Biochemistry

Lecture 7 Glycogen metabolism

Glycogen
Glycogen is a branched polymer of glucose. It has a tree-like structure; It is a molecule with one start and many ends. The core of glycogen is the protein glycogenin.

Glycogen
Glycogen is the macromolecular storage form of glucose. This form of energy is readily available. Glucose molecules are connected by -1,4glycosidic bonds in long chains. Branches are connected by -1,6glycosidic bonds.

Glycogen

Glucose molecules are connected by -1,4-glycosidic bonds in long chains. Branches are connected by -1,6-glycosidic bonds.

Glycogen balance

Glycogen balance: Liver

Glycogen is found in many cells. Large amounts are stored in liver (up to 150 g) and muscle cells (up to 300 g). The glycogen of the liver serves as a glucose buffer for the blood glucose.

Glycogen balance: Muscle

The glycogen of the muscle serves for its own energy demand exclusively.

Glycogen metabolism

Glycogen biosynthesis
In liver cells glycogen is either synthesized or degraded depending on the nutritional status. Biosynthesis of glycogen begins with the reversible conversion of glucose 6-phosphate to glucose 1phosphate. Step 1: glucose 1-phosphate is converted to uridine diphosphate glucose (UDP-glucose), a compound with a high transfer potential (active glucose)

Glycogen biosynthesis
Step 2: UDP-glucose is used to build up glycogen by extending an existing chain. The enzyme glycogen synthase forms -1,4 glycosidic bonds. This is a key enzyme of biosythesis and a point of regulation. Step 3: Branches will be made by a branching enzyme which transfers blocks of about 7 glucose units from the end of the growing chain.

Glycogen metabolism

Glycogen breakdown
Also the breakdown of glycogen requires the interplay of several enzymes. The degradation of glycogen always starts at the ends. Step 4: Phosphorylase catalyzes the phosphorolytic cleavage of glycogen to release glucose 1-phosphate. Phosphorylase is the key enzyme of the breakdown of glycogen. A special point of this reaction is that glycogen is not split with water but with phosphoric acid.

Reaction of glycogen phosphorylase

Glycogen breakdown
Glucose 1-phosphate is easily isomerized to glucose 6-phosphate, the active form of glucose in the cells, which can be used for many purposes. Step 5 and 6: Branch points are degraded by the concerted action of a glucanotransferase and an 1,6-glucosidase.

Glycogen breakdown

Control of glycogen metabolism

The glycogen metabolism in the liver is controlled by hormones. Synthesis and breakdown are reciprocally regulated. Insulin stimulates biosynthesis. Epinephrin (adrenalin) and glucagon stimulate degradation, concomitantly they also inhibit biosynthesis. Muscle is the primary target of epinephrin, whereas liver is responsive to glucagon. AMP, the intracellular signal for lack of energy, also stimulates degradation.

Activation of phosphorylase by hormones

Activation of phosphorylase by hormones

The hormones act by binding to their membrane receptors. A signal transduction cascade transmits and amplifies the signal. Details of this cascade are complex and depend on the cell type. The example shows a need of energy signalled by epinephrin and glucagon. The final response is that phosphorylase is converted from an inactive state (phosphorylase b) to an active state (phosphorylase a) by phosphorylation, which immediately starts the degradation of glycogen. Eventually, glucose 6-phosphate or glucose is made available.

Glycogen storage diseases

Glycogen-storage diseases
Several inherited defects of individual enzymes of the glycogen metabolism are known. Collectively they are called Glycogen-storage diseases. They may cause a variety of different clinical symptoms. The most common disease is the type I von Gierke disease, in which glucose 6-phosphatase or a transport system for sugars is absent. Since glucose 6-phosphate accumulates in the liver, the degradation of glycogen is inhibited causing a massive enlargement of the liver, severe hypoglycaemia and a few other symptoms.

Pompe disease
Type II glycogenstorage disease (Pompe disease) The lysosomes are filled with glycogen because of a deficiency in -1,4glucosidase, a hydrolytic enzyme confined to lysosomes. Glycogen in the cytoplasm is normal.

Key words
Glycogen Glycogenin -1,4- and -1,6-glycosidic bond Glycogen balance, biosynthesis and degradation Glucose 1-phosphate, glucose 6-phosphate UDP-glucose Glycogen synthase Branching enzyme Phosphorylase a and b Phosphorolysis hydrolysis Glucanotransferase

-1,6-glucosidase Epinephrine, glucagon, insulin Signal transduction cascade Glycogen storage disease Type I von Gierke disease Type II Pompe disease