1. BIOC 460 - DR. TISCHLER LECTURE 31 GLYCOGEN METABOLISM: PATHWAYS/ALLOSTERIC CONTROL

2. OBJECTIVES Glycogenolysis Pathway 1. general features; describe glycogen phosphorylase. 2.different fates of glucose-6-P from glycogenolysis in liver vs muscle 3.Tense vs relaxed forms of glycogen phosphorylase – activity 4.Function of phosphorylase kinase in promoting glycogen mobilization relative to the phosphorylation state of glycogen phosphorylase. 5.Explain the physiological basis for: a) AMP activating and ATP inhibiting glycogen phosphorylase b) calcium activating phosphorylase kinase c)G-6-P inhibiting phosphorylase/activating glycogen synthase 6.Why glycogen storage disease type I (von Gierke's disease) can lead to severe hypoglycemia but type V (McArdle's disease) does not cause hypoglycemia

3. Glycogenesis Pathway 1.general features describe glycogen synthase 2.Carbohydrate loading 3.Explain the physiological basis for G-6-P activating glycogen synthase 4.Compare two forms of glycogen synthase (d-form and i-form).

4. Figure 1. The glycogen structure showing the glycosidic bonds liver stores glycogen that provides 75% of glucose needed (mostly by RBC and brain) during first 24 hours of food deprivation muscle stores glycogen solely for its own needs; lack of G-6-Pase prevents formation and secretion of glucose for use by other tissues highly branched structure to increase solubility; provides many more sites for removal of glucose units that are phosphorylated by glycogen phosphorylase

5. PiPi glycogen phosphorylase phosphoglucomutase glucose-6-phosphatase Glucose-1-phosphate Glucose-6-phosphate Glycogen Glucose X glycolysis LIVER PATHWAY Figure 2a. Glycogenolysis and the fate of glycogen in liver and kidney (inhibited by lack of fructose-2,6-bisP) PiPi

6. Figure 2b. Glycogenolysis and the fate of glycogen in muscle. glycolysis Pyruvate MUSCLE PATHWAY lactate dehydrogenase Lactate Anaerobic glycolysis pyruvate dehydrogenase Acetyl CoA PiPi glycogen phosphorylase phosphoglucomutase Glucose-1-phosphate Glucose-6-phosphate Glycogen CO 2 Aerobic metabolism

7. Figure 3. Pathway of glycogen synthesis (glycogenesis) Glucose (Glucose) n+1 UDP (Glucose) n Glycogen Synthase UTPPPi UDP-glucose Glucose-1-P Uridyltransferase Glucose-1-phosphate Phospho- glucomutase Glucose-6-phosphate Hexokinase (muscle) Glucokinase (liver) ADP ATP

8. OH relaxed active +G-6-P +ATP (in muscle) +AMP (in muscle) activation by calcium inhibition by glucose-6-P PiPi protein phosphatase-1 tense- inactive phosphorylase-b OH ATP ADP phosphorylase kinase phosphorylase-a OPO 3 relaxed active Figure 4. Regulation of glycogen phosphorylase

9. OH relaxed active +G-6-P +ATP (in muscle) +AMP (in muscle) activation by calcium inhibition by glucose-6-P PiPi protein phosphatase-1 tense- inactive phosphorylase-b OH ATP ADP phosphorylase kinase phosphorylase-a OPO 3 relaxed active Figure 4. Regulation of glycogen phosphorylase

10. ATP ADP variety of protein kinases active Glycogen synthase-i OH +glucose-6-P active enzyme Figure 6. Regulation of glycogen synthase PiPi protein phosphatase inactive OPO 3 Glycogen synthase-d

11. GLYCOGEN STORAGE DISEASES DiseaseTypeEnzyme DeficiencyOrgan Location Type I: Von Gierke Disease Hypoglycemia due to defect of the final step of gluconeogenesis Decreased mobilization of glycogen produces hepatomegaly. Type V: McArdle Disease Skeletal muscle affected, but liver enzyme is normal No hypoglycemia - muscle glycogen does not produce glucose Temporary weakness and cramping of muscle after exercise No rise in blood lactate during strenuous exercise Muscle contains a high level of glycogen von Gierke diseaseIglucose-6-phosphataseliver McArdle diseaseVglycogen phosphorylasemuscle