Glycogen Metabolism II Flashcards
Regulation of glycogen metabolism is important for maintaining ___ ____ and providing ____ ___ ____
Blood sugar
Energy to muscles
Are the pathways for glycogen synthesis and degradation independent? If so, what does this allow for?
Yes, which allows for separate regulation
What are the 2 key enzymes in glycogen metabolism?
Glycogen synthase- rate-limiting step for synthesis
Glycogen phosphorylase- rate-limiting step for degradation
How are Glycogen synthase and Glycogen phosphorylase regulated?
Allosteric regulators
Reversible phosphorylation (under the control of hormones)
*Note that the effects are in opposite directions
During the regulation of Glycogen Synthesis, what is the active and inactive form of glycogen synthase?
Active- Nonphosphorylated “a” form
Inactive- Phosphorylated “b” form
What enzyme phosphorylates Glycogen Synthase?
Glycogen Synthase Kinase (GSK)
What controls the activity of GSK?
Insulin and PKB (protein kinase B)
What is another regulator of Glycogen Synthase? Describe its effects and what type of regulation is this?
Glucose-6-Phosphate
Activates Glycogen Synthase by allosteric regulation
During the regulation of Glycogen Breakdown, what is the active and inactive form of glycogen phosphorylase? Describe the location of the active/inactive form.
Active “a” form (R relaxed state)- in the liver Phosphorylated
Inactive “b” form (T tense state)- in muscle Dephosphorylated
Describe the regulation of Glycogen phosphorylase.
Several Allosteric effectors- signal energy state of the cell
Phosphorylation- responsive to hormones
The liver enzyme Glycogen Phosphorylase “a” is inactivated by what? What is it unaffected by?
Inactivated by free glucose (an indicator of blood sugar levels)
Unaffected by AMP
The muscle enzyme Glycogen Phosphorylase “b” is allosterically activated by what?
AMP (a measure of the low energy status of the cell)
ATP that is consumed by active muscle creates AMP, which stimulates the breakdown of glycogen for energy.
What are 2 negative allosteric regulators of muscle Glycogen Phosphorylase “b”?
ATP
Glucose-6-Phosphate
What are the 3 conditions that favor Glycogenesis and in what state does this occur in?
High blood glucose
High insulin levels
High cellular ATP levels
Favored during the fed state
What are the 2 conditions that favor Glycogenolysis during the fasting state?
Low blood glucose
High glucagon
What are the 2 conditions that favor Glycogenolysis during the exercise?
High cellular calcium (in exercising muscle) High AMP (from the breakdown of ATP)
What are the forms of glycogen synthase and glycogen phosphorylase during the breakdown of glycogen (glycogenolysis)?
The phosphorylated form of glycogen synthase (inactive)
The phosphorylated form of glycogen phosphorylase (active)
What kind of receptor is Insulin?
Tyrosine Kinase Receptor** Test Question
During the activation of glycogen synthase via Insulin, what does insulin activate? Describe the rest of the activation cascade for glycogen synthase. Where are these insulin receptors found?
Insulin activates Protein Kinase B
PKB stimulates Protein Phosphatase 1, which dephosphorylates Glycogen Synthase and activates it
PkB also inhibits Glycogen Synthase Kinase 3 (GSK3), which when active would inhibit GS
GS stimulates glycogen formation
*This all occurs in both muscles and in the liver
During the inactivation of glycogen phosphorylase via Insulin, what does insulin activate? Describe the rest of the activation cascade for glycogen phosphorylase. Where are these insulin receptors found?
Insulin activates Protein Kinase B
PkB stimulates Protein Phosphatase 1 to dephosphorylate Glycogen Phosphorylase (which inactivates it)
Glycogen phosphorylase is inactivated now
*This occurs in both the muscles and in the liver
During insulin activation, what does PkB also stimulate to increase the activation of Glycogen Synthase?
PkB stimulates the translocation of GLUT4 (in muscles), which is used to bring Glucose into the cell
*Remember that G6P activates GS allosterically
What is the net result for the activation of Insulin?
Glycogen synthesis via activation of glycogen synthase and inactivation of glycogen phosphorylase
What are the 4 key proteins involved in the regulation of insulin?
