-1,6 link. Biochemistry For Medics 8/12/2012 20
  21. 21. A block of residues, typically 7 in number, istransferred to a more interior site.The branching enzyme that catalyzes thisreaction is quite exacting.The block of 7 or so residues must include thenonreducing terminus and come from a chain atleast 11 residues long.In addition, the new branch point must be atleast 4 residues away from a preexisting one. Biochemistry For Medics 8/12/2012 21
  22. 22. Branching is important because it increases the solubility of glycogen.Furthermore, branching creates a large number of terminal residues,the sites of action of glycogen phosphorylase and synthase. Thus,branching increases the rate of glycogen synthesis and degradation. Biochemistry For Medics 8/12/2012 22
  23. 23. Glycogen degradation consists of threesteps:(1) The release of glucose 1-phosphate from glycogen,(2) The remodeling of the glycogen substrate to permit further degradation, and(3) The conversion of glucose 1-phosphate into glucose 6-phosphate for further metabolism. Biochemistry For Medics 8/12/2012 23
  24. 24. The efficient breakdown of glycogen to provideglucose 6-phosphate for further metabolismrequires four enzyme activities:one to degrade glycogen,two to remodel glycogen so that it remains asubstrate for degradation, and one to convert the product of glycogenbreakdown into a form suitable for furthermetabolism. Biochemistry For Medics 8/12/2012 24
  25. 25. a) Phosphorylase- Glycogen phosphorylase,the key enzyme in glycogen breakdown,cleaves its substrate by the addition oforthophosphate (Pi) to yield glucose 1-phosphate. The cleavage of a bond by theaddition of orthophosphate is referred to asphosphorolysis. Biochemistry For Medics 8/12/2012 25
  26. 26. b) Transferase and Debranching enzyme-The Transferase shifts a block of three glucosylresidues from one outer branch to the other.This transfer exposes a single glucose residuejoined by an α -1,6-glycosidic linkage.α-1,6-Glucosidase, also known as thedebranching enzyme, hydrolyzes the α -1, 6-glycosidic bond, resulting in the release of a freeglucose molecule. Biochemistry For Medics 8/12/2012 26
  27. 27. c) Phosphoglucomutase- Glucose 1-phosphate formed in the phosphoroylyticcleavage of glycogen must be converted intoglucose 6-phosphate to enter the metabolicmainstream. This shift of a phosphoryl groupis catalyzed by Phosphoglucomutase. Biochemistry For Medics 8/12/2012 27
  28. 28. 1) Release of Glucose-1-PPhosphorylase catalyzes the sequentialremoval of glucosyl residues from thenonreducing ends of the glycogen molecule (theends with a free 4-OH group.Orthophosphate splits the glycosidic linkagebetween C-1 of the terminal residue and C-4 ofthe adjacent one. Biochemistry For Medics 8/12/2012 28
  29. 29. The phosphoroylytic cleavage of glycogen isenergetically advantageous because the releasedsugar is already phosphorylated. In contrast, a hydrolytic cleavage would yieldglucose, which would then have to bephosphorylated at the expense of the hydrolysis of amolecule of ATP to enter the glycolytic pathway. An additional advantage of phosphoroylyticcleavage for muscle cells is that glucose 1-phosphate, negatively charged under physiologicalconditions, cannot diffuse out of the cell. Biochemistry For Medics 8/12/2012 29
  30. 30. The α-1,6-glycosidic bonds at the branchpoints are not susceptible to cleavage byphosphorylase.Glycogen phosphorylase stops cleaving α -1,4linkages when it reaches a terminal residue fourresidues away from a branch point.Because about 1 in 10 residues is branched,glycogen degradation by the phosphorylasealone would come to a halt after the release ofsix glucose molecules per branch. Biochemistry For Medics 8/12/2012 30
  31. 31.  Transferase shifts a block of three glycosyl residues from one outer branch to the other. This transfer exposes a single glucose residue joined by an α-1,6- glycosidic linkage. Debranching enzyme, hydrolyzes the α -1, 6- glycosidic bond, resulting in the release of a free glucose molecule.Biochemistry For Medics 8/12/2012 31
  32. 32. Transferase and α-1,6-glucosidase, remodel the glycogenfor continued degradation by the phosphorylase. The free glucose molecule released by the action ofdebranching enzyme is phosphorylated by the glycolyticenzyme hexokinase.Thus, the Transferase and α-1,6-glucosidase convert thebranched structure into a linear one, which paves the way forfurther cleavage by phosphorylase. Biochemistry For Medics 8/12/2012 32
