Lecture 23, Glyc Metabolism II (Zaidi) Flashcards
Why is the regulation of glycogen metabolism important?
Maintain blood sugar and provide energy to muscles
T or F: The pathways of glycogen metabolism synthesis and degradation are independent.
True.
What allows for the separate regulation of glycogen metabolism?
Pathways of synthesis and degradation are independent
What are the 2 key enzymes of glycogen metabolism?
Glycogen synthase and glycogen phosphorylase
Which enzyme is the rate limiting step on glycogen metabolism synthesis?
Glycogen synthase
Which enzyme is the rate limiting step on glycogen metabolism degradation?
Glycogen phosphorylase
How are glycogen synthase and glycogen phosphorylase regulated? What is this under the control of?
By allosteric regulators and by reversible phosphorylation (effects are in opposite directions); Under the control of hormones
What are the 2 forms that glycogen synthase exists in?
Active, non-phosphorylated A form; Inactive, phosphorylated B form
What is the interconversion of the 2 forms of glycogen synthase mediated by?
Covalent modification
Which enzymes phosphorylates glycogen synthase?
Several kinases, but most importantly glycogen synthase kinase (GSK)
What is GSK under the control of?
Insulin and PKA
What is the relationship between G6P and glycogen synthesis?
G6P provides allosteric regulation of glycogen synthase (powerful activator); Stabilizes the active form of the enzyme
What are the 2 forms that glycogen phosphorylase exists in?
Active A form (relaxed) in liver; Inactive B form (tense) in muscle
T or F: The isozymes of glycogen phosphorylase exist in excess of R and small amounts of T.
False. Both isozymes of glycogen phosphorylase exist in equilibrium between R and T.
What is glycogen phosphorylase regulated by?
Several allosteric effectors (signal energy state of cell) and reversible phosphorylation (responsive to hormones)
Why is GP called an isozyme?
GP in the liver and in the muscle are the products of separate genes
How does GP different in the liver and the muscle?
In sensitivity to regulatory molecules
Describe the activation of liver GP.
Inactivated by free glucose (indicator of blood sugar levels), unaffected by AMP
Describe the activation of muscle GP.
Allosterically activated by AMP (measure of low energy status of cell)
What is Hers disease caused by?
Mutation in liver GP
What is McArdle syndrome caused by?
Mutation in muscle GP
Describe the allosteric regulation of liver GP.
Default A (active) form, inactivated by glucose
How is liver GP inactivated by glucose?
Glucose binds to active site and stabilizes conformation in the T (inactive) state; When glucose levels are high, there is no need for glycogen breakdown
Describe the allosteric regulation of muscle GP.
Default B (inactive) form, activated by AMP
How is muscle GP activated by AMP?
Binds to active site and stabilizes conformation of B in R (active) state; During muscle concentration, ATP is converted to AMP by myosin and adenylate kinase signaling to the GP to breakdown glycogen
What is the relationship between ATP and G6P with the allosteric regulation of muscle GP?
Negative allosteric regulators; Under normal physiological conditions, GP is inactive because of the inhibitory effect of ATP and G6P
Which process of glycogen metabolism is favored in the fed state?
Glycogenesis
Describe the “fed state.”
Blood glucose high, insulin high, cellular ATP high
When glycogen synthesis is favored, which enzyme states of glycogen metabolism are predominant?
Dephosphorylated form of glycogen synthase (active), dephosphorylated form of glycogen phosphorylase (inactive)
Describe the “fasting state.”
Blood glucose low, glucagon high
Which process of glycogen metabolism is favored in the fasting state?
Glycogenolysis
In which 2 states is glycogenolysis favored?
Fasting state and during exercise
Describe the state of the body during exercise.
Cellular calcium high (in exercise muscles), AMP high (from breakdown of ATP)
When glycogen breakdown is favored, which enzyme states are predominant?
Phosphorylated form of glycogen synthase (inactive), phosphorylated form of glycogen phosphorylase (active)
Which cells in the body release insulin?
Beta cells of pancreas
What kind of receptor is the insulin receptor?
RTK
What are the 4 key proteins in the activation of the signaling cascade in the regulation of insulin?
GLUT4, PKB, PP1, GSK3
What is PKB?
Protein kinase B
What is PP1?
Protein phosphate 1
What is GSK3?
Glycogen synthase kinase 3
After activation of the signaling cascade in the regulation of insulin, outline what happens.
Formation of the insulin receptor complex, activation of PKB, translocation of GLUT4 to the membrane, PKB phosphorylated PP1 and GSK3, glycogen synthesis
What does PKB phosphorylate?
PP1 and GSK3
What does active PP1 do?
Dephosphorylates glycogen synthase and dephosphorylates glycogen phosphorylase
What is the net result of the mechanism of regulation of insulin?
Glycogen synthesis via activation of glycogen synthase and inactivation of glycogen phosphorylase
Type 2 diabetes is also called ___ ___.
Insulin resistance
What is the pathology of T2D?
Reduced sensitivity to insulin because of mutations in insulin receptor/downstream signaling proteins
Describe the down-regulation in receptor levels in T2D.
Triggered by elevated insulin, endocytosis and degradation of the insulin receptor, defective receptors not replaced by translation
What is normal blood glucose criteria?
70-100 mg/dL (fasting); =< 140 mg/dL (fed)
What is prediabetic/at risk blood glucose criteria?
100-125 mg/dL (fasting); > 140 mg/dL (fed)
What is the blood glucose criteria for diabetes mellitus?
> = 126 mg/dL (fasting); >= 199 mg/dL (fed)
In the hormonal control of GP, what do low blood sugar levels release?
Glucagon (acts on liver)
In the hormonal control of GP, what does muscle activity release?
Epinephrine (effects are on the muscle)
In the hormonal control of GP, what are the effects of the hormones mediated by?
GPCR
What do epinephrine and glucagon signal in the hormonal control of GP?
Glycogen breakdown
What does the phosphorylation of a single serine residue covert?
B to A
In the conversion of B to A by phosphorylation, what is the conversion initiated by?
Hormones
T or F: Phosphorylation is carried out by phosphorylase kinase.
True.
In regard to the regulation of glycogen, what do low blood glucose levels promote?
Glycogen breakdown
Which cells in the pancreas release glucagon?
Alpha cells
Glucagon binds the GPCR on which cells? What does this trigger?
Hepatocytes; Triggers signaling cascade
What are the key enzymes and second messengers in the regulation by glucagon?
G protein, AC and cAMP, PKA, PP1, PK
Outline the signaling cascade that has been triggered in the regulation by glucagon after the glucagon binds the GPCR on hepatocytes.
Glucagon binds to GPCR and turns on G protein, activates AC which forms cAMP, activates PKA, PKA phosphorylates glycogen synthase (inactivated), PKA phosphorylates PK (active), PKA phosphorylates an inhibitor which inactivates PP1, active PK phosphorylates glycogen phosphorylase (active), glycogen breakdown
What is the net result of the signaling cascade of the regulation by glucagon?
Glycogen breakdown (via inactivation of glycogen synthase and activation of glycogen phosphorylase)
What is epinephrine released by?
Adrenal glands
What does epinephrine promote the degradation of? What is this similar to?
Glycogen; Pathway is similar to glucagon
Describe what the allosteric regulators of epinephrine are.
G6P, free glucose, calcium, AMP
How is G6P an allosteric regulator of epinephrine?
Activates glycogen synthase, inactivates glycogen phosphorylase
How is free glucose an allosteric regulator of epinephrine?
Inