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metabolism_lecture_6

metabolism_lecture_6 - Ana bol i sm of gl ycogen = Gl...

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Anabolism of glycogen = Glycogenesis Luis Lenoir Discovered the role of sugar nucleotides in synthesis of glycogen (and other carbohydrate derivatives). Reaction driven by the hydrolysis of pyrophosphate PP 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 pyrophosphorylase (prominent in liver and skeletal muscle) UDP-glucose pyrophosphorylase
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Glycogen synthase Uses UDP-glucose to generate new α 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
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Branching enzyme (amylo (1-4) to (1-6) transglycosylase) Introduces branches by cleaving a α 1-4 and forming a new α 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 primer : glycogen synthase attaches glucose units branching enzyme introduces branches
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Regulation of glycogen metabolism Glycogen phosphorylase is regulated allosterically and by hormones through phosphorylation AMP ATP,Glu6-P + Resting muscle: Almost only phosphorylase b (less active) Working muscle: High [AMP] activates phosphorylase b Increased epinephrine level, [Ca 2+ ]: Transition to from a (active) Fig.15-3,Voet& Voet AMP glycogen active site Ser14 glycogenolysis
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Glycogen phosphorylase 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)
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Epinephrine (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) Epinephrine and Glucagon Stimulate Breakdown of Glycogen cAMP
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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 Important basics of biological signal transduction have been discovered with the regulation of glycogen metabolism.
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Insulin triggers activation of glycogen synthase by: blocking activity of glycogen synthase kinase 3 (GSK3) activating phosphoprotein phosphatase 1 Control of Glycogen Synthesis Insulin signaling pathway increases glucose import into muscle stimulates the activity of muscle hexokinase activates glycogen synthase
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Stepwise phosphorylation of glycogen synthase by glycogen synthase kinase 3 (GSK3) Requires prior phosphorylation of glycogen synthase by casein kinase II GSK3 is regulated through phosphorylation by PKA or PKB.
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