2 25 15 Biochemistry 401 Lecture 24 Glycogen Metabolism Regulation Local signals Global signals GLYCOGEN CATABOLISM Primary Site of Regulation 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 noncovalent allosteric regulators 1 2 25 15 Glycogen Phosphyorylase Regulation Equilibrium Tense T Relaxed R states In the tense state the active site is partially blocked Watch the arrows R Phosphorylation P Serine results in formation of phosphorylase a favors the R state and therefore is more active Global Control T Skeletal Muscle Isozyme Glycogen Phosphorylase a Phosphorylated at key serine residue by Phosphorylase kinase Muscle Phosphorylase Kinase phosphorylates phosphorylase b Homotetramer 4 Catalytic Regulatory calmodulin analog binds Ca2 phosphorylation site 2 2 25 15 Phosphorylase kinase Global Phosphorylation by PKA Local Increase in intracellular Ca Adrenal glands secrete epinephrine adrenaline Pancreas secretes glucagon Global signals Epinephrine Glucagon Adrenal glands secrete epinephrine adrenaline 3 2 25 15 Epinephrine Pancreas Alpha islet cells of the pancreas secrete glucagon seven transmembranehelix 7TM receptors 4 2 25 15 Exercise Local Ca Global Epinephrine Reciprocal Effects of Phosphorylation Phosphorylation Activates Glycogen Phosphorylase and Inactivates Glycogen Synthase Local control 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 5 2 25 15 Local control At high concentrations free glucose binds a regulatory site so that even phosphorylase a favors the tense state Inactivation of this part Inactivation of Glycogen Phophorylase and activation of glycogen synthase by Protein Phosphatase 1 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 6 2 25 15 Insulin Activates Glycogen Synthesis and Inhibits Glycogen Breakdown Activation of Protein Phosphatase 1 Insulin 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 b 7
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