GLYCOGEN METABOLISM

• Glycogen = Polymer of glucose with α (1à 4) linkage for the linear chain and, for every 8-14 residues, α (1 à 6) linkage for a branch (Fig. 15-2).
• As 100-400 Å diameter cytoplasmic granules containing up to 120,000 glucose units.
• Highly branched, permits rapid degradation through simultaneous release of glucose units from the end of each branch.
• Liver and muscle are two major storage sites.

GLYCOGEN BREAKDOWN (or Glycogenolysis)

• In Muscle: glycogen → G6P → enetr glycolysis.
• In Liver: glycogen → G6P → G → released into blood.

1. Glycogen Phosphorylase

• (Glu)_n + P_i → G1P + (Glu)_n-1 where (Glu)_n = initial glycogen molecule
• For each cycle, the glucose unit that is released must be at least 5 units from a branch point.
• Catalyzes the rate-limiting step in glycogen breakdown.

2. Glycogen Debranching Enzyme (Fig. 15-6)

• Seeks out a shortened branch with only 4 glucose units.
• Transfers the last 3 units to the 4-OH group at the end of another longer branch.
• Hydrolyzes off the α (1 → 6) linkage of the last glucose unit at the branch point, and releases it as a free glucose.  About 10% of glycogen degradation products are free Glu.

3. Phosphoglucomutase

• Requires trace amount of Glucose-1,6-bisphosphate for catalysis.
• G-1,6-bisP + Enz ⇌ G6P + Enz-P
• Enz-P + G1P ⇌ Enz + G-1,6-bisP

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• Overall = G1P ⇌ G6P

GLYCOGEN SYNTHESIS

1. UDP-Glucose Pyrophosphorylase

• G1P + UTP ⇌ UDP-glucose + PP_i ( ΔG°’ ~ 0 kJ• mol^-1 )

• Would be readily reversible. Requires inorganic pyrophosphatase to push the reaction to the right.

• PP_i + H ₂O ⇌ 2 P_i ( ΔG°’ = -19.2 kJ• mol^{- 1})
• This is a rather common strategy by nature.

2. Glycogen Synthase

• UDP-glucose + (Glu) _n  → UDP + (Glu)_n+1
• Elongation of each linear chain.

3. Branching Enzyme (Fig. 15-11)

• Seeks out a linear chain with at least 11 units of glucose in length from the branching point.
• Transfers the terminal chain segment with ~ 7 units of glucose to the C6-OH group of a glucose unit in the same or a different chain.
• This acceptor chain must beat least 4-unit long from an existing branching point.

REGULATION

1. Allosteric (Fig. 15-13)

• Allosteric enzyme: (1) has an active site and at least one separate effector site; (2) the binding of an activator or an inhibitor to an effector site results in a conformational change of the enzyme, (3) the conformational change induced by the activator leads to enzyme activation whereas the conformational change induced by the inhibitor leads to enzyme inactivation.

• Glycogen Phosphorylase: Activator:AMP          Inhibitor: ATP, G6P, Glu

• Glycogen Synthase:         Activator: G6P

• When ATP is in need:       Low ATP, Low G6P, High AMP.

• Results in enhanced activity of Glycogen Phosphorylase and inhibition of Glycogen Synthase. Favors glycogen breakdown.

2. Covalent Modification (Protein Phosphorylation & Dephosphorylation

     (A) Phosphorylase a and b

• Phosphorylase a and b both exist in either the inactive T or the active R conformation (Fig. 15-13).  Under physiological conditions, phosphorylase a is mostly in the R conformation whereas phosphorylase b is mostly T.  Hence phosphorylase a is more active than phosphorylase b.
• Only the T form of phosphorylase b can be phosphorylated, resulting in the transformation to phosphorylase a in the T, and in turn, the R conformation.

(B)  Summary of Cascade Regulation (replacing Figs. 15-20, 21)