  33. 33. Phosphoglucomutase converts glucose 1- phosphate into glucose 6- phosphate in a reversible reaction. Glucose 6-phosphate derived from glycogen can (1) be used as a fuel for muscle; (2) be converted into free glucose in the liver and subsequently released into the blood; (3) be processed by the pentose phosphate pathway.Biochemistry For Medics 8/12/2012 33
  34. 34. The liver contains a hydrolytic enzyme, glucose 6-phosphatase, which cleaves the phosphoryl groupto form free glucose and orthophosphate.Glucose 6-phosphatase is absent from mostother tissues.Consequently, glucose 6-phosphate is retainedfor the generation of ATP.The liver releases glucose into the blood duringmuscular activity and between meals to be takenup primarily by the brain and skeletal muscle. Biochemistry For Medics 8/12/2012 34
  35. 35. Pyridoxal phosphate (PLP), a derivative ofvitamin B6, serves as prosthetic group forGlycogen Phosphorylase. H O O C O H2 P C OH O O N CH3 H pyridoxal phosphate (PLP) Biochemistry For Medics 8/12/2012 35
  36. 36. Pyridoxal phosphate (PLP)is held at the active site by a EnzSchiff base linkage, formed (CH2)4by reaction of the aldehydeof PLP with the -amino N+group of a lysine residue. O O H2 HC HIn contrast to its role in P C O Oother enzymes, the Ophosphate of PLP is involvedin acid/base catalysis by N H CH3Phosphorylase. Enzyme (Lys)-PLP Schiff base Biochemistry For Medics 8/12/2012 36
  37. 37. Biochemistry For Medics 8/12/2012 37
  38. 38. one ATP is hydrolyzed incorporating glucose 6-phosphate into glycogen.The energy yield from the breakdown of glycogen ishighly efficient. About 90% of the residues are phosphorolyticallycleaved to glucose 1-phosphate, which is convertedat no cost into glucose 6-phosphate.The other 10% are branch residues, which arehydrolytically cleaved.One molecule of ATP is then used to phosphorylateeach of these glucose molecules to glucose 6-phosphate. Biochemistry For Medics 8/12/2012 38
  39. 39. The principal enzymes controlling glycogenmetabolism—glycogen phosphorylase andglycogen synthase—are regulated byallosteric mechanisms and covalentmodifications due to reversiblephosphorylation and dephosphorylation ofenzyme protein in response to hormoneaction Biochemistry For Medics 8/12/2012 39
  40. 40. Glycogen Synthase is allosterically activated byglucose-6-P.Thus Glycogen Synthase is active when highblood glucose leads to elevated intracellularglucose-6-P.Itis useful to a cell to store glucose as glycogenwhen the input to Glycolysis (glucose-6-P), andthe main product of Glycolysis (ATP), are adequate. Biochemistry For Medics 8/12/2012 40
  41. 41. The hormones glucagon and epinephrineactivate G-protein coupled receptors to triggercAMP cascades.Both hormones are produced in response to lowblood sugar.Glucagon, which is synthesized by -cells ofthe pancreas, activates cAMP formation in liver.Muscle cells lack Glucagon receptorsEpinephrine activates cAMP formation in muscle Biochemistry For Medics 8/12/2012 41
  42. 42. Glycogen synthase exists in bothphosphorylated or nonphosphorylated statesActive glycogen synthase a isdephosphorylated and inactive glycogensynthase b is phosphorylatedThe cAMP cascade results in phosphorylation of aserine hydroxyl of Glycogen synthase, whichpromotes transition to the inactive state. Biochemistry For Medics 8/12/2012 42
  43. 43. Phosphorylation ofGlycogen Synthase Glycogen Glucosepromotes the "b" (less Hexokinase or Glucokinaseactive) conformation.The cAMP cascade thus Glucose-6-Paseinhibits glycogen synthesis. Glucose-1-P Glucose-6-P Glucose + Pi Glycolysis Instead of being Pathwayconverted to glycogen,glucose-1-P in liver may be Pyruvateconverted to glucose-6-P,and dephosphorylated for Glucose metabolism in liver.release to the blood. Biochemistry For Medics 8/12/2012 43
  44. 44. Insulin, produced in response to high blood glucose,triggers a separate signal cascade that leads toactivation of Phosphoprotein Phosphatase.Thisphosphatase catalyzes removal of regulatoryphosphate residues from Glycogen Synthase enzyme.Thus insulin antagonizes effects of the cAMP cascadeinduced by glucagon & epinephrine.cAMP is hydrolyzed by phosphodiesterase, soterminating hormone action; in liver insulin increasesthe activity of phosphodiesterase. Biochemistry For Medics 8/12/2012 44
