Glycogen metabolism
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GLYCOGEN METABOLISM - PowerPoint PPT Presentation

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GLYCOGEN METABOLISM. Glycogen Structure. Most of the glucose residues in glycogen are linked by a -1,4-glycosidic bonds . Branches at about every tenth residue are created by a -1,6-glycosidic bonds. Glycogen is an important fuel reserve for several reasons.

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Glycogen Structure

  • Most of the glucose residues in glycogen are linked by a-1,4-glycosidic bonds.

  • Branches at about every tenth residue are created by a-1,6-glycosidic bonds.

Glycogen is an important fuel reserve for several reasons

  • Glycogen serves as a buffer to maintain blood-glucose levels

    • Especially important because glucose is virtually the only fuel used by the brain.

    • Is good source of energy for sudden, strenuous activity

  • Unlike fatty acids, it can provide energy in the absence of oxygen

The major sites of glycogen storage

  • The liver (10% by weight)

  • The skeletal muscle (2% by weight)

  • Glycogen is present in the cytosol in the form of granules ranging in diameter from 10 to 40 nm

Glycogen degradation consists of three steps

  • The release of G1-P from glycogen

  • The remodeling of the glycogen substrate to permit further degradation

Glycogen degradation consists of three steps

  • The conversion of G1-P into G6-P.

    • It is the initial substrate for glycolysis

    • it can be processed by the pentose phosphate pathway to yield NADPH and ribose derivatives

    • it can be converted into free glucose for release into the bloodstream.

Glycogen metabolism is regulated by

  • Allosterically:

    • Allosteric responses allow the adjustment of enzyme activity to meet the needs of the cell in which the enzymes are expressed.

  • Hormones stimulate cascades that lead to reversible phosphorylation of the enzymes, which alters their kinetic properties.

    • Regulation by hormones allows glycogen metabolism to adjust to the needs of the entire organism.

Glycogen Breakdown Requires the Interplay of Several Enzymes

  • Four enzyme activities:

    • one to degrade glycogen,

    • two to remodel glycogen so that it remains a substrate for degradation

    • one to convert the product of glycogen breakdown into a form suitable for further metabolism.

GlycogenPhosphorylase:the key enzyme

  • Cleaves its substrate by the addition of orthophosphate (Pi) to yield G1-P (phosphorolysis)

  • Catalyzes the sequential removal of glycosyl residues from the nonreducing ends of the glycogen molecule (the ends with a free 4-OH groups)

  • DG°´ for this reaction is small because a glycosidic bond is replaced by a phosphoryl ester bond that has a nearly equal transfer potential.

  • Phosphorolysis proceeds far in the direction of glycogen breakdown in vivo because the [Pi]/[G6-P] ratio is usually >100, substantially favoring phosphorolysis.

  • The phosphorolytic cleavage of glycogen is energetically advantageous because the released sugar is already phosphorylated

Two Remodeling Enzymes

  • Transferase:

    • Shifts a block of three glycosyl residues from one outer branch to the other

  • a-1,6-glucosidase (debranching enzyme)

    • Hydrolyzes the a-1, 6-glycosidic bond, resulting in the release of a free glucose molecule.

    • Glucose is phosphorylated by hixokinase (glycolysis)

  • This paves the way for further cleavage by phosphorylase.

  • In eukaryotes, the transferase and the a-1,6-glucosidase activities are present in a single polypeptide chain, in a bifunctional enzyme


  • G1-P formed in the phosphorolytic cleavage of glycogen must be converted into G6-P to enter the metabolic mainstream.

  • This enzyme is also used in galactose metabolism






Liver Contains G6-Pase, a Hydrolytic Enzyme Absent from Muscle

  • A major function of the liver is to maintain a near constant level of glucose in the blood.

  • The liver G6-Pase, cleaves the phosphoryl group to form free glucose and orthophosphate.

  • This G6-Pase, is located on the lumenal side of the smooth endoplasmic reticulum membrane


Pyridoxal Phosphate integral group of the Enzyme

The Pi substrate binding site

  • In human beings, liver phosphorylase and muscle phosphorylase are approximately 90% identical in amino acid sequence.

  • The differences result in important shifts in the stability of various forms of the enzyme.

Phosphorylas exists in two states

The T state is less active because the catalytic site is partly blocked.

The R state, catalytic site is more accessible and a binding site for orthophosphate is well organized.

