25-Glycogen+Synthesis

Glycogen Synthesis Overview

  • Glycogen is synthesized from UDP-glucose.

UDP-glucose Formation

  • UDP-glucose as a glucose donor:

    • Synthesized by UDP-glucose pyrophosphorylase from glucose 1-phosphate and UTP.

    • Hydrolysis of pyrophosphate product during this reaction is crucial for its irreversibility.

Key Enzymatic Steps in Glycogen Synthesis

  • Glycogen Synthase:

    • Transfers a glucose moiety from UDP-glucose to the C-4 terminal residue of a glycogen chain.

    • Forms an α-1,4-glycosidic bond during the process.

  • Oligosaccharide Primer Requirement:

    • Glycogen synthase requires a primer, an oligosaccharide of glucose residues.

    • Glycogenin (a homo-dimer enzyme) synthesizes this primer, generating an oligosaccharide of glucose 8 residues long.

Primer and Branching in Glycogen

  • Branching Enzyme Role:

    • Glycogen synthase can synthesize only α-1,4-linkages.

    • Branching enzyme cleaves an α-1,4-linkage, taking a block of about 7 glucoses and forming an α-1,6-linkage.

    • Branch points must be separated by at least 4 glucose residues.

Energy Efficiency of Glycogen

  • Incorporating one glucose into glycogen requires only two ATP molecules.

  • Complete oxidation of glucose derived from glycogen yields 30 ATP molecules.

  • Regulation:

    • Glycogen synthase is usually inactive in the phosphorylated b form and active in the unphosphorylated a form.

    • Key regulatory process involves conversion from b form T state to active b form R state via binding of glucose 6-phosphate.

Reciprocal Regulation of Glycogen Metabolism

  • Glycogen synthase kinase phosphorylates and inhibits glycogen synthase.

  • Glucagon (in the liver) and epinephrine (in muscle and liver) stimulate glycogen breakdown and inhibit glycogen synthesis.

  • Protein kinase A (PKA) phosphorylates glycogen synthase leading to inhibition of glycogen synthesis.

Insulin's Role in Glycogen Synthesis

  • In muscle, insulin activates protein kinases that inactivate glycogen synthase kinase, promoting glycogen synthesis.

  • Protein Phosphatase 1 (PP1) promotes insulin's effects by dephosphorylating and activating glycogen synthase.

  • Insulin receptor acts as a tyrosine kinase that phosphorylates insulin receptor substrate.

  • Insulin also increases number of glucose transporters (GLUT4) in plasma membrane, facilitating glycogen synthesis.

Protein Phosphatase 1 (PP1) Mechanism

  • PP1 shifts glycogen metabolism from degradation to synthesis by:

    • Removing phosphoryl groups from phosphorylase kinase and glycogen phosphorylase, inhibiting degradation.

    • Converting glycogen synthase b (less active) to a form (more active).

  • Regulatory Subunits of PP1:

    • Composed of a catalytic subunit (PP1) and two regulatory subunits.

    • G subunit (GL in liver and GM in muscle) helps localize PP1 to glycogen substrates.

    • Phosphorylation leads to dissociation of PP1 from glycogen, reducing activity in muscle.

Regulation by Blood Glucose Levels

  • High blood glucose levels inhibit glycogen degradation while stimulating synthesis.

  • Conversion of glycogen phosphorylase a from R state to T state leads to activating PP1, promoting glycogen synthesis.

  • The lag between decreased degradation and increased synthesis is due to small proportion of phosphorylase molecules associated with PP1.

Role of Glucagon and Insulin

  • Pancreatic Regulation:

    • Insulin stimulates beta cells' glucose uptake, promoting hyperglycemia.

    • Glucagon stimulates gluconeogenesis and glycogenolysis in liver, releasing glucose to plasma during hypoglycemia.

  • Insulin and glucagon play critical roles in maintaining normal blood glucose levels.