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
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