metabolism_lecture_6 - Anabolism of glycogen = Glycogenesis...

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Unformatted text preview: Anabolism of glycogen = Glycogenesis Lui s Lenoi r Discovered the role of sugar nucleotides in synthesis of glycogen (and other carbohydrate derivatives). Reaction driven by the i Glucose (from gluconeogenesis) gets phosphorylated by hexokinase , producing Glucose 6-P Phosphoglucomutase converts it to Glucose 1-P Glucose 1-P gets activated for glycogen synthesis by UDP-glucose pyr ophosphor ylase (prominent in liver and skeletal muscle) UDP-gl ucose pyr ophosphor ylase Glycogen synthase Uses UDP-glucose to generate new 1- 4 glycosidic bond at non-reducing end of glycogen ( n > 4! ) Glycogen synthase cannot initiate a new glycogen chain-> needs a primer = glycogenin Fig.15-30 UDP-glucose Glycogenin Transfers six glucose to OH of it Tyr 194 Br anching enzyme (amylo (1-4) to (1-6) transglycosylase) I ntroduces branches by cleaving a 1-4 and forming a new 1-6 glycosidic bond. Transfers 6-7 units to a C 6-OH of a glucose further towards the glycogen core. Starting at the glycogenin pr imer : glycogen synthase attaches glucose units br anching enzyme introduces branches Regulation of glycogen metabolism Glycogen phosphorylase is regulated alloster ically and by hormones through phosphor ylation AMP ATP,Glu6-P + Resting muscle: Almost only phosphorylase b (less active) Working muscle: High [AMP] activates phosphorylase b I ncreased epinephrine level, [Ca 2+ ]: Transition to from a (active) Fig.15-3,Voet& Voet AMP glycogen active site Ser14 glycogenolysis Glycogen phosphor ylase of the liver acts as a glucose sensor : Binding of Glucose to phosphorylase a (active) -> leads to conformational change-> exposes P-Ser to the phosphorylase a phosphatase (PP1)-> dephosphorylation results in less active phosphorylase b Blood glucose level: ~ 80-120 mg/ 100 ml Release of PP1 from phosphorylase-> Activation of synthase (turns off glycogen degradation) Epinephr ine (muscle) and glucagon (liver ) activate glycogenolysis through G-protein / cAMP coupled cascades Cascades lead to strong enhancement of the hormone signal. cAMP gets hydrolyzed by phosphodiesterases, which are inhibited by methylxanthines (caffeine, theophylline) Epinephr ine and Glucagon Stimulate Br eakdown of Glycogen cAMP Earl Sutherland: Cyclic AMP Nobel prize 1971 Edwin Krebs and Edmond Fischer: Protein kinase A Nobel prize 1991 Carl and Gerty Cori: Phosphorylase Nobel prize 1947 I mportant basics of biological signal transduction have been discovered with the regulation of glycogen metabolism. I nsulin triggers activation of glycogen synthase by: blocking activity of glycogen synthase kinase 3 (GSK3) activating phosphoprotein phosphatase 1 Contr ol of Glycogen Synthesis I nsulin signaling pathway increases glucose import into muscle stimulates the activity of muscle hexokinase activates glycogen synthase Stepwise phosphor ylation of glycogen synthase by glycogen synthase kinase 3 (GSK3) Requires prior phosphorylation of glycogen synthase by casein kinase I I...
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metabolism_lecture_6 - Anabolism of glycogen = Glycogenesis...

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