Lecture 8 - Glycogen Metabolism
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Transcript of 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
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GlycogenA storage form of glucose
GlycogenA storage form of glucose
IntroductionIntroduction
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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
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Glycogen degradation occurs in three steps
Glycogen degradation occurs in three steps
IntroductionIntroduction
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Glycogen synthesis uses activated precursor UDP–glucose
Glycogen synthesis uses activated precursor UDP–glucose
IntroductionIntroduction
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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
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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
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Cleavage uses orthophosphate in phosphorolysis reactions
Cleavage uses orthophosphate in phosphorolysis reactions
1.1 Phosphorylase1.1 Phosphorylase
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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
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Mechanism is like that of phosphoglycerate mutase
Mechanism is like that of phosphoglycerate mutase
1.3 Phosphoglucomutase1.3 Phosphoglucomutase
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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
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1.5 Mechanism for Phosphorolysis1.5 Mechanism for Phosphorolysis
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1.5 Mechanism for Phosphorolysis1.5 Mechanism for Phosphorolysis
Pyridoxyl phosphate coenzyme
Pyridoxyl phosphate coenzyme
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1.5 Mechanism for Phosphorolysis1.5 Mechanism for Phosphorolysis
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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
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2.1 Muscle Phosphorylase2.1 Muscle Phosphorylase
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2.1 Muscle Phosphorylase2.1 Muscle Phosphorylase
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2.1 Muscle Phosphorylase2.1 Muscle Phosphorylase
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2.2 Liver Phosphorylase2.2 Liver Phosphorylase
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2.3 Phosphorylase Kinase2.3 Phosphorylase Kinase
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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
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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
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Epinephrine binds to a 7TM receptorEpinephrine binds to a 7TM receptor
3.1 G-protein Signal Transduction3.1 G-protein Signal Transduction
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Glucagon also binds to a 7TM receptorGlucagon also binds to a 7TM receptor
3.1 G-protein Signal Transduction3.1 G-protein Signal Transduction
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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
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3.1 α–Adrenergic Receptors in Liver3.1 α–Adrenergic Receptors in Liver
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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)
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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
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UDP-Glucose is an activated form of glucose
UDP-Glucose is an activated form of glucose
4.1 UDP-Glucose4.1 UDP-Glucose
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UDP-Glucose is an activated form of glucose
UDP-Glucose is an activated form of glucose
4.1 Glycogen Synthesis4.1 Glycogen Synthesis
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4.2 Glycogen Synthase4.2 Glycogen Synthase
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4.3 Branching Enzyme4.3 Branching Enzyme
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4.3 Branching Enzyme4.3 Branching Enzyme
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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
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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
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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
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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
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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
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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
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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
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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