Glycogen
- Glucose is stored as glycogen because
- it is compact
- Has solubility
- Stored only in the liver and skeletal muscle.
- Only site where Glycogen synthesis and glycogenolysis happens
- Has the most branched structure.
- Glucose linked by α-1,4 linkage in straight chains.
- α-1,6 linkage forms branch points.
Glycogenolysis
- Nature: Catabolic
- Active in
- fasting (4–16 h),
- starvation (1–3 d)
- Compartment:
- Cytoplasm (exception for catabolism)
- Site
- Liver, muscle
- Lysosomes
- Small amount
- lysosomal α-1,4-glucosidase (acid maltase)
- (Pompe’s Disease)
Steps
- Glycogen phosphorylase (rate-limiting)
- breaks only α-1,4 linkage.
- Coenzyme: Vitamin: B6 (PLP)
- glycogen → Glucose-1-phosphate
- De-branching enzyme
- breaks α-1,6 linkage.
- Phosphoglucomutase :
- Common to glycogen synthesis & glycogenolysis.
- Glucose-1-phosphate ⇔ Glucose-6-phosphate
- Glucose-6-phosphatase
- Glucose-6-phosphate ⇔ Glucose
- Present in Endoplasmic reticulum
- Present in both Gluconeogenesis and Glycogenolysis pathways.
- Present only in liver and kidney, called Gluconeogenic organs
Fate of Glucose-6-Phosphate
Fate of Glucose 6 Phosphate | ㅤ |
Glycogen Synthesis | In Liver • Glucose-6-phosphate ⇔ Glucose ↳ by Glucose-6-phosphatase • Source of Glucose for Brain and RBC during fasting • Energetics ◦ From free glucose: ↳ 2 ATP ◦ From via 1 G6P : ↳ 3 ATP In muscle • G6P → Pyruvate → Lactate + 3 ATP • Selfish • ATP production for muscle only • No release of glucose into blood ↳ As muscle lacks glucose-6-phosphatase |
HMP Shunt (Pentose phosphate pathway) | • NADPH • Ribose 5 Phosphate |
Glycogen synthesis and breakdown occur in the same cell, which contains the enzymes required for both pathways. Why is it that freshly generated glucose-6-phosphate in the cytoplasm of hepatocytes is not instantly degraded by the enzyme glucose-6-phosphatase?
- INICET November 2015
- The thermodynamics does not favor such a reaction to occur
- Glucose-6-phosphatase is present in the endoplasmic reticulum and cannot act on glycogen formed in the cytoplasm
- Glycogenesis and glycogenolysis are tightly regulated such that enzymes of only one of those is present at a time
- Steric hindrance due to albumin
- Glucose-6-phosphatase is present in the endoplasmic reticulum
- cannot act on glycogen formed in the cytoplasm
ANS
Regulation of Glycogenolysis
Hormones
- Glucagon (liver), Epinephrine (liver+muscle):
- ↑ cAMP → Protein Kinase A → Phosphorylation →
- Activate glycogen phosphorylase
- Inhibit glycogen synthase
- Growth Hormone
- Cortisol
- Insulin:
- ↓cAMP → Protein phosphatase → Dephosphorylation → opposite effect
- Ca²⁺ - calmodulin
- Muscle-specific
- activates Phosphorylase kinase
- glycogenolysis independent of cAMP
Glycogen phosphorylase is activated directly/indirectly by
- Ca+2
- Glucose-6-Phophatase
- Insulin
- Glucose
- Ca+2
ANS
Glycogen Phosphorylase enzymes require which of the following for its activation?
- Magnesium
- Calcium
- Glucose
- Insulin
- Calcium
ANS
Allosteric
- 5′ AMP
- Activator (muscle)
- In extreme anoxia
- Inhibitors:
- G6P, ATP (liver + muscle);
- Glucose (liver only)
Glycogenesis
- Condition:
- Well-fed,
- high insulin : glucagon ratio
- Site:
- Cytoplasm of liver and skeletal muscle
Stages
1. Formation of UDP-glucose
- Glucose → Glucose-6-P
- Enzyme: Hexokinase
- Glucose-6-P → Glucose-1-P
- Enzyme: Phosphoglucomutase
- Glucose-1-P + UTP → UDP-glucose + PPi
- Enzyme: UDP-glucose pyrophosphorylase
2. Formation of linear glycogen polymer
- Primer:
- Glycogenin
- polypeptide primer
- tyrosine residue attachment
- UDP-glucose
- adds 4 glucose units to glycogenin
- Glycogen synthase (RLE):
- Forms only α-1,4 linkage.
- Active in dephosphorylated state
- After 11–12 residues:
- Branching enzyme (α-1,4 → α-1,6 glucan transferase)
- creates branches via α (1→6) linkages
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