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Glycogen metabolism

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Title: Glycogen metabolism


1
Glycogen metabolism
  • UNIT II
  • Intermediary Metabolism

2
(No Transcript)
3
Figure 11.1. Glycogen synthesis and degradation
shown as a part of the essential reactions of
energy metabolism (see Figure 8.2, p. 90, for a
more detailed view of the overall reactions of
metabolism)..
4
Overview
  • A constant source of blood glucose is an absolute
    requirement for human life
  • Glucose is the greatly preferred energy source
    for the brain, the required energy source for
    cells with few or no mitoch., e.g., mature RBCs
  • Glucose is also essential as an energy source for
    exercising muscle, where it is the substrate for
    anaerobic glycolysis.
  • Blood glucose can be obtained from 3 primary
    sources diet, degradation of glycogen,
    gluconeogenesis.
  • Dietary intake of gluc gluc precursors, e.g.,
    starch, monosacchs, disacchs, is sporadic
    and, depending on diet, is not always a reliable
    source of gluc.
  • In contrast, gluconeogenesis can provide
    sustained synthesis of gluc, but it is somewhat
    slow in responding to falling blood gluc level
  • Therefore, body has developed mechanisms of
    storing a supply of glucose in a rapidly
    mobilizable form i.e., glycogen.

5
  • In absence of a dietary source of gluc, this cpd
    is rapidly released from liver kidney glycogen.
    Similarly, muscle glycogen is extensively
    degraded in exercising muscle to provide that
    tissue with an important energy source
  • When glycogen stores are depleted, specific
    tissues synthesize gluc de novo, using aas from
    bodys proteins as primary source of carbons for
    gluconeogenic pathway.

6
  • II. Structure and function of glycogen
  • The main stores of glycogen in the body are found
    in skeletal muscle liver, although most other
    cells store small amounts of glycogen for their
    own use
  • Function of muscle glycogen is to serve as a fuel
    reserve for synthesis of ATP during muscle
    contraction
  • That of liver glycogen is to maintain blood
    glucose conc., particularly during early stages
    of fast
  • A. Amounts of liver and muscle glycogen
  • 400 g of glycogen make up one to two percent of
    the fresh weight of resting muscle, 100 g of
    glycogen make up to 10 of the fresh weight of a
    well-fed adult liver. What limits production of
    glycogen at these levels is not clear.
  • However, in some glycogen storage diseases, the
    amount of glycogen in liver and/or muscle can be
    significantly higher

7
Figure 10.2. Functions of muscle and liver
glycogen.
8
  • B. Structure of glycogen
  • Glycogen is a branched-chain homo-polysaccharide
    made exclusively from a-glucose
  • The primary glycosidic bond is an a(1?4) linkage.
  • After an av. of 8-10 glucosyl residues, there is
    a branch containing an a(1?6) linkage.
  • A single molecule of glycogen can have a
    molecular mass of up to 108 daltons.
  • These molecules exist in discrete cytoplasmic
    granules that contain most of the enzs necessary
    for glycogen synthesis degradation

9
Figure 11.3. Branched structure of glycogen,
showing a-1,4 and a-1,6 linkages.
10
  • C. Fluctuation of glycogen stores
  • Liver glycogen stores increase during the
    well-fed state are depleted during a fast
  • Muscle glycogen is not affected by short periods
    of fasting ( a few days) is only moderately
    decreased in prolonged fasting (weeks).
  • Muscle glycogen is synthesized to replenish
    muscle stores after they have been depleted,
    e.g., following strenuous exercise.
  • Note synthesis degradation of glycogen are
    processes that go on continuously. Differences
    b/w rates of these 2 processes determine levels
    of stored glycogen during specific physiologic
    states

11
III. Synthesis of glycogen (glycogenesis)
  • - Glycogen is synthesized from molecules of
    a-D-glucose. The process occurs in cytosol, and
    requires energy supplied by ATP (for
    phosphorylation of gluc) uridine triphosphate
    (UTP)
  • A. Synthesis of UDP-glucose
  • a-D-gluc attached to UDP is the source of all of
    glucosyl residues that are added to the growing
    glycogen molecule
  • UDP-gluc is synthesized from glucose-1-P UTP by
    UDP-glucose pyrophosphorylase
  • The high-energy bond in pyrophosphate (PPi), the
    2nd product of the reaction, is hydrolyzed to 2
    inorganic phosphates (Pi) by pyrophosphatase,
    which ensures that synthesis of UDP-gluc proceeds
    in direction of UDP-gluc production
  • Note G-6-P is converted to G-1-P by
    phosphoglucomutase. G-1,6-BP is an obligatory
    intermediate in this reaction

