Glycogen Metabolism Notes

Glycogen Metabolism

Objectives

  • Explain the importance of glycogen synthesis, mainly in the liver and muscles.

  • Identify the steps of glycogen synthesis.

  • Understand the regulation of glycogen metabolism.

Throwback: Glycogen Structure

  • Glycogen is a homopolysaccharide composed of glucose units.

  • The glucose units are linked by \alpha-1,4 linkages in a straight line and \alpha-1,6 linkages at branching points.

  • Branching makes the molecule more globular and less space-consuming.

  • All enzymes related to glycogen metabolism are cytoplasmic.

Function of Glycogen

  • Glycogen is the storage form of carbohydrates in the human body, primarily in the liver and muscle.

  • Liver glycogen's major function is to provide glucose during fasting.

  • The glycogen content in the liver is approximately 10 g/100 g of tissue, while in skeletal muscle, it is 1-2 g/100 g.

  • However, the total quantity of muscle glycogen is greater than liver glycogen due to the larger muscle mass.

  • When blood glucose levels decrease, liver glycogen is broken down to maintain blood glucose levels.

  • After food intake, blood sugar levels rise, promoting glycogen deposition in the liver.

  • About 5 hours after eating, blood sugar levels tend to fall, and glycogen is broken down into glucose to meet energy needs.

  • After approximately 18 hours of fasting, most liver glycogen is depleted, and the body relies on the hydrolysis of depot fats and fatty acid oxidation for energy.

Muscle Glycogen

  • The function of muscle glycogen is to serve as a reserve fuel for muscle contraction.

Glycogenesis: Synthesis of Glycogen

  • Definition: Glycogenesis is the synthesis of glycogen from glucose.

  • Site: Occurs mainly in the liver and muscle.

  • Glycogenesis operates when high levels of glucose-6-phosphate are formed during glycolysis.

  • It does not operate when energy stores (glycogen) are full; excess glucose is converted to body fat.

Steps of Glycogen Synthesis

1. Formation of Glucose-6-Phosphate

  • Glucose is initially converted to glucose-6-phosphate using ATP.

  • This reaction is catalyzed by hexokinase (in muscle) or glucokinase (in liver).

2. Formation of Glucose-1-Phosphate

  • Glucose-6-phosphate is isomerized to glucose-1-phosphate by phosphoglucomutase.

3. Formation of UDP-Glucose (Activation)

  • Glucose-1-phosphate is activated by UTP to form UDP-glucose and pyrophosphate (PPi), catalyzed by UDP-Glc pyrophosphorylase.

4. Activation of Glucose

  • The pyrophosphate (PPi) produced is spontaneously hydrolyzed.

  • This step, catalyzed by inorganic pyrophosphatase, is the only energy-consuming step in glycogen synthesis.

5. Initiation: Primer Requirement

  • Glycogen synthesis requires a primer.

  • Glycogen synthase can add to:

    • A polysaccharide with 4 or more glucose residues.

    • Glycogenin: a protein consisting of two identical subunits, each carrying an oligosaccharide chain with \alpha-1,4-linked glucose residues.

  • Glycogenin acts as a primer by catalyzing the addition of eight glucose units to its partner in the glycogenin dimer . After this glycogen synthase takes over further elongation of the glycogen molecule

6. Elongation: Adding UDP-Glucose

  • UDP-glucose adds to the residual glycogen or glycogenin, forming \alpha(1\rightarrow4) glycosidic bonds.

  • Elongation continues with the addition of UDP-glucose until approximately 11 residues are added, at which point branching occurs.

  • This step is catalyzed by glycogen synthase: UDP-Glucose + glycogen \rightarrow glycogen-glucose + UDP.

7. Branching

  • Glycogen synthase only catalyzes the synthesis of \alpha-1,4 linkages.

  • A branching enzyme is required to form the \alpha-1,6 linkages that create the branched structure of glycogen.

  • Branching occurs after glucosyl residues are joined in \alpha-1,4 linkage by glycogen synthase.

  • A branch is created by breaking an \alpha-1,4 link and forming an \alpha-1,6 link.

  • Branching is important because it increases the solubility of glycogen.

  • It also creates a large number of terminal residues, which are the sites of action for glycogen phosphorylase and glycogen synthase, thus increasing the rates of glycogen synthesis and degradation.

  • A block of residues (typically 7) is transferred to a more interior site.

  • The branching enzyme is specific: the block of 7 or so residues must include the nonreducing terminus and come from a chain at least 11 residues long.

  • The new branch point must be at least 4 residues away from a pre-existing one.