2/25/151Biochemistry401Lecture 24 Glycogen MetabolismRegulationLocal signalsGlobal signalsPrimary Site of Regulation GLYCOGEN CATABOLISM Glycogen Phosphorylase: Allosterically regulated homodimer. One subunit is shown in yellow. This enzyme is found attached to glycogen. It’s activity, however is dictated by it’s phosphorylation state and presence of non-covalent allosteric regulators.2/25/152Equilibrium Tense (T), Relaxed (R) states In the tense state, the active site is partially blocked. Phosphorylation P-Serine: results in formation of phosphorylase a, favors the R state and therefore is more active. (Global Control) R T Skeletal Muscle Isozyme Glycogen Phosphyorylase: Regulation Watch the arrows! Muscle Glycogen Phosphorylase a Phosphorylase kinase Phosphorylated at key serine residue by Phosphorylase Kinase phosphorylates phosphorylase b Homotetramer (αβγδ)4 γ : Catalytic, α,β,δ: Regulatory δ: calmodulin analog, binds Ca2+ β: phosphorylation site2/25/153Global: Phosphorylation by PKA Local: Increase in intracellular Ca++ Phosphorylase kinase Adrenal glands!secrete epinephrine (adrenaline) !Pancreas secretes glucagon!Global signals!Epinephrine!Glucagon !Adrenal glands!secrete epinephrine (adrenaline) !2/25/154EpinephrineAlpha-islet cells of the pancreas!secrete glucagon !Pancreasseven-transmembrane-helix (7TM) receptors2/25/155ExerciseLocal: Ca++!Global: Epinephrine!Phosphorylation Activates Glycogen Phosphorylase, and Inactivates Glycogen Synthase Reciprocal Effects of Phosphorylation High levels of AMP (in muscle) cause AMP to bind to the nucleotide binding site and cause phosphorylase b to favor the relaxed state, too. Local control2/25/156At high concentrations, free glucose binds a regulatory site so that even phosphorylase a favors the tense state. Local control Inactivation of this part Activation of this part inactivates glycogen phosphorylase, and phosphorylase kinase, and activates glycogen synthase through removal of inhibiting phosphates from glycogen synthase, thus activating synthesis. Inactivation of Glycogen Phophorylase and activation of glycogen synthase by Protein Phosphatase 12/25/157Insulin Activates Glycogen Synthesis and Inhibits Glycogen Breakdown Activation of Protein Phosphatase 1Insulin is released from pancreatic beta-islet cells Insulin binds its receptor, causing dimerization. Insulin receptor becomes phosphorylated Adaptor proteins bind insulin receptor. Downstream effect results in PP1 activation. Dephosphorylation of: Glycogen synthase Glycogen phosphorylase kinase Glycogen phosphorylase a to form phosphorylase
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