12
Figure 11.4. The structure of UDP-glucose.
13
  • B. Synthesis of a primer to initiate glycogen
    synthesis
  • Glycogen synthase is responsible for making a
    (1?4) linkages in glycogen. This enz cant
    initiate chain synthesis using free gluc as an
    acceptor of a molecule of gluc from UDP-gluc.
    Instead, it can only elongate already existing
    chains of gluc
  • Therefore, a fragment of glycogen can serve as a
    primer in cells whose glycogen stores are not
    totally depleted
  • In the absence of a glycogen fragment, a protein,
    called glycogenin, can serve as an acceptor of
    gluc residues
  • Side chain hydroxyl group of a specific Tyr
    serves as the site at which the initial glucosyl
    unit is attached
  • Transfer of first few molecules of gluc from
    UDP-gluc to glycogenin is catalyzed by glycogenin
    itself, which can then transfer additional
    glucosyl units to the growing a (1?4)-linked
    glucosyl chain
  • This short chain serves as an acceptor of future
    gluc residues
  • Note glycogenin stays associated with is found
    in center of completed glycogen molecule

14
Figure 11.5. Glycogen synthesis.
15
  • C. Elongation of glycogen chain by glycogen
    synthase
  • - Elongation of glycogen chain involves transfer
    of gluc from UDP-gluc to the non-reducing end of
    growing chain, forming a new glycosidic bond b/w
    the anomeric hydroxyl of C-1 of activated gluc
    C-4 of accepting glucosyl residue
  • Note non-reducing end of a CHO chain is one in
    which anomeric C of terminal sugar is linked by a
    glycosidic bond to another cpd, making terminal
    sugar non-reducing.
  • - The enz responsible for making a (1?4) linkages
    in glycogen is glycogen synthase
  • Note UDP released when the new a (1?4)
    glycosidic bond is made can be converted back to
    UTP by nucleoside diphosphate kinase (UDP ATP ?
    UTP ADP)

16
Figure 11.6. Interconversion of glucose
6-phosphate and glucose 1-phosphate by
phosphoglucomutase.
17
  • D. Formation of branches in glycogen
  • If no other synthetic enzs acted on the chain,
    resulting structure would be a linear molecule of
    glucosyl residues attached by a (1?4) linkages.
  • Such a cpd is found in plant tissues, is called
    amylose. In contrast, glycogen has branches
    located, on av., 8 glucosyl residues apart,
    resulting in a highly branched, tree-like
    structure that is far more soluble than
    unbranched amylose
  • Branching also increases the of non-reducing
    ends to which new glucosyl residues can be added
    (and also, from which these residues can be
    removed), thereby greatly accelerating the rate
    at which glycogen synthesis degradation can
    occur, dramatically increasing the size of the
    molecule

18
  • 1. Synthesis of branches
  • Branches are made by action of branching
    enzyme, amylo-a (1?4) ? a (1?6)-transglucosidase.
    This enz transfers a chain of 5 to 8 glucosyl
    residues from non-reducing end of glycogen chain
    breaking a (1?4) bond to another residue on the
    chain and attaches it by an a (1?6) linkage
  • Resulting new, non-reducing end, as well as the
    old non-reducing end from which the 5 to 8
    residues were removed, can now be elongated by
    glycogen synthase
  • 2. Synthesis of additional branches
  • - After elongation of these two ends has been
    accomplished by glycogen synthase, their terminal
    5 to 8 glucosyl residues can be removed used to
    make further branches

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IV. Degradation of glycogen (glycogenolysis)
  • The degradative pathway that mobilizes stored
    glycogen in liver skeletal muscle is not a
    reversal of the synthetic reactions. Instead a
    separate set of cytosolic enzs is required.
  • When glycogen is degraded, the primary product is
    G-1-P, obtained by breaking a (1?4) glycosidic
    bonds. In addition, free gluc is released from
    each a (1?6)-linked glucosyl residue

20
  • A. Shortening of chains
  • Glycogen phosphorylase sequentially cleaves the a
    (1?4) glycosidic bonds b/w the glucosyl residues
    at the non-reducing ends of glycogen chains by
    simple phosphorolysis until 4 glucosyl units
    remain on each chain before a branch point
  • Note this enz contains a molecule of covalently
    bound pyridoxal phosphate that is required as a
    coenzyme
  • - Resulting structure is called a limit dextrin,
    phosphorylase cant degrade it any further

