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Glycogen Metabolism

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Phosphorylase is regulated by allosteric interactions and ... Glycogen breakdown and synthesis are reciprocally regulated. Glycogen synthesis: glycogenesis ... – PowerPoint PPT presentation

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Title: Glycogen Metabolism


1
Glycogen Metabolism
  • OUTLINE
  • Glycogen breakdownrequires the interplay of
    several enzymes
  • Phosphorylase is regulated by allosteric
    interactions and reversible phosphorylation
  • Epinephrine and glucagon signal the need for
    glycogen breakdown
  • Glycogen is synthesized and degraded by different
    pathways
  • Glycogen breakdown and synthesis are reciprocally
    regulated
  • Glycogen synthesis glycogenesis
  • Degradation of glycogen glycogenolysis.

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Glycogen
  • Glycogen is a highly branched, very large polymer
    of glyc mols linked ? 1? 4
  • Branches arise by ? 1? 6 at about every 8-10th
    residue
  • It is found in the cytosol.
  • It is the storage form of Glc.
  • Liver and muscle are the major sites for the
    storage of glycogen.

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Degradation of Glycogen
  • Is not a simple reversal of the synthetic pathway
  • Other enzymes involved
  • Glycogen ? G-1-P
  • Shortening of chains
  • Glycogen phosphorylase (?-1 ? 4)
  • It is an exoglucosidase
  • Degrades the gly. Chains at their non-reducing
    ends until four glucosyl units remain on each
    chain before the branch point
  • The resulting structure ? a limit dextrin
  • Phosphorylase cannot grade this any further!

9
Degradation of Glycogen Continued
  • Removal of branches
  • Branches are removed through two enzymatic
    activities of the debranching enzyme
  • a. Glucosyl 44 transferase removes the outer 3
    of 4 glucosyl residues
  • b. Single glucose residue attached in an ? 1?6
    cinkage is then removed by the ?-amylo (16)
    glucosidase activity of the debranching enzyme,
    releasing free glucose

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Glycogen degradation
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Regulation phosphorylase
  • Regulation of glycogen metabolism is different in
    muscle and liver.
  • In muscle the end served by glycolysis is ATP
    production, and the rate of glycolysis increases
    as muscle works more, demanding more ATP.
  • The liver has a different role in whole-body
    metabolism and glucose metabolism in the liver is
    different. The liver makes sure that glucose
    level is constant in the blood. Producing and
    exporting Glc.

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Regulation of Glycogen Breakdown
  • Glycogen represents the most immediately
    available large-scale source of metabolic energy.
    Therefore it is important that animals be able
    to activate glycogen mobilization very rapidly.
  • Glycogen breakdown is the hormone-controlled
    process.
  • Structure of glycogen phosphorylase
  • Dimer exists in two forms.
  • Active phosphorylase a
  • Inactive phosphorylase b
  • Activation ? by phosphorylase kinase
  • Deactivation ? phosphorylase phosphatase
  • Control of phosphorylase activity
  • Phosphorylase kinase is activated by c-AMP
    protein kinase

17
Muscle phosphorylase
  • In muscle, phosphorylase has 2 forms.
  • Phosphorylase a active form
  • Phosphorylase b inactive form (in especially
    resting muscle)
  • The rate of glycogen breakdown is due to the a/b
    which is controlled by hormones especially by
    epinephrine.
  • Phosphorylase a 2 subunits, in each Ser residue
    at position 14 is Plated (Phosphorylase kinase
    does this).
  • Phosphorylase b structurally identical except
    that Ser residues are not Plated. It is active
    when AMP is high! It is inactive when ATP and Glc
    6-P are high!So, muscle phosphorylase b is active
    only when the energy charge of the muscle is low.
  • Resting muscle all enzyme is its ianctive form.
  • Phosphorylase a--------gt phosphorylase b by
    dephosphorylation catalyzed by phosphorylase a
    phosphatase.

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Phosphorylase b
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Muscle phosphorylase
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Control of Glycogen Phosphorylase in Muscle
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Muscle phosphorylase regulation
  • Both phosphorylase b and phosphorylase a exist as
    equilibria between an active R state and a less
    active T state. Phosphorylase b is usually
    inactive because the equilibrium favors the T
    state. Phosphorylase a is usually active because
    the equilibrium favors the R state. Regulatory
    structures are shown in blue and green.

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AMP dependency of phosphorylase b
  • Phosphorylase a is AMP-independent
  • Phosphorylase b is AMP-dependent.
  • The stimulation of phosphorylase b by AMP can be
    prevented by high ATP concentrations. AMP binds
    its allosteric site and stabilizes the
    conformation of phosphyrylase b in the R state
    (figure 21.11). ATP acts as a negative allosteric
    modulator by competing with AMP and so favors the
    T state.
  • Intensive exercise---------gt AMP/ATP (?)
    Phosphorylase b (active)
  • In resting muscle------gt AMP/ATP (?)
    Phosphorylase b (inactive)
  • Exercise will also result in hormone release
    (epinephrine) that generates the phosphorylated a
    form of the enzyme.