  45. 45. Glycogen Synthase and Glycogen Phosphorylaseare reciprocally regulated, by allosteric effectorsand by phosphorylation.The control of phosphorylase differs betweenliver & muscleIn the liver the role of glycogen is to provide freeglucose for export to maintain the bloodconcentration of glucose; In muscle the role of glycogen is to provide asource of glucose 6-phosphate for glycolysis inresponse to the need for ATP for musclecontraction. Biochemistry For Medics 8/12/2012 45
  46. 46.  Glycogen Phosphorylase in muscle is subject toallosteric regulation by AMP, ATP, and glucose-6-phosphate.A separate isozyme of Phosphorylase expressed inliver is less sensitive to these allosteric controls.AMP (present significantly when ATP is depleted)activates Phosphorylase, promoting the relaxedconformation.ATP & glucose-6-phosphate, which both have bindingsites that overlap that of AMP, inhibit PhosphorylaseThus glycogen breakdown is inhibited when ATP andglucose-6-phosphate are plentiful. Biochemistry For Medics 8/12/2012 46
  47. 47. The cAMP cascade results in phosphorylation of a serinehydroxyl of Glycogen Phosphorylase, which promotestransition to the active state.The phosphorylated enzyme is less sensitive to allostericinhibitors.Thus,even if cellular ATP & glucose-6-phosphate are high,Phosphorylase will be active.The glucose-1-phosphate produced from glycogen in livermay be converted to free glucose for release to the blood.With this hormone-activated regulation, the needs of theorganism take precedence over needs of the cell. Biochemistry For Medics 8/12/2012 47
  48. 48. The enzyme phosphorylase is activated byphosphorylation catalyzed by phosphorylasekinase (to yield phosphorylase a) andInactivated by dephosphorylation catalyzedby phosphoprotein phosphatase (to yieldphosphorylase b), in response to hormonaland other signals. Biochemistry For Medics 8/12/2012 48
  49. 49. Hormone (epinephrine or glucagon) via G Protein (G -GTP)Adenylate cyclase Adenylate cyclase(inactive) (active) catalysis ATP cyclic AMP + PPi Activation Phosphodiesterase AMP Protein kinase A Protein kinase A (inactive) (active) ATP ADP Phosphorylase kinase Phosphorylase kinase (P) (b-inactive) (a-active) Phosphatase ATP Pi ADP Phosphorylase Phosphorylase (P) (b-allosteric) (a-active) Phosphatase Biochemistry For Medics Pi 8/12/2012 49
  50. 50. Increasing the concentration of cAMP activates cAMP-dependent protein kinase, which catalyzes thephosphorylation by ATP of inactive phosphorylase kinase bto active phosphorylase kinase a, which in turn,phosphorylates phosphorylase b to phosphorylase a.In the liver, cAMP is formed in response to glucagon,which is secreted in response to falling blood glucose;muscle is insensitive to glucagon.In muscle, the signal for increased cAMP formation is theaction of norepinephrine, which is secreted in response tofear or fright, when there is a need for increasedglycogenolysis to permit rapid muscle activity. Biochemistry For Medics 8/12/2012 50
  51. 51. Ca++ also regulates glycogen breakdown inmuscle.During activation of contraction in skeletalmuscle, Ca++ is released from the sarcoplasmicreticulum to promote actin/myosin interactions.The released Ca++ also activates PhosphorylaseKinase, which in muscle includes calmodulin as its subunit.Phosphorylase Kinase is partly activated bybinding of Ca++ to this subunit. Biochemistry For Medics 8/12/2012 51
  52. 52. Muscle phosphorylase kinase, which activates glycogenphosphorylase, is a tetramer of four different subunits-α, β ,Υ andδ.The α and β subunits contain serine residues that arephosphorylated by cAMP-dependent protein kinase. The δ subunitis identical to the Ca2+-binding protein calmodulin.The binding of Ca2+ activates the catalytic site of the subunit evenwhile the enzyme is in the dephosphorylated b state; thephosphorylated a form is only fully activated in the presence ofCa2+. Phosphorylase Kinase inactive Phosphorylase Kinase-Ca++ partly active P-Phosphorylase Kinase-Ca++ fully active Biochemistry For Medics 8/12/2012 52