21
Cleavage of an a (1? 4)-glycosidic bond.
22
  • B. Removal of branches
  • Branches are removed by 2 enzymatic activities.
    1st oligo-a(1?4)?a (1?4)-glucan transferase
    removes the outer 3 of the 4 glucosyl residues
    attached at a branch. It next transfers them to
    the non-reducing end of another chain,
    lengthening it accordingly. Thus, an a(1?4) bond
    is broken and an a(1?4) bond is made.
  • Next, the remaining single gluc residue attached
    in an a(1?6) linkage is removed hydrollytically
    by amylo- a(1?6)-glucosidase activity, releasing
    free gluc.
  • Note both the transferase glucosidase are
    domains of a single polyp molecule, the
    debranching enzyme.
  • - The glucosyl chain is now available for
    degradation by glycogen phosphorylase until 4
    glucosyl units from next branch are reached

23
Figure 11.8 Glycogen degradation, showing some of
the glycogen storage diseases. (Continued on next
page.)
24
Figure 11.8 (Continued )
25
  • C. Conversion of G-1-P to G-6-P
  • G-1-P, produced by glycogen phosphorylase, is
    converted in the cytosol to G-6-P by
    phosphoglucomutase, a reaction that produces
    G-1,6-BP as a temporary but essential
    intermediate
  • In liver, G-6-P is translocated into ER by
    glucose 6-phosphate translocase. There it is
    converted to glucose by glucose 6-phosphatase,
    the same enz used in last step of gluconeogenesis
  • Resulting glu is then transported out of ER to
    cytosol. Hepatocytes release glycogen-derived
    gluc into blood to help maintain blood gluc
    levels until gluconogenic pathway is actively
    producing gluc
  • Note in muscle, G-6-P cant be dephosphorylated
    because of a lack of glucose-6-phosphatase.
    Instead, it enters glycolysis, providing energy
    needed for muscle contraction

26
  • D. Lysosomal degradation of glycogen
  • A small amount of glycogen is continuously
    degraded by lysosomal enz, a(1?4)-glucosidase
    (acid maltase). Purpose of this pathway is
    unknown
  • However, a deficiency of this enz causes
    accumulation of glycogen in vacuoles in the
    cytosol, resulting in the serious glycogen
    storage disease type II (Pompe disease)

27
V. Regulation of glycogen synthesis degradation
  • Because of importance of maintaining blood gluc
    levels, synthesis degradation of its glycogen
    storage form are tightly regulated
  • In liver, glycogen synthesis accelerates during
    periods when the body has been well fed, whereas
    degradation accelerates during periods of
    fasting.
  • In skeletal muscle, glycogen degradation occurs
    during active exercise, synthesis begins as
    soon as the muscle is again at rest
  • Regulation of glycogen synthesis degradation is
    accomplished on two levels

28
  • First, glycogen synthase glycogen phosphorylase
    are allosterically controlled.
  • Second, the pathways of glycogen synthesis
    degradation are hormonally regulated
  • Note regulation of glycogen synthesis
    degradation is extremely complex, involving many
    enzs (e.g., protein kinases phosphatases),
    calcium, enz inhibitors, among others

29
  • A. Allosteric regulation of glycogen synthesis
    degradation
  • Glycogen synthase glycogen phosphorylase
    respond to levels of metabolites energy needs
    of cell. It is logical, therefore, that glycogen
    synthesis is stimulated when substrate
    availability energy levels are high, whereas
    glycogen degradation is increased when energy
    levels available gluc supplies are low
  • 1. Regulation of glycogen synthesis degradation
    in the well fed state
  • In the well fed state, glycogen synthase is
    allosterically activated by G-6-P when it is
    present in elevated concs. in contrast, glycogen
    phosphorylase is allosterically inhibited by
    G-6-P, as well as ATP, a high-energy signal in
    cell.
  • Note in liver, gluc also serves as an allosteric
    inhibitor of glycogen phosphorylase

30
Figure 11.9. Allosteric regulation of glycogen
synthesis and degradation in A. Liver, and B.
Muscle.
31
  • 2. Activation of glycogen degradation in muscle
    by calcium
  • During muscle contraction, there is a rapid
    urgent need for ATP, the energy for which is
    supplied by muscles stores of glycogen.
  • Nerve impulses cause memb depolarization, which
    in turn promotes Ca2 release from sarcoplasmic
    reticulum into sarcoplasm of muscle cells
  • Ca2 binds to calmodulin, one of a family of
    small, calcium-binding proteins
  • Note calmodulin is the most widely distributed
    of these proteins, is present in virtually all
    cells
  • - Binding of 4 molecules of Ca2 to calmodulin
    triggers conformational change such that
    activated Ca2-calmodulin complex binds to
    activates protein molecules, often enzs, that
    are inactive in absence of this complex
  • Thus, calmodulin functions as an essential
    subunit of many complex proteins. One such
    protein is phosphorylase kinase, which is
    activated by Ca2-calmodulin complex without need
    for the kinase to be phosphorylated by
    cAMP-dependent protein kinase
  • When muscle relaxes, Ca2 returns to sarcoplasmic
    reticulum phosphorylase kinase becomes inactive
  • Note phosphorylase kinase is maximally active in
    exercising muscle when it is both phosphorylated
    bound to Ca2

