Chem 454: Regulatory Mechanisms in BiochemistryUniversity of Wisconsin-Eau Claire

Lecture 8 - Glycogen Metabolism

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TextGlycogen

A storage form of glucose

Introduction

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TextGlycogen is stored primarily in the liver and skeletal muscles.

Liver - used for maintaining blood glucose levelsMuscles - used to meet energy needs of the muscles

Introduction

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TextGlycogen degradation occurs in three steps

Introduction

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TextGlycogen synthesis uses activated precursor UDP–glucose

Introduction

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TextRegulation of glycogen metabolism is complex.

Allosteric regulation to meet the needs of the cellHormonal regulation to meet the needs of the organsim

Introduction

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TextRequires three enzymes and produces glucose 6–phosphate

Glycogen Phosphorylase

Debranching Enzyme

Phosphoglucomutase

In the liver, an additional enzyme produces free glucose

Glucose 6–phosphatase

1. Glycogen Breakdown

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TextCleavage uses orthophosphate in phosphorolysis reactions

1.1 Phosphorylase

glycogen + Pi glucose 1-phosphate + glycogenn residues n-1 residues

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TextTwo enzymes activities are needed to deal with the α–1,6 branch points

1.2 Debranching Enzyme

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TextMechanism is like that of phosphoglycerate mutase

1.3 Phosphoglucomutase

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TextEnzyme is found primarily in the liver and is used to release glucose into the bloodstream

1.4 Glucose 6-phosphatase

glucose 6-phosphate + H2O glucose + Pi

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1.5 Mechanism for Phosphorolysis

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1.5 Mechanism for Phosphorolysis

Pyridoxyl phosphate coenzyme

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1.5 Mechanism for Phosphorolysis

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TextPhosphorylase is regulated by several 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

2. Regulation of Phosphorylase

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2.1 Muscle Phosphorylase

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2.1 Muscle Phosphorylase

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2.1 Muscle Phosphorylase

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2.2 Liver Phosphorylase

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2.3 Phosphorylase Kinase

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TextEpinephrine and glucagon signal the need for glycogen breakdown

Epinephrine stimulates glycogen breakdown to a greater extent in the muscle than the liver.

3. Epinephrine and Glucagon

HO

HO HNCH3

HO H

Epinephrine

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TextEpinephrine and glucagon signal the need for glycogen breakdown

Glucagon is a peptide hormone that is secreted by the α–cells of the pancreases when blood glucose levels are low

3. Epinephrine and Glucagon

H3N His-Ser-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Tyr

Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln

Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr COO

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Glucagon

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TextEpinephrine binds to a 7TM receptor

3.1 G-protein Signal Transduction

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TextGlucagon also binds to a 7TM receptor

3.1 G-protein Signal Transduction

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TextIn the liver, epinephrine also binds to 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

3.1 α–Adrenergic Receptors in Liver

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3.1 α–Adrenergic Receptors in Liver

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3.2 Turning It Off

Glycogen breakdown can also be rapidly 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)

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TextDifferent pathways are used for the synthesis and degradation.

4. Glycogen Synthesis vs Degradation

Glycogenn+1 + Pi Glycogenn + Glucose 1-phosphate

Glycogenn + UDP-Glucose Glycogenn+1 + UDP

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TextUDP-Glucose is an activated form of glucose

4.1 UDP-Glucose

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TextUDP-Glucose is an activated form of glucose

4.1 Glycogen Synthesis

Glucose 1-phosphate + UTP UDB-Glucose + PPiPPi + H2O 2 Pi

Glucose 1-phosphate + UTP + H2O Glycogenn+1 + UDP + 2 Pi

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4.2 Glycogen Synthase

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4.3 Branching Enzyme

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4.3 Branching Enzyme

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TextGlycogen Synthase is also regulated by phosphorylation

Protein kinase A catalyses the phosphorylationGlycogen synthase a is the more active, dephosphorylated formGlycogen synthase b is the less active, phosphorylated form

4.4 Regulation of Glycogen Synthase

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TextOnly 1 equivalent of ATP is used for storing each glucose unit

4.5 Glycogen is an Efficient Storage Form of Glucose

Glucose 6-phosphate Glucose 1-phosphateGlucose 1-phosphate + UTP UDP-Glucose + PPi

PPi + H2O 2 PiUDP-Glucose + Glycogenn Glycogenn+1 + UDP

UDP + ATP UTP + ADPGlucose 6-phosphate + ATP + Glycogenn + H2O Glycogenn+1 + ADP + 2 Pi

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TextRegulation by hormone triggered c-AMP cascade:

5. Reciprocal Regulation ofSynthesis vs Breakdown

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TextPP1 reverses regulatory effects of kinases

PP1 dephosphorylatesglycogen phosphorylasephosphorylase kinaseglycogen synthase

5.1 Protein Phosphatase 1

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TextPP1 is inactivated by the hormone-triggered c-AMP cascade

5.1 Protein Phosphatase 1

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TextThe insulin-triggered tyrosine kinase cascade activates PP1

5.2 Insulin Activates Protein Phophatase 1

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TextBlood glucose levels regulate glycogen metabolism in the liver

5.3 Regulation by Blood Glucose

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TextGlucose allosterically converts phosphorylase a from the R-state to the T-State

5.3 Regulation by Blood Glucose