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Liver phosphorylase
  • Liver phosphorylase and muscle phosphorylase are
    90 identical in amino acid sequence.
  • Liver phosphorylase a but not b has the most
    responsive T-to-R transition.
  • The binding of Glc shifts the allosteric
    equilibrium of the a form from the R to the T
    state, deactivating the enzyme (Figure 21.12).
  • Why would Glc function as a negative regulator of
    liver phosphorylase a?
  • When there is plenty of Glc, no need to breakdown
    liver glycogen!

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Liver Glycogen phosphorylase is regulated by
hormones and blood glucose.
  • Liver glycogen has a different role in our
    system, it is the reservoir which releases
    glucose whenever it is needed
  • When blood glucose is low (lower than 4-5 mM)
  • Glycogen --------gt Glc-1-P---------gt
    Glc-6-P-------------gt Glc
  • So, when blood glucose low, glucose is released
    into the blood stream and carried to the needy
    tissues.
  • Glycogen phosphorylase of liver is under hormonal
    control, glucagon is the hormone.
  • When glucose is low------------------gt glucagon
    is released.
  • Liver phosphorylase is allosterically regulated
    by Glc not AMP.
  • When Glc is high in blood, it enters hepatocytes,
    binds regulatory sites of the enzyme, causing
    conformational changes (favoring the T state).
    Therefore glycogen phosphorylase is a glucose
    sensor. When Glc is high, it stops its own
    FORMATION., efficiency..

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Phosphorylase kinase is activated by
phosphorylation and calcium ions
  • Phosphorylation of phosphorylase enzyme is done
    by phosphorylase kinase enzyme. This enzyme also
    is found in two forms 1) fully active and 2)
    inactive form.
  • 1200 kd
  • 4 subunits (abgd)
  • g catalytic activity, the other subunits are
    regulatory subunits.
  • It is under dual control, it is regulated by
    phosphorylation (b subunit is phosphorylated by
    cAMP dependent PKA).
  • Phosphorylase kinase can also be partly activated
    by calcium levels of the order of 1 mM. Its d
    subunit is calmodulin, a calsium sensor that
    stimulates many enzymes.
  • Phosphorylase kinase has the highest activity
    only after both phosphorylation of the b subunit
    and activation of the d subunit by Ca binding.

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Epi and Glucagon signal the need for glycogen
breakdown
  • PKA---gt activates phosphorylase kinase
  • Glycogen phosphorylase activated
  • Glc 1-P is made
  • What activates PKA then?
  • HORMONES
  • Glucagon
  • Epinephrine
  • Signal transduction
  • Epi
  • GTP-bound G proteins
  • Increased cAMP
  • PKA increases
  • cAMP amplifies the effects of hormones

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What shuts off glycogen breakdown?
  • This signal transduction pathway is shut down by
    the same pathway.
  • How?
  • GTP is deactivated by its inherent GTPase
    activity
  • cAMP is converted to AMP (not a second messenger)
    by phosphodiesterase enzyme.

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Steps in Glycogen Synthesis
  • UDPG synthesis
  • G-6-P
  • G-1-P UTP ? UDPG PPi
  • A primer is required for glycogen synthesis
  • If there is glycogen ? it serves as primer
  • If not, a specific protein glycogenin
  • Elongation of glycogen chains
  • UDP-G transfer ? to the non reducing end of the
    growing chain.
  • New glycosidic bond
  • C-1 and C-4
  • Enzyme glycogen synthase
  • If no other enzyme acted on the chain ? ? 1-4,
    amylose

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Steps in Glycogen Synthesis Continued
  • UDP is released
  • UDP ATP ? UTP ADP
  • Creating branches in glycogen
  • Amylose ? unbranched
  • Glygogen ? branches (8)
  • - the branching enzyme (glucosyl 46
    transferase)
  • - amylo ? 1, 4 - ? 1,6 transglycosylase)
  • This enzyme transfers 5-8 from the non-reducing
    ends to another residue by ? 1,6 link.
  • Further elongation
  • Branches have two important functions
  • - increase solutions of glycogen.
  • - increase number of non-reducing ends
  • - therefore increase the rate of glycogen
    synthesis

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Initiation of Glycogenesis By Glycogenin
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Elongation
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Branching
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Summary of the synthesis
  • UDP-Glucose synthesis UDP-glucose phosphorylase
  • A primer is required for glycogen synthesis
    (glycogenin or a fragment of glycogen)
  • Glc units are added to the either the existing
    glycogen chains or glycogenin (enzyme glycogen
    synthase).
  • C-4 is the nonreducing end of glycogen chaain,
    new glucose molecules are always added to this
    nonreducing terminus.
  • Elongation of glucose chains
  • Creating branches in glycogen (enzyme
    transferase)
  • Branches have 2 functions
  • 1. An increase in solubility of glycogen molecule
  • 2. Increase the rate of glycogen synthesis