32
Figure 11.10. Calmodulin mediates many effects of
intracellular calcium.
33
  • 3. Activation of glycogen degradation in muscle
    by AMP
  • Muscle glycogen phosphorylase is active in
    presence of high AMP concs that occur in muscle
    under extreme conditions of anoxia ATP
    depletion
  • AMP binds to the inactive form of glycogen
    phosphorylase, causing its activation without
    phosphorylation

34
  • B. Activation of glycogen degradation by
    cAMP-directed pathway
  • Binding of hormones, e.g., glucagon
    epinephrine, to memb receptors signals the need
    for glycogen to be degraded, either to elevate
    blood gluc levels or to provide energy for
    exercising muscle
  • 1. Activation of protein kinase
  • Binding of glucagon or epinephrine to their
    specific CM receptors ? cAMP-mediated activation
    of cAMP-dependent protein kinase.
  • This enz is a tetramer, having 2 regulatory (R)
    2 catalytic (C) subunits.
  • cAMP binds R subunit dimer, releasing individual
    C subunits that are active
  • Note when cAMP removed, inactive tetramer R2C2,
    is again formed

35
  • 2. Activation of phosphorylase kinase
  • Phosphorylase kinase exists in 2 forms an
    inactive b form an active a form
  • Active cAMP-dependent protein kinase
    phosphorylates inactive form of phosphorylase
    kinase ? activation
  • Note phosphorylated enz can be inactivated by
    hydrolytic removal of its P by protein
    phosphatase 1. This enz is activated by a
    kinase-mediated signal cascade initiated by
    insulin
  • 3. Activation of glycogen phosphorylase
  • Glycogen phosphorylase also exists in 2 forms
    the dephosphorylated, inactive b form
    phosphorylated, active a form.
  • Active phosphorylase kinase phosphorylates
    glycogen phosphorylase a, which then begins
    glycogen breakdown

36
  • - Phosphorylase a is converted to phosphorylase b
    by hydrolysis of its P by protein phosphatase 1.
  • Note
  • - when gluc is bound to glycogen phosphorylase a,
    thus signaling that glycogen degradation is no
    longer required, the complex becomes a better
    substrate for protein phosphatase 1.
  • In addition, when muscle glycogen phosphorylase b
    is bound to glucose, it cant be allosterically
    activated by AMP
  • In the muscle, insulin indirectly inhibits the
    enz by increasing uptake of gluc, leading to an
    increased level of G-6-P, a potent allosteric
    inhibitor of glycogen phosphorylase

37
Figure 11.11. Stimulation and inhibition of
glycogen degradation.
38
  • 4. Summary of regulation of glycogen degradation
  • Cascade of reactions listed above result in
    glycogen degradation
  • The large of sequential steps serves to amplify
    the effect of the hormonal signal, i.e., a few
    hormone molecules binding to their receptors
    result in a of protein kinase molecules being
    activated that can each activate many
    phosphorylase kinase molecules
  • This causes production of many active glycogen
    phosphorylase a molecules that can degrade
    glycogen

39
  • C. Inhibition of glycogen synthesis by a
    cAMP-directed pathway
  • The regulated enz in glycogen synthesis is
    glycogen synthase.
  • It also exists in 2 forms, the a form which is
    not phosphorylated is the most active form,
    b form, which is phosphorylated inactive.
  • Glycogen synthase a is converted to b form by
    phosphorylation at several sites on the enz, with
    the level of inactivation is proportional to its
    degree of phosphorylation
  • This conversion process is catalyzed by several
    different protein kinases that are regulated by
    cAMP or other signaling mechanisms
  • Note protein kinase C, a Ca2
    phospholipid-dependent protein kinase, also
    phosphorylates glycogen synthase. Neither protein
    kinase A nor C directly phosphorylates glycogen
    phosphorylase

40
  • - Binding of glucagon or epinephrine to
    hepatocyte receptors, or of epinephrine to muscle
    cell receptors, results in the activation of
    adenylyl cyclase, mediated by G-protein
  • This enz catalyzes synthesis of cAMP, which
    activates cAMP-dependent protein kinase A
  • Protein kinase A then phosphorylates thereby
    inactivates glycogen synthase
  • Glycogen synthase b can be transformed back to
    synthase a by protein phosphatase 1, which
    removes P groups hydrolytically

