Nutr 470 1st Edition Lecture 8Current Lecture- Nutritional Regulation of Glycogen Metabolism -Glycogen• Glycogen is the major storage of carbohydrate in animals. -when we have extra it becomes storage-and access it when we are in a fasting condition• Glycogen is a polymer of glucose residues linked by a(1–4) glycosidic bonds, mainly and a(1–6) glycosidic bonds, at branch points. -Glycogen Metabolism • Glycogen in the liver and muscle represents nearly the total glycogen of the body. • Glycogen provides glucose/glucose-6-phosphate. • Liver glycogen produces glucose that can be exported and used by other tissues/organs. • Muscle glycogen provides G-6-P, which can be used through glycolysis within muscle. -Glycogen Metabolism • Glycogenesis: The synthesis of glycogen -from glucose to G6P to glucose-1-P to glycogen• Glycogenolysis: The breakdown of glycogen -glycogen—> glucose-1-P—> G6P —> glucose-reverse of above, but use of different enzymes-glycogen phosphylate, rate determining step-generate metabolites-way to provide energy— only glucose can be export to the circulation and used• Glycogenesis and glycogenolysis can occur simultaneously – glycogen cycling • Major flux of glucose metabolism in liver cells • G-6-P links glycogen metabolism to glycolysis and gluconeogenesis. • others mentioned: glycolysis, gluconeogensisDiabetes:• There are diabetes treatments… but drug isn’t safe• this pathway leads to toxic products. When the chemical is toxic you have a problem.. Sometimes you can modify the chemical and make it better, but othertimes you can’t mimic or modify it and reduce toxicity. if the toxicity is mechanism related, than you cannot avoid this affect — the toxicity. -Glycogen Metabolism • Source of G-6-P -Gluconeogenic pathway -Glycogenolytic pathway -Glycolytic pathway • Glucose-6-phosphate links glycogen metabolism to glycolysis and gluconeogenesis.-Glycogenesis • Direct pathway for glycogen synthesis • Indirect pathway for glycogen synthesis • Indirect pathway likely makes a significant contribution to glycogenesis after a meal. -Glycogen Synthesis • Glucose-6-phosphate is converted to glucose-1-phosphate by phosphoglucomutase. • Glucose-1-phosphate reacts with UTP to form the active nucleotide UDPG and pyrophosphate. • Glycogen synthase -catalyzes the formation of a glycoside bond between C1 of the glucose of UDPG and C4 of a terminal glucose residue of glycogen. -Glycogen synthase can only extend an already existing a(1→4) linked glucan chain. -Branch enzyme transfers a part of 1→4 chain to a neighbor chain to form a 1→6 linkage, establishing a branch point. -Glycogenesis and Glucose Homeostasis • Glycogenesis is crucial for the control of glucose homeostasis. • Glycogenesis in the liver -Hepatic glycogenesis is tightly associated with suppression of glucose produced by the liver.• Glycogenesis in muscle -Glycogenesis in muscle is associated with glucose uptake/phosphorylation, contributing to the regulation of glucose homeostasis. -Regulation of Glycogen Synthesis • Glycogen synthase-is the key enzyme that controls the rates of glycogen synthesis -Allosteric activator • Glucose-6-phosphate is the most powerful activator of glycogen synthase • Small molecule compounds have been verified to activate glycogen synthase• kinetics— the activators will reduce Km, decrease Vmax-Covalent inhibition • The cAMP, at high levels, activates cAMP-dependent protein kinase. • The cAMP-dependent protein kinase phosphorylates and inactivates glycogen synthase. • Insulin-increases the activity of glycogen synthase. • Insulin increases the activity of glucokinase in the liver, which promotes glucose phosphorylation. • Insulin promotes GLUT4 translocation in muscle, which is linked to an increasein glucose phosphorylation. • increase of G-6-P, increases Glycogen synthase • Insulin promotes the generation of glucose-6-phosphate in both the liver and muscle. • Insulin and glucose-6-phospohate synergistically activates glycogen synthase. • Insulin inhibits the production of cAMP, and thereby suppresses the inhibitory effect of cAMP on glycogen synthase. • Insulin inhibits the activity of glycogen synthase kinase. -Glycogen synthase kinase phosphorylates and inhibits glycogen synthase. • Inhibition of the inhibitory effect on glycogen synthase • Glucose-at elevated levels, promotes glycogen synthesis, likely through secondary effects. -Glucose stimulates insulin secretion. -In the liver, glucose stimulates glucokinase translocation, which is usually associated with with an increase in glucose phosphorylation. -Cooperative Regulation of Glycogenesis • After a meal, the levels of glucose and insulin are increased. • Glycogenesis is cooperatively regulated in response to feeding. • Glucose and insulin increase —> glycogenesis increase, thus increasing glycolysis-Coordination in Glycogenesis and Glycolysis • Glycogenesis and glycolysis is regulated in a coordinate pattern. • Rapid regulation of glucose homeostasis.Summary -Glycogen and glucose storage -Pathways of glycogenesis -Cooperative regulation of glycogenesis -Regulation of glycogen