  53. 53. Both phosphorylase a and phosphorylase kinase aare dephosphorylated and inactivated by proteinphosphatase-1.Protein phosphatase-1 is inhibited by a protein,inhibitor-1, which is active only after it has beenphosphorylated by cAMP-dependent protein kinase.Thus, cAMP controls both the activation andinactivation of phosphorylase.Insulin reinforces this effect by inhibiting theactivation of phosphorylase b.It does this indirectly by increasing uptake ofglucose, leading to increased formation of glucose6-phosphate, which is an inhibitor of phosphorylasekinase. Biochemistry For Medics 8/12/2012 53
  54. 54. Glycogen Synthase & Phosphorylase activity arereciprocally regulatedAt the same time as phosphorylase is activated by arise in concentration of cAMP (via phosphorylasekinase), glycogen synthase is converted to theinactive form;both effects are mediated via cAMP-dependentprotein kinase .Thus, inhibition of glycogenolysis enhances netglycogenesis, and inhibition of glycogenesisenhances net glycogenolysis Biochemistry For Medics 8/12/2012 54
  55. 55. Glycogen Storage Diseases"Glycogen storage disease" is a generic termto describe a group of inherited disorderscharacterized by deposition of an abnormaltype or quantity of glycogen in tissues, orfailure to mobilize glycogen. Biochemistry For Medics 8/12/2012 55
  56. 56. Symptoms in addition to excess glycogenstorage:When a genetic defect affects mainly anisoform of an enzyme expressed in liver, acommon symptom is hypoglycemia, relating toimpaired mobilization of glucose for release tothe blood during fasting.When the defect is in muscle tissue, weakness& difficulty with exercise result from inability toincrease glucose entry into Glycolysis duringexercise.Additional symptoms depend on theparticular enzyme that isBiochemistry For Medics 8/12/2012 deficient. 56
  57. 57. Name Enzyme Clinical FeaturesType Deficiency — Glycogen Hypoglycemia;0 synthase hyperketonemia; early death Von Gierkes Glucose 6- Glycogen disease phosphatase accumulation in liver and renalI tubule cells; hypoglycemia; lactic acidemia; ketosis; hyperlipemia Pompe’s Disease Lysosomal 14 Accumulation of and 16 glycogen in glucosidaseFor Medics 8/12/2012 Biochemistry (acid lysosomes: 57
  58. 58. Type Name Biochemical Clinical Features defectIII Limit dextrinosis, Debranching Fasting Forbes or Coris enzyme hypoglycemia; disease hepatomegaly in infancy; accumulation of characteristic branched polysaccharideIV Amylopectinosis, Branching Hepatosplenome Andersens enzyme galy; disease accumulation of polysaccharide with few branch points; death from heart or liver failure in Biochemistry For Medics 8/12/2012 58 first year of life
  59. 59. Type Name Biochemical defect Clinical FeaturesV Myophosphorylase Muscle Poor exercise deficiency, phosphorylase tolerance; muscle McArdles glycogen syndrome abnormally high (2.5–4%); blood lactate very low after exerciseVI Hers disease Liver Hepatomegaly; phosphorylase accumulation of glycogen in liver; mild hypoglycemia; generally good prognosis Biochemistry For Medics 8/12/2012 59
  60. 60. Type Name Biochemical defect Clinical FeaturesVII Taruis disease Muscle and Poor exercise erythrocyte tolerance; muscle phosphofructokina glycogen se 1 abnormally high (2.5–4%); blood lactate very low after exercise; also hemolytic anemiaVIII Liver Hepatomegaly; phosphorylase accumulation of kinase glycogen in liver; mild hypoglycemia; generally good prognosis Biochemistry For Medics 8/12/2012 60
  61. 61. Type Name Biochemical defect Clinical FeaturesIX Liver and muscle Hepatomegaly; phosphorylase accumulation of kinase glycogen in liver and muscle; mild hypoglycemia; generally good prognosisX cAMP-dependent Hepatomegaly; protein kinase A accumulation of glycogen in liver Biochemistry For Medics 8/12/2012 61
  62. 62. Glycogen represents the principal storage form ofcarbohydrate in the body, mainly in the liver and muscle.Glycogen is synthesized from glucose by the pathway ofglycogenesis.It is broken down by a separate pathway, glycogenolysis.Glycogenolysis leads to glucose formation in liver andlactate formation in muscle owing to the respectivepresence or absence of glucose 6-phosphatase.Cyclic AMP integrates the regulation of glycogenolysisand glycogenesis by promoting the simultaneousactivation of phosphorylase and inhibition of glycogensynthase.Insulin acts reciprocally by inhibiting glycogenolysis andstimulating glycogenesis.Inherited deficiencies in specific enzymes of glycogenmetabolism in both liver and muscle are the causes ofglycogen storage diseases. Biochemistry For Medics 8/12/2012 62