GLUT4- in muscles only
Protein Kinase B (PkB)
Protein Phosphatase 1 (PP1)
Glycogen Synthase Kinase 3 (GSK3)
Describe Type 2 diabetes.
Reduced sensitivity to insulin AKA insulin resistance
What 3 problems can cause down-regulation in insulin receptor levels?
Triggered by elevated insulin
Endocytosis and degradation of the insulin receptor
Defective receptors not replaced by translation
What are the 3 blood glucose criteria for:
Normal patients
Prediabetic/at risk
Diabetes Mellitus patients
Normal patients: 70-100 mg/dL (fasting), ≤140 mg/dL (fed)
Prediabetic/at risk: 100-125 mg/dL (fasting), >140 mg/dL (fed)
Diabetes Mellitus patients: ≥126 mg/dL (fasting), ≥199 mg/dL (fed)
What are the 2 hormones that control Glycogen Phosphorylase? What stimulates the release of these hormones and where do they act?
Low blood sugar levels release Glucagon- acts on the liver
Muscle activity releases Epinephrine- effects are on the muscle
What type of receptors responds to the hormones glucagon and epinephrine used to control Glycogen phosphorylase? What does this stimulate?
G Protein-Coupled Receptors (GPCRs)
Stimulates breakdown of glycogen (glycogenolysis)
During the inactivation of glycogen synthase via Glucagon and Epinephrine, what do these GPCR’s activate? Describe the rest of the inactivation cascade for glycogen synthase. Where are these GPCR’s found?
Glucagon and Epinephrine both bind to their respective GPCR’s and activate Adenylate Cyclase
Adenylate cyclase activates cAMP
cAMP stimulates PkA to inhibit Protein Phosphatase 1, therefore, leaving Glycogen Synthase in its inactive, phosphorylated state
- Glucagon GPCR is found only in the liver
- Epinephrine GPCR is found in both muscle and liver
During the activation of glycogen phosphorylase via Glucagon and Epinephrine, what do these GPCR’s activate? Describe the rest of the activation cascade for glycogen phosphorylase. Where are these GPCR’s found?
Glucagon and Epinephrine both bind to their respective GPCR’s and activate Adenylate Cyclase
Adenylate cyclase activates cAMP
cAMP stimulates PkA to inactivate Protein Phosphatase 1, therefore, leaving Glycogen Phosphorylase in its active, phosphorylated state
PkA also activates Phosphorylase Kinase, which phosphorylates Glycogen phosphorylase and activates it
- Glucagon GPCR is found only in the liver
- Epinephrine GPCR is found in both muscle and liver
What is the net result of the regulation by glucagon?
Glycogen breakdown via inactivation of glycogen synthase and activation of glycogen phosphorylase
What are the 5 key enzymes and second messengers involved in the regulation by glucagon?
GPCR's Adenylate Cyclase and cAMP Protein Kinase A (PKA) Protein Phosphatase 1 (PP1) Phosphorylase Kinase (PK)
During the regulation by epinephrine, what are the 4 allosteric regulators? What are their effects?
G6P- activates glycogen synthase, inactivates glycogen phosphorylase
Free glucose- inhibits glycogen phosphorylase in liver but not muscle
**Ca2+- activates glycogen phosphorylase kinase
**AMP- activates glycogen phosphorylase (especially during periods of exercise)
What is the off switch for glycogenolysis?
Shutting down the secretion of hormones
Phosphorylase Kinase and Glycogen Phosphorylase are inactivated
Breakdown of glycogen stops
Synthesis of glycogen is promoted
Glucagon does NOT act on ______
Muscle!
What happens to Glucose 1 phosphate in the liver?
In the liver, Glu-1-phosphate is converted to G6P and then to glucose by Glucose 6 phosphatase.
Free glucose is then released into the bloodstream.
Glucose 1 Phosphate can be converted to free glucose in the liver and released into the bloodstream. Why can’t it do this in muscles? What happens to G1P in muscles?
Cardiac and skeletal muscles lack glucose 6 phosphatases and therefore cannot hydrolyze G6P.
Glucose 1 phosphate is converted to glucose 6-phosphate in muscles. G6P can’t leave muscle cells so instead it is used to generate energy via glycolysis and TCA cycle.
______ _______ is the glucose sensor in liver cells.
Glycogen Phosphorylase