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How Is Glycogen Synthesis Regulated?
  • Glucagon and Epi promote glycogenolysis, at the
    same time they inhibit glycogen synthesis.
  • Both effects are mediated by cAMP and cAMP
    dependent protein kinase.
  • Regulated enzyme glycogen synthase
  • PKA and other kinases phosphorylate the enzyme.
  • Plated form is inactive (b).
  • Protein kinase (Ser phosphorylated)
  • a form active (no phosphorylation)
  • b form inactive (phosphorylated)
  • Steps after the binding of the hormones
  • Epi ? liver cell recep.
  • Adenylate cyclase activity
  • cAMP
  • cAMP ? Pkinase which phosphorylates and
    inactivates glycogen synthase

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Coordinate Control of Glycogen Breakdown and
Synthesis by cAMP Cascades
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Breakdown and synthesis are reciprocally regulated
  • Hormone -triggered cAMP cascade acting through
    PKA
  • Glycogen breakdown and synthesis are
    reciprocally regulated.
  • A. Glycogen degradation
  • B. Glycogen synthesis
  • Inactive forms are shown in red, active forms are
    shown in green.
  • Phosphorylase kinase also inactivates glycogen
    synthase.
  • PP1(protein phosphatase 1) reverses the
    regulatory effects of glycogen metabolism.
  • PKA action is reversed by phosphatases
  • PP1 inactivates phosphorylase kinase and
    phosphorylase a by dephosphorylating these
    enzymes.
  • PP1 also removes P groups from glycogen synthase
    b to a form (more active)

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  • PP1 has 3 components
  • P1
  • Rgl
  • I
  • How is phosphatase activity of PP1 regulated?
  • Rgl phosphorylation by PKA prevents its binding
    to PP1, therefore activation of cAMP cascade
    leads to the inactivation of PP1 because it
    cannot bind to its substrate.
  • Phosphorylation of inhibitor 1 by protein kinase
    A blocks catalysis by PP1.
  • Thus, Epi increases glycogen breakdown by making
    phosphorylase a and decreases glycogen synthesis
    by making inactive phosphatase.

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Insulin stimulates glycogen synthesis by
activating protein phosphatase 1
  • When blood glucose is high, insulin is
    stimulated.
  • Figure 21.20
  • Activated insulin-sensitive protein kinase makes
    activated protein phosphatase
  • The consequent dephosphorylation of glycogen
    synthase, phosphorylase kinase and phosphorylase
    promotes glycogen synthesis and blocks its
    degradation!

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Phosphorylation of the enzymes is regulated by
hormones
  • Phosphorylated groups can be removed by
    phosphatases, therefore the action of
    phosphatases always opposes kinases. If kinases
    activity is greater than activity of phosphatase
    enzyme is in the phosphorylated mode.
  • Insulin, Glucagon, Epi are three important
    hormones which affect glycogen metabolism!

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Glycogen metabolism in the liver regulates the
blood-glucose level
  • After a carbohydrate-rich meal blood glucose
    increases.
  • Insulin is the primary signal for glycogen
    synthesis.
  • Blood glucose level 80-120 mg/dL (4.4-6.7 mM)
  • The liver senses the concentration of blood
    glucose either release or takes up glucose.
  • Glucose infusion changes the enzymes involved in
    glycogen metabolism

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Events Followed by Glucose Infusion
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Glucose regulation of glycogen metabolism
  • Phosphorylase a is the glucose sensor in liver
    cells
  • Glucose is high
  • Binding of Glc converts R----gtT
  • PP1 is released
  • Inactivation of glycogen breakdown and the
    activation of glycogen synthesis take place..

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Glucose regulation of glycogen metabolism
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Glucose regulation of glycogen metabolism
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Reciprocal Regulation of Glycogen Synthase and
Glycogen Phosphorylase
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Summary of the Regulation of Glycogen Synthesis
and Degradation
  • Synthesis and degradation are regulated by the
    same hormonal signals!
  • Increase insulin ? Increase glycogen synthesis
  • Increase glucagon and Epi ? glycogen degradation
  • cAMP increase ? in response to Epi and glucogon
    release
  • cAMP decrease ? in the presence of insulin!
  • Key enzymes are phophorylated by a family of
    kinases, some of which are cAMP dependent.
  • Phosphorylation of an enzyme causes 3D change
    that affects the active site. It may either
    increase or decrease its activity depending on
    the type of enzyme.

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Glycogen storage diseases
  • Glycogen metabolism is a finely controlled
    system.
  • It is not surprising that genetically determined
    enzyme deficiencies result in disease state.
  • Genetic diseases are in fact valuable research
    tools for us.
  • There are VIII glycogen storage diseases
  • Type I and Type V will be covered
  • Type I Von Gierke Disease, Glc 6-phosphatase is
    missing.
  • Type V McArdle Disease, Phosphorylase is
    missing.

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