41
Figure 11.12. Hormonal regulation of glycogen
synthesis. Note In contrast to glycogen
phosphorylase, glycogen synthase is inactive if
phosphorylated.
42
  • VI. Glycogen storage diseases
  • These are a group of genetic diseases that result
    from a defect in an enz required for glycogen
    synthesis or degradation
  • They result either in formation of glycogen that
    has an abnormal structure, or in the accumulation
    of excessive amounts of normal glycogen in
    specific tissues as a result of impaired
    degradation
  • A particular enz may be defective in a single
    tissue, such as liver, or the defect may be more
    generalized, affecting liver, muscle, kidney,
    intestine, myocardium
  • Severity of glycogen storage diseases (GSDs)
    ranges from fatal in infancy to mild disorders
    that are not life-threatening

43
Summary
  • Main stores of glycogen in body are found in
    skeletal muscle, where they serve as a fuel
    reserve for synthesis of ATP during muscle
    contraction, in liver, where glycogen is used
    to maintain blood glucose conc, particularly
    during early stages of a fast
  • Glycogen is a highly branched polymer of
    a-D-glucose. The primary glycosidic bond is an a
    (1?4) linkage. After 8-10 gluc residues, there
    is a branch containing an a (1?6) linkage.
  • UDP-gluc, building block of glycogen, is
    synthesized from G-1-P UTP by UDP-glucose
    pyrophosphorylase
  • Gluc from UDP-glucose is transferred to the
    non-reducing ends of glycogen chains by glycogen
    synthase, which makes a (1?4) linkages

44
  • Branches are formed by amylo-a(1?4) ?
    a(1?6)-transglucosidase, which transfers a chain
    of 5-8 glucosyl residues from the non-reducing
    end of glycogen chain (breaking an a(1?4)
    linkage), and attaches it with an a(1?6) linkage
    to another residue in the chain
  • Glycogen phosphorylase cleaves the a(1?4) bonds
    b/w glucosyl residues at the non-reducing ends of
    glycogen chains, producing G-1-P. it requires
    pyridoxyl phosphate as a coenz.
  • This sequential degradation continues until 4
    glucosyl units remain on each chain before a
    branch point. The resulting structure is called a
    limit dextrin.
  • Oligo-a(1?4)?a(1?4)-glucan transferase common
    name, glucosyl (44) transferase removes the
    outer 3 of the 4 glucosyl residues attached at a
    branch, transfers them to the non-reducing end
    of another chain where they can be converted to
    G-1-P by glycogen phosphorylase.

45
  • Next, the remaining single gluc residue attached
    in an a(1?6) linkage is removed hydrolytically by
    the amylo-a(1?6)-glucosidase activity, releasing
    free gluc.
  • G-1-P is converted to G-6-P by phosphoglucomutase.
    In the muscle, G-6-P enters glycolysis. In
    liver, the P is removed by glucose-6-phosphatase,
    releasing free gluc that can be used to maintain
    blood gluc levels at beginning of a fast
  • A deficiency of the phosphatase causes glycogen
    storage disease type 1 (Von Gierke disease). This
    disease results in an inability of liver to
    provide free gluc to body during a fast. It
    affects both glycogen degradation last step in
    gluconeogenesis

46
  • Glycogen synthase glycogen phosphorylase are
    allosterically regulated. In well-fed state,
    glycogen synthase is activated by G-6-P, as well
    as ATP
  • In liver, gluc also serves as an allosteric
    inhibitor of glycogen phosphorylase
  • Ca2 is released from sarcoplasmic reticulum
    during exercise. It activates phosphorylase
    kinase in the muscle by binding to enzs
    calmodulin subunit. This allows the enz to
    activate glycogen phosphorylase, thereby causing
    glycogen degradation
  • Glycogen synthesis degradation are reciprocally
    regulated by the same hormonal signals, namely,
    an elevated insulin level results in overall
    increased glycogen synthesis decreased
    degradation, whereas elevated glucagon (or
    epinephrine) level causes increased glycogen
    degradation decreased synthesis.

47
  • Key enzs are phosphorylated by a family of
    protein kinases, some of which are cAMP-dependent
    (a cpd increased by glucagon and epinephrine).
    Phosphate groups are removed by protein
    phosphatase 1 (activated when insulin levels are
    elevated).

48
Figure 11.13. Key concept map for glycogen
metabolism in liver.
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