Phosphorylase Is Regulated by:

  • Allosteric Interactions:

    • By several allosteric effectors that signal the energy state of the cell

  • Reversible Phosphorylation:

    • responsive to hormones such as:

      • Insulin

      • Epinephrine

      • Glucagon

  • The glycogen metabolism regulation differs in muscle than in liver because:

    • The muscle uses glucose to produce energy for itself, whereas the liver maintains glucose homeostasis of the organism as a whole



usually active



usually inactive


Phosphorylase kinase

Depending on

cellular conditions

The R and T states of each of the aor b forms are in equilibrium

The equilibrium for phosphorylase a, favors the R-state

The equilibrium for phosphorylase b, favors the T-state

Phosphorylase a differs from b by a phosphoryl group on each subunit

In muscles-Posphorylase b

  • High AMP, binds to a nucleotide-binding site and stabilizes the conformation of phosphorylase bin the R-state.

  • ATP acts as a negative allosteric effector by competing with AMP and so favors the T-state.

  • G6-P also favorsthe T-state of phosphorylase b, an example of feedback inhibition

  • Under most physiological conditions, phosphorylase b is inactive because of the inhibitory effects of ATP and G6-P.

  • In contrast, phosphorylase a is fully active, regardless of the levels of AMP, ATP, and G6-P.

Liver Phosphorylase Produces Glucose for Use by Other Tissues

  • In contrast with the muscle enzyme, liver phosphorylase abut notb exhibits the most responsive T-to-R transition.

  • The binding of glucose shifts the allosteric equilibrium of the aform from the R to the T state, deactivating the enzyme

  • Unlike the enzyme in muscle, the liver phosphorylase is insensitive to regulation by AMP because the liver does not undergo the dramatic changes in energy charge seen in a contracting muscle

  • Phosphorylase kinase in the skeletal muscle: is (abgd)4

  • gis catalytic

  • abd areregultory

  • dis calmodulin

Muscular activity or its anticipation leads to the release of epinephrine (adrenaline),from the adrenal medulla.

Epinephrine markedly stimulates glycogen breakdown in muscle and, to a lesser extent, in the liver.

The liver is more responsive to glucagon, a polypeptide hormone that is secreted by the a cells of the pancreas when the blood-sugar level is low.

Epinephrine and Glucagon Signal the Need for Glycogen Breakdown

  • Epinephrine binds to the b-adrenergic receptor in muscle, whereas glucagon binds to the glucagon receptor in liver.

  • These binding events activate the a subunit of the heteromeric Gs protein.

  • A specific external signal is transmitted into the cell

  • Epinephrine also binds to the 7TM a-adrenergic receptor in the liver, which then activates phospholipase C and, hence, initiates the phosphoinositide cascade

  • The consequent rise in the level of inositol 1,4,5-trisphosphate induces the release of Ca2+ from endoplasmic reticulum stores.

  • Recall that the dsubunit of phosphorylase kinase is the Ca2+ sensor calmodulin.

  • Binding of Ca2+ to calmodulin leads to a partial activation of phosphorylase kinase.

  • Stimulation by both glucagon and epinephrine leads to maximal mobilization of liver glycogen.

Glycogen Is Synthesized and Degraded by Different Pathways

  • glycogen is synthesized by a pathway that utilizes uridine diphosphate glucose (UDP-glucose) rather than G1-P as the activated glucose donor.

UDP-Glucose Is an Activated Form of Glucose

  • UDP-glucose, the glucose donor in the biosynthesis of glycogen, is an activated form of glucose.

  • The C-1 carbon atom of the glucosyl unit of UDP-glucose is activated because its hydroxyl group is esterified to the diphosphate moiety of UDP.

  • UDP-glucose is synthesized fromG1-P and (UTP) in a reaction catalyzed by UDP-glucose pyrophosphorylase.

  • This reaction is readily reversible.

  • Pyrophosphate is rapidly hydrolyzed in vivo to orthophosphate by an inorganic pyrophosphatase.

  • The essentially irreversible hydrolysis of pyrophosphate drives the synthesis of UDP-glucose.

Glycogen Synthase Catalyzes the Transfer of Glucose from UDP-Glucose to a Growing Chain

  • glycogen synthase, is the key regulatory enzyme in glycogen synthesis.

  • Glycogen synthase can add glucosyl residues only if the polysaccharide chain already contains more than four residues.

  • Thus, glycogen synthesis requires a primer.

    • This priming function is carried out by glycogenin, a protein composed of two identical 37-kd subunits, each bearing an oligosaccharide of a-1,4-glucose units.

    • C1 of the first unit of this chain, the reducing end, is covalently attached to the phenolic hydroxyl group of a specific tyrosine in each glycogenin subunit.

How is this chain formed?

  • Each subunit of glycogenin catalyzes the addition of eight glucose units to its partner in the glycogenin dimer.

  • UDP-glucose is the donor in this autoglycosylation.

  • At this point, glycogen synthase takes over to extend the glycogen molecule

A Branching Enzyme Forms a-1,6 Linkages

  • Branching occurs after a number of glucosyl residues are joined in a-1,4 linkage by glycogen synthase.

  • A branch is created by the breaking of an a-1,4 link and the formation of an a-1,6 link.

  • A block of residues, typically 7 in number, is transferred to a more interior site.

  • The block of 7 or so residues must include the nonreducing terminus and come from a chain at least 11 residues long.

  • The new branch point must be at least 4 residues away from a preexisting one.

  • Branching is important because it increases the solubility of glycogen.

  • 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.

Net charge after posphorylation

Glycogen Synthase Is the Key Regulatory Enzyme in Glycogen Synthesis

  • Glycogen synthase is phosphorylated at multiple sites by protein kinase A and several other kinases.

  • The resulting alteration of the charges in the protein lead to its inactivation

  • Phosphorylation has opposite effects on the enzymatic activities of glycogen synthase and phosphorylase

  • Phosphorylation converts the activea form of the synthase into a usually inactiveb form.

  • The phosphorylatedb form requires a high level of the allosteric activatorG6-P for activity

  • The a form is active whether or notG6-P is present

Glycogen Is an Efficient Storage Form of Glucose

  • One ATP is hydrolyzed incorporating glucose 6-phosphate into glycogen









-1 ATP

-1 ATP


The complete oxidation of glucose 6-phosphate yields about 31 molecules of ATP.

Storage consumes slightly more than one molecule of ATP per molecule of glucose 6-phosphate; so the overall efficiency of storage is nearly 97%.

+31 ATP


Glycogen Breakdown and Synthesis Are Reciprocally Regulated

  • By a hormone-triggered cAMP cascade acting through protein kinase A

Protein Phosphatase 1 Reverses the Regulatory Effects of Kinases on Glycogen Metabolism

  • The hydrolysis of phosphorylated serine and threonine residues in proteins is catalyzed by protein phosphatases.

  • Phosphatase 1 (PP1), plays key roles in regulating glycogen metabolism.

Insulin Stimulates Glycogen Synthesis by Activating Protein Phosphatase 1

  • When blood-glucose levels are high, insulinstimulates the synthesis of glycogen by triggering a pathway that activates protein phosphatase 1

Glycogen Metabolism in the Liver Regulates the Blood-Glucose Level

  • After a meal rich in carbohydrates, blood-glucose levels rise, leading to an increase in glycogen synthesis in the liver

  • Insulin is the primary signal for glycogen synthesis

  • The liver senses the concentration of glucose in the blood, (~80 to 120 mg/100ml).

  • The liver takes up or releases glucose accordingly.

  • The amount of liver phosphorylase adecreases rapidly when glucose is infused.

  • After a lag period, the amount of glycogen synthase aincreases, which results in the synthesis of glycogen.

  • Phosphorylase a is the glucose sensor in liver cells.

    • The binding of glucose to phosphorylase ashifts its allosteric equilibrium from the active R form to the inactive T form.

    • This conformational change renders the phosphoryl group on serine 14, a substrate for PP1.

    • It is significant that PP1 binds tightly to phosphorylase a but acts catalytically only when glucose induces the transition to the T form.

    • Recall that the R-T transition of muscle phosphorylase ais unaffected by glucose and is thus unaffected by the rise in blood-glucose levels

  • Phosphorylase b, in contrast with phosphorylase a, does not bind the PP1.

  • Consequently, the conversion of a into b is accompanied by the release of PP1, which is then free to activate glycogen synthase

  • There are about 10 phosphorylase a molecules per molecule of phosphatase.

  • Hence, the activity of glycogen synthase begins to increase only after most of phosphorylase ais converted into b.

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