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Lecture 8 - Glycogen Metabolism

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Lecture 8 - Glycogen Metabolism Lecture 8 - Glycogen Metabolism Chem 454: Regulatory Mechanisms in Biochemistry University of Wisconsin-Eau Claire Introduction Glycogen Text A storage form of glucose 2 Introduction Glycogen is stored primarily in the liver and Text skeletal muscles. Liver - used for maintaining blood glucose levels Muscles - used to meet energy needs of the muscles 3 Introduction Glycogen Text degradation occurs in three steps 4 Introduction Glycogen Text synthesis uses activated precursor UDP–glucose 5 Introduction Regulation of glycogen metabolism is Text complex. Allosteric regulation to meet the needs of the cell Hormonal regulation to meet the needs of the organsim 6 1. Glycogen Breakdown Requires three enzymes and produces Text glucose 6–phosphate Glycogen Phosphorylase Debranching Enzyme Phosphoglucomutase In the liver, an additional enzyme produces free glucose Glucose 6–phosphatase 7 1.1 Phosphorylase Cleavage uses orthophosphate in Text phosphorolysis reactions glycogen + Pi glucose 1-phosphate + glycogen n residues n-1 residues 8 1.2 Debranching Enzyme Two enzymes Text activities are needed to deal with the α–1,6 branch points 9 1.3 Phosphoglucomutase Mechanism is like that of phosphoglycerate Text mutase 10 1.4 Glucose 6-phosphatase Enzyme is found primarily in the liver and is Text used to release glucose into the bloodstream glucose 6-phosphate + H2O glucose + Pi 11 1.5 Mechanism for Phosphorolysis Text 12 1.5 Mechanism for Phosphorolysis Pyridoxyl phosphate Text coenzyme 13 1.5 Mechanism for Phosphorolysis Text 14 2. Regulation of Phosphorylase Phosphorylase is regulated by several Text allosteric effectors that signal the energy state of the cell It is also regulated by reversible phosphorylation in response to the hormones insulin, epinephrine, and glucagon 15 2.1 Muscle Phosphorylase Text 16 2.1 Muscle Phosphorylase Text 17 2.1 Muscle Phosphorylase Text 18 2.2 Liver Phosphorylase Text 19 2.3 Phosphorylase Kinase Text 20 3. Epinephrine and Glucagon Epinephrine and glucagon signal the need for Text glycogen breakdown Epinephrine stimulates glycogen breakdown to a greater extent in the muscle than the liver. HO H H HO N CH3 HO Epinephrine 21 3. Epinephrine and Glucagon Epinephrine and glucagon signal the need for Text glycogen breakdown Glucagon is a peptide hormone that is secreted by the α–cells of the pancreases when blood glucose levels are low 5 10 H3N His-Ser-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Tyr 15 20 Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln 25 29 Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr COO Glucagon 22 3.1 G-protein Signal Transduction Epinephrine binds to a 7TM receptor Text 23 3.1 G-protein Signal Transduction Glucagon also binds to a 7TM receptor Text 24 3.1 α–Adrenergic Receptors in Liver In the liver, epinephrine also binds to Text α–adrenergic receptors, which activate the phosphoinositide signal transduction pathway Release of inositol 1,4,5–trisphosphate by phospholipase C induces the release of Ca2+ from the ER. Binding of Ca2+ to calmodulin partially activates phosphorylase kinase 25 3.1 α–Adrenergic Receptors in Liver Text 26 3.2 Turning It Off Glycogen breakdown can also be rapidly Text turned off. GTPase activity of the G–proteins cAMP phosphodiesterase Protein kinase A also phophorylates the α–subunit of phosphorylase kinase. This makes it more susceptible to dephosphorylation (inactivation) by protein phosphatase 1 (PP1) 27 4. Glycogen Synthesis vs Degradation Different pathways are used for the synthesis Text and degradation. Glycogenn+1 + Pi Glycogenn + Glucose 1-phosphate Glycogenn + UDP-Glucose Glycogenn+1 + UDP 28 4.1 UDP-Glucose UDP-Glucose is an Text activated form of glucose 29 4.1 Glycogen Synthesis UDP-Glucose is an activated form of glucose Text Glucose 1-phosphate + UTP UDB-Glucose + PPi PPi + H2O 2 Pi Glucose 1-phosphate + UTP + H2O Glycogenn+1 + UDP + 2 Pi 30 4.2 Glycogen Synthase Text 31 4.3 Branching Enzyme Text 32 4.3 Branching Enzyme Text 33 4.4 Regulation of Glycogen Synthase Glycogen Synthase is also regulated by Text phosphorylation Protein kinase A catalyses the phosphorylation Glycogen synthase a is the more active, dephosphorylated form Glycogen synthase b is the less active, phosphorylated form 34 4.5 Glycogen is an Efficient Storage Form of Glucose Only 1 equivalent of ATP is used for storing Text each glucose unit Glucose 6-phosphate Glucose 1-phosphate Glucose 1-phosphate + UTP UDP-Glucose + PPi PPi + H2O 2 Pi UDP-Glucose + Glycogenn Glycogenn+1 + UDP UDP + ATP UTP + ADP Glucose 6-phosphate + ATP + Glycogenn + H2O Glycogenn+1 + ADP + 2 Pi 35 5. Reciprocal Regulation of Synthesis vs Breakdown Regulation by hormone triggered c-AMP Text cascade: 36 5.1 Protein Phosphatase 1 PP1 reverses regulatory effects of kinases Text PP1 dephosphorylates glycogen phosphorylase phosphorylase kinase glycogen synthase 37 5.1 Protein Phosphatase 1 PP1 is inactivated by the hormone-triggered Text c-AMP cascade 38 5.2 Insulin Activates Protein Phophatase 1 The insulin-triggered tyrosine kinase cascade Text activates PP1 39 5.3 Regulation by Blood Glucose Blood glucose levels regulate glycogen Text metabolism in the liver 40 5.3 Regulation by Blood Glucose Glucose allosterically converts phosphorylase a Text from the R-state to the T-State 41.
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