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Glycogen

Where glycogen is stored and why

  • liver stores glycogen for storage and release
  • muscle stores glycogen for self-usage
  • glycogen helps regulate blood glucose
  • typical blood glucose range: 70–100 mg/dL
  • glycogen becomes especially relevant after ~2 hours of elevated blood glucose

Key terms

  • glycogenolysis: glycogen → glucose
  • glycogenesis: glucose → glycogen

Glycogen structure

  • glucose chains with:

  • \(\alpha(1\to4)\) glycosidic bonds

  • \(\alpha(1\to6)\) glycosidic bonds (branch points)
  • branching is more frequent than starch (about every 10 vs 25 residues)

Glycogenesis (glycogen synthesis)

  1. glucose → glucose-6-phosphate via hexokinase / glucokinase
  2. glucose-6-phosphate → glucose-1-phosphate via phosphoglucomutase

  3. glucose-1-phosphate is activated:

  4. UDP-glucose pyrophosphorylase + UTP → UDP-glucose

  5. glucosyltransferase activity:

  6. cleaves UDP and binds glucose to glycogenin

  7. repeats to extend (attaches 8 in total)
  8. all bonds formed here are \(\alpha(1\to4)\)
  9. glycogen synthase transfers glucose from UDP-glucose to the growing glycogen chain

  10. branching enzyme (amylo-\((1,4\to1,6)\)-transglycosylase):

  11. breaks an \(\alpha(1\to4)\) bond (7-residue chunk)

  12. forms an \(\alpha(1\to6)\) bond

Energy cost

  • 1 UTP and 1 ATP per glucose added (as noted)

Glycogenolysis (glycogen breakdown)

  1. glycogen phosphorylase performs phosphorolysis:

  2. inorganic phosphate breaks \(\alpha(1\to4)\) bonds

  3. phosphate binds to the anomeric oxygen atom
  4. when within 4 residues of a branch point:
  5. transferase moves 3 residues to another branch
  6. \(\alpha(1\to6)\)-glycosidase uses water to remove the \(\alpha(1\to6)\) bond

Products:

  • ~90% becomes glucose-1-phosphate
  • ~10% becomes free glucose

Then:

  • glucose-1-phosphate → glucose-6-phosphate

In liver:

  • glucose-6-phosphatase converts glucose-6-phosphate → glucose for release into blood

Hormonal control overview

Major hormones:

  • insulin (beta islet cells of Langerhans; anabolic; nutrient excess)
  • glucagon (alpha islet cells of Langerhans; catabolic; breaking)
  • epinephrine (adrenal gland)

Insulin effects

  • increases glycogen synthesis
  • increases fatty acid synthesis
  • increases triglyceride synthesis
  • increases liver glycolysis

Glucagon effects

  • increases glycogenolysis
  • increases gluconeogenesis
  • increases lipolysis
  • decreases liver glycolysis

Key phosphorylation logic:

  • glycogen phosphorylase b phosphorylated → active (glycogen phosphorylase a)
  • glycogen synthase a (or I) phosphorylated → inactive (glycogen synthase b or D)

Net control:

  • insulin promotes dephosphorylation (glycogen phosphorylase b and glycogen synthase a)
  • glucagon promotes phosphorylation (glycogen phosphorylase a and glycogen synthase b)

Note:

  • muscle cells have no glucagon receptors

Glucagon signaling in liver (Gs pathway)

  • liver responds to glucagon via Gs
  • cAMP activates PKA
  • PKA activates phosphorylase kinase
  • phosphorylase kinase activates glycogen phosphorylase (b → a)
  • glycogen\(*n\) → glycogen\(*{n-1}\)

Also:

  • PKA phosphorylates glycogen synthase a → b (inactivates glycogen synthesis)

Insulin signaling (enzyme-linked receptor)

  1. insulin receptor dimerizes
  2. tyrosine kinase receptor is phosphorylated
  3. docking site for IRS-1 (insulin receptor substrate-1), which becomes phosphorylated
  4. IRS-1 docks PI3-kinase
  5. PI3K converts PIP\(_2\) → PIP\(_3\)
  6. PIP\(_3\) activates PIP\(_3\)-dependent protein kinase → activates protein kinase B (Akt)

Akt effects

  1. promotes translation of cAMP-degrading phosphodiesterase
  2. inhibits glycogen synthase kinase-3 (GSK-3)

  3. activates protein phosphatase-1 (PP1), which:

  4. inactivates glycogen phosphorylase (reduces glycogen degradation)

  5. inactivates phosphorylase kinase (turns down glucagon pathway)
  6. activates glycogen synthase a (promotes glycogen synthesis)

Epinephrine signaling

Epinephrine in liver

Gs pathway

  • can produce the same response as glucagon via Gs

Gq pathway

  • Ca\(^{2+}\) and DAG activate PKC
  • PKC phosphorylates glycogen synthase
  • Ca\(^{2+}\) activates Ca\(^{2+}\)-calmodulin
  • Ca\(^{2+}\)-calmodulin amplifies phosphorylase kinase activity
  • phosphorylase kinase phosphorylates (activates) glycogen phosphorylase b → a
  • phosphorylation inactivates glycogen synthase
  • Ca\(^{2+}\)/calmodulin-dependent protein kinase also phosphorylates (inactivates) glycogen synthase

Epinephrine in muscle

  • Gs → PKA (slowest)
  • Ca\(^{2+}\) from sarcoplasmic reticulum activates Ca\(^{2+}\)-calmodulin
  • AMP (quickest) activates phosphorylase kinase → activates glycogen phosphorylase a

Glycogen storage diseases

Von Gierke disease

  • autosomal recessive
  • no liver glucose-6-phosphatase
  • hypoglycemia
  • hepatomegaly (enlarged liver, from glycerol)

McArdle disease

  • no muscle glycogen phosphorylase
  • muscle weakness