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Glycogen metabolism and control

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Title: Glycogen metabolism and control


1
Glycogen metabolism and control
  • Reading
  • Harpers Biochemistry Chapter 20

2
OBJECTIVES
  • To understand how glycogen is synthesized and
    degraded in liver and muscle.
  • To understand how hormones like adrenalin and
    glucagon affect glycogen synthesis and breakdown.

3
  • Glycogen is the major storage form of
    carbohydrate in animals and corresponds to starch
    in plants.
  • Occurs mainly in liver and muscle.

4
Biomedical Importance
  • Muscle glycogen acts as a convenient source of
    hexose units for glycolysis within muscle itself.
    Only depleted significantly after prolonged
    vigorous exercise.
  • Liver glycogen is largely concerned with storage
    and export of hexose units for maintenance of
    blood glucose, particularly between meals. After
    12-18h of fasting, the liver becomes nearly
    depleted of glycogen.
  • Glycogen storage diseases are a group of
    inherited disorders characterized by deficient
    mobilization of glycogen or deposition of
    abnormal forms of glycogen.

5
Glycogenesis- glycogen synthesis
  • Occurs mainly in muscle and liver.
  • Glucose is phosphorylated to glucose 6-phosphate
    as in the first step of glycolysis.
  • Glucose-6-phosphate is converted to
    glucose-1-phosphate by phosphoglucomutase. In
    this reaction, the enzyme itself becomes
    phosphorylated and glucose 1,6-bisphosphate is an
    intermediate.
  • Glucose 6-phosphate Glucose 1-phosphate
  • The key reaction in glycogen synthesis is the
    formation of UDP-glucose by the action of
    UDP-glucose pyrophosphorylase.
  • Glucose 1-phosphate UTP? UDP-glucose PPi
  • This reaction proceeds to the right because PPi
    is rapidly hydrolyzed to inorganic phosphate.

6
  • Uridine diphosphate glucose (UDPGlc)

7
  • UDP-glucose is the immediate donor of glucose
    residues in the reaction catalyzed by glycogen
    synthase, which promotes the transfer of the
    glucose residue of UDP-glucose to a non-reducing
    end of a branched glycogen molecule (primer must
    have at least 8 glucose residues)

8
  • Glycogen synthase cannot make the (?1?6) bonds
    found at branch points of glycogen. This is done
    by the glycogen-branching enzyme amylo (1?4) to
    (1?6) transglycosylase. Branching makes
    glycogen more soluble and provides more
    non-reducing ends which act as sites for glycogen
    synthase and glycogen phosphorylase

9
Initiation of a glycogen particle
  • Because glycogen synthase requires a primer, a
    new glycogen particle is formed by the protein
    glycogenin (MV 37kD).
  • Glycogenin becomes glycosylated on a specific
    tyrosine residue by UDP-glucose. Further glucose
    molecules are attached in the 1? 4 position to
    make a short glucose chain which can then act as
    a primer for glycogen synthase.

10
Glycogenolysis- glycogen breakdown
  • Glycogen can enter the glycolytic pathway as
    glucose 6-phosphate following the action of two
    enzymes glycogen phosphorylase and
    phosphoglucomutase.
  • Glycogen phosphorylase releases terminal glucose
    residues from the non-reducing end of glycogen
    chains

11
Glycogen breakdown near a branch point
  • This requires a debranching enzyme -
    amylo(1?6)glucosidase - which has a transferase
    and a glucosidase activity

12
  • Glucose 1-phosphate, the end product of the
    glycogen phosphorylase reaction, is converted to
    glucose 6-phosphate by phosphoglucomutase
  • glucose 1-phosphate glucose 6-phosphate
  • In liver (and kidney), but not in muscle, there
    is a specific enzyme, glucose 6-phosphatase, that
    removes phosphate from glucose 6-phosphate. The
    glucose formed can diffuse from the cell into the
    blood.

13
Cyclic AMP integrates the regulation of
glycogenolysis and glycogenesis
  • The principle enzymes controlling glycogen
    metabolism are glycogen phosphorylase and
    glycogen synthase.
  • These enzymes are regulated by a complex series
    of reactions involving both allosteric mechanisms
    and covalent modification by phosphorylation/depho
    sphorylation.
  • Glycogen phosphorylase is activated by
    phosphorylation
  • Glycogen synthase is inactivated by
    phosphorylation

14
Cyclic AMP activates muscle phosphorylase
  • Epinephrine (adrenaline) activates the
    ?-adrenergic receptor on the surface of muscle
    cells
  • This activates, via trimeric G proteins, the
    enzyme adenylate cyclase, which makes cyclic AMP
    from ATP
  • Cyclic AMP, or cAMP, activates cAMP-dependent
    protein kinase (PKA)
  • R2C2 (inactive) 4cAMP R2-(AMP)4 2C
    (active)
  • Active PKA phosphorylates and activates
    phosphorylase b kinase
  • Active phosphorylase b kinase phosphorylates and
    activates phosphorylase b, which can now mobilize
    glycogen

15
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16
Activation of phosphorylase kinase in muscle
  • Phosphorylase kinase is also activated by Ca2
  • Subunit structure (????)2
  • ?,? - phosphorylated by PKA
  • ? - catalytic subunit
  • ? - calmodulin
  • Calmodulin binds Ca2
  • Binding of Ca2 by ? subunit enhances activity of
    phosphorylase kinase
  • Therefore, Ca2 synchronizes the activation of
    phosphorylase with muscle contraction

17
  • Control of phosphorylase in muscle. The sequence
    of reactions arranged as a cascade allows
    amplification of the hormonal signal at each step
    (n number of glucose residues G6P, glucose
    6-phosphate).

18
Glycogen Synthase
  • Glycogen synthase is also regulated by reversible
    phosphorylation, but in this case, the
    phosphorylated enzyme is inactive.
  • Glycogen synthase a - active form-
    dephosphorylated
  • Glycogen synthase b - inacitve form-
    phosphorylated

19
  • In muscle, when PKA is active and glycogenolysis
    is promoted, glycogen synthase is maintained
    inactive by the same pathway

20
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21
SUMMARY
  • 1. Glycogen represents the principal storage
    form of carbohydrate in the mammalian body,
    present mainly in the liver and muscle.
  • 2. In the liver, its major function is to
    service the other tissues via formation of blood
    glucose. In muscle, it serves the needs of that
    organ only, as a ready source of metabolic fuel.
  • 3. Glycogen is synthesized from glucose and
    other precursors by the pathway of glycogenesis.
    It is broken down by a separate pathway known as
    glycogenolysis. Glucose is not exported from
    muscle due to absence of glucose 6-phosphatase.

22
SUMMARY
  • 4. Cyclic AMP integrates the regulation of
    glycogenolysis and glycogenesis by promoting the
    simultaneous activation of phosphorylase and
    inhibition of glycogen synthase. Insulin acts
    reciprocally by inhibiting glycogenolysis and
    stimulating glycogenesis.
  • 5. Inherited deficiencies in specific enzymes of
    glycogen metabolism in both liver and muscle are
    the causes of glycogen storage diseases.
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