Question

4. Glycogen Synthesis

a) What is the role of Glycogenin in glycogen synthesis?

b) Which enzymes regulate glycogen synthesis and degradation (directly or indirectly)?

c) Hers disease is caused by mutations in the liver form of glycogen phosphorylase and often has mild symptoms. In contrast von Gierke disease, which is caused by mutations in glucose 6-phosphatase, has severe symptoms including severe hypoglycemia (low blood sugar). Based on your knowledge of glycogen and glucose metabolism, why does von Gierke disease have more severe symptoms than Hers disease?

Answer 1

4a. Glycogenin is a 38 KDa self glucosylating glucosyltransferase that is involved in the de novo glycogen synthesis. It transfers a glucosyl residue from UDP-glucose to the hydroxyl group to a tyrosine 194 present in it via a glucose-1-O-tyrosyl linkage. Further, glucose units are subsequently added in a 1,4-linkage thereby forming 7-8 glucosyly residues long oligosaccharide. Glucosylated glycogenin, is a specialized initiator protein or primer for glycogen synthesis in muscle and in other tissues. It is also a substrate for glycogen synthase 1, and 2.

b. Glycogen synthesis and degradation are regulated by cAMP-protein kinase A cascade that is hormonally stimulated. Protein kinase A adds phosphate groups to phosphorylase kinase and activates it. The kinase then phosphorylase b to active phosphorylase a, thereby stimulating glycogen breakdown. Protein kinase A along with glycogen synthase kinase inactivates glycogen synthase and decreases its activity to shut off glycogen synthesis.

Glucose inhibits liver phosphorylase by preventing the transition to active state that is required to release phosphatase 1. Calcium inhibits muscle phosphorylase enzymes, which is insensitive to glucose. In muscle, epinephrine or glucagon activates protein kinase A.

Protein phosphatase 1 removes phosphate groups from serine and threonine residues in phosphorylase kinase and phosphorylase a, thereby inactivating them. This causes a decrease in glycogen degradation. It also removes phosphate groups from phosphorylase b, and converts it to active form of phosphorylase a. This increases glycogen biosynthesis.

When blood glucose levels are high, insulin triggers the pathway, which activates protein phosphatase 1. This will cause increase in glycogen biosynthesis and prevents its breakdown. Insulin also inactivates glycogen synthase kinase and prevents phosphorylation of glycogen synthase. Increase glucose in blood causes inactivation of phosphorylase and later activates glycogen synthase.

c. The von Gierke disease was describe by Edgar von Gierke in 1929, wherein there is prolonged hypoglycemia between meals. In this disease, glucose-6-phosphatase is absent in liver and kidneys. As glucose-6-phosphatase is absent, glucose cannot be formed glucose -6-phosphate in the cells. Glucose-6-phosphate cannot cross plasma membrane and accumulates in cells, causing increased glycolysis and accumulation of lactate and pyruvate and increase fats. This disease is mostly genetic and passed through families. Low blood sugar causes seizures and death in infants. Glucose-6 phosphate deficiency leads to increased glycogen and fat buildup in liver, kidneys, blood cells and intestine, which is lethal for cells. Glucose -6-phosphatase step is the final step in gluconeogenesis and is required for regulation of glucose levels. As gluconeogenesis is affected, the symptoms are drastic. Absence of gluconeogenesis will affect fat metabolism and other functions such as pyruvate to alanine conversion, uric acid synthesis etc.

Mutations in glycogen phosphorylase cause Hers disease, which is milder form. In this disease, glycogen phosphorylase is deficient, causing accumulation of glycogen in body. Although, there is hepatomegaly of the lover, the hypoglycemia is moderate as only release of glucose from the liver is impaired. Only the liver and blood cells are affected in this condition. Glycogen phosphorylase is involved in the last steps of glycogen breakdown as it releases glucose from glycogen. Hence, only glucose from glycogen breakdown is affected.

Liver glycogen phosphorylase catalyzes the breakdown of a ?-1,4-glycosidic bond in glycogen. Thus, there is formation of glucose-1-phosphate, which is then converted to glucose. This enzyme is only required during starvation when sugar levels reduce. Gluconeogensis is preserved in this disease. Thus, symptoms will be milder.