Glycogen metabolism and control

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Glycogen metabolism and control

• Reading
• Harpers Biochemistry Chapter 20

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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.

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

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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.

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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.

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• Uridine diphosphate glucose (UDPGlc)

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• 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)

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• 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

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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.

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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

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Glycogen breakdown near a branch point

• This requires a debranching enzyme -
  amylo(1?6)glucosidase - which has a transferase
  and a glucosidase activity

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• 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.

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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

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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

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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

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• 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).

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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

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

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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.

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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.