Lecture 8 - Glycogen Metabolism · Lecture 8 - Glycogen Metabolism 1 2 Text Glycogen A storage form...
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Chem 454: Regulatory Mechanisms in Biochemistry University of Wisconsin-Eau Claire Lecture 8 - Glycogen Metabolism 1 2 Glycogen A storage form of glucose Introduction 2 3 Glycogen is stored primarily in the liver and skeletal muscles. Liver - used for maintaining blood glucose levels Muscles - used to meet energy needs of the muscles Introduction 3 4 Glycogen degradation occurs in three steps Introduction 4
Transcript of Lecture 8 - Glycogen Metabolism · Lecture 8 - Glycogen Metabolism 1 2 Text Glycogen A storage form...
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
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