lecture 8 - glycogen metabolism

Chem 454: Regulatory Mechanisms in Biochemistry

University of Wisconsin-Eau Claire

Chem 454: Regulatory Mechanisms in Biochemistry

University of Wisconsin-Eau Claire

Lecture 8 - Glycogen MetabolismLecture 8 - Glycogen Metabolism

22

GlycogenA storage form of glucose

GlycogenA storage form of glucose

IntroductionIntroduction

33

Glycogen is stored primarily in the liver and skeletal muscles.

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

Glycogen is stored primarily in the liver and skeletal muscles.

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

IntroductionIntroduction

44

Glycogen degradation occurs in three steps

Glycogen degradation occurs in three steps

IntroductionIntroduction

55

Glycogen synthesis uses activated precursor UDP–glucose

Glycogen synthesis uses activated precursor UDP–glucose

IntroductionIntroduction

66

Regulation of glycogen metabolism is complex.

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

Regulation of glycogen metabolism is complex.

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

IntroductionIntroduction

77

Requires three enzymes and produces glucose 6–phosphate

Glycogen Phosphorylase

Debranching Enzyme

Phosphoglucomutase

In the liver, an additional enzyme produces free glucose

Glucose 6–phosphatase

Requires 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 Breakdown1. Glycogen Breakdown

88

Cleavage uses orthophosphate in phosphorolysis reactions

Cleavage uses orthophosphate in phosphorolysis reactions

1.1 Phosphorylase1.1 Phosphorylase

99

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

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

1.2 Debranching Enzyme1.2 Debranching Enzyme

1010

Mechanism is like that of phosphoglycerate mutase

Mechanism is like that of phosphoglycerate mutase

1.3 Phosphoglucomutase1.3 Phosphoglucomutase

1111

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

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

1.4 Glucose 6-phosphatase1.4 Glucose 6-phosphatase

1212

1.5 Mechanism for Phosphorolysis1.5 Mechanism for Phosphorolysis

1313

1.5 Mechanism for Phosphorolysis1.5 Mechanism for Phosphorolysis

Pyridoxyl phosphate coenzyme

Pyridoxyl phosphate coenzyme

1414

1.5 Mechanism for Phosphorolysis1.5 Mechanism for Phosphorolysis

1515

Phosphorylase 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

Phosphorylase 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 Phosphorylase2. Regulation of Phosphorylase

1616

2.1 Muscle Phosphorylase2.1 Muscle Phosphorylase

1717

2.1 Muscle Phosphorylase2.1 Muscle Phosphorylase

1818

2.1 Muscle Phosphorylase2.1 Muscle Phosphorylase

1919

2.2 Liver Phosphorylase2.2 Liver Phosphorylase

2020

2.3 Phosphorylase Kinase2.3 Phosphorylase Kinase

2121

Epinephrine and glucagon signal the need for glycogen breakdown

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

Epinephrine 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 Glucagon3. Epinephrine and Glucagon

2222

Epinephrine 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

Epinephrine 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 Glucagon3. Epinephrine and Glucagon

2323

Epinephrine binds to a 7TM receptorEpinephrine binds to a 7TM receptor

3.1 G-protein Signal Transduction3.1 G-protein Signal Transduction

2424

Glucagon also binds to a 7TM receptorGlucagon also binds to a 7TM receptor

3.1 G-protein Signal Transduction3.1 G-protein Signal Transduction

2525

In 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

In 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 Liver3.1 α–Adrenergic Receptors in Liver

2626

3.1 α–Adrenergic Receptors in Liver3.1 α–Adrenergic Receptors in Liver

2727

3.2 Turning It Off3.2 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)

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)

2828

Different pathways are used for the synthesis and degradation.

Different pathways are used for the synthesis and degradation.

4. Glycogen Synthesis vs Degradation4. Glycogen Synthesis vs Degradation

2929

UDP-Glucose is an activated form of glucose

UDP-Glucose is an activated form of glucose

4.1 UDP-Glucose4.1 UDP-Glucose

3030

UDP-Glucose is an activated form of glucose

UDP-Glucose is an activated form of glucose

4.1 Glycogen Synthesis4.1 Glycogen Synthesis

3131

4.2 Glycogen Synthase4.2 Glycogen Synthase

3232

4.3 Branching Enzyme4.3 Branching Enzyme

3333

4.3 Branching Enzyme4.3 Branching Enzyme

3434

Glycogen 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

Glycogen 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 Synthase4.4 Regulation of Glycogen Synthase

3535

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

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

4.5 Glycogen is an Efficient Storage Form of Glucose

4.5 Glycogen is an Efficient Storage Form of Glucose

3636

Regulation by hormone triggered c-AMP cascade:

Regulation by hormone triggered c-AMP cascade:

5. Reciprocal Regulation ofSynthesis vs Breakdown

5. Reciprocal Regulation ofSynthesis vs Breakdown

3737

PP1 reverses regulatory effects of kinases

PP1 dephosphorylatesglycogen phosphorylasephosphorylase kinaseglycogen synthase

PP1 reverses regulatory effects of kinases

PP1 dephosphorylatesglycogen phosphorylasephosphorylase kinaseglycogen synthase

5.1 Protein Phosphatase 15.1 Protein Phosphatase 1

3838

PP1 is inactivated by the hormone-triggered c-AMP cascade

PP1 is inactivated by the hormone-triggered c-AMP cascade

5.1 Protein Phosphatase 15.1 Protein Phosphatase 1

3939

The insulin-triggered tyrosine kinase cascade activates PP1

The insulin-triggered tyrosine kinase cascade activates PP1

5.2 Insulin Activates Protein Phophatase 1

5.2 Insulin Activates Protein Phophatase 1

4040

Blood glucose levels regulate glycogen metabolism in the liver

Blood glucose levels regulate glycogen metabolism in the liver

5.3 Regulation by Blood Glucose 5.3 Regulation by Blood Glucose

4141

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

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

5.3 Regulation by Blood Glucose 5.3 Regulation by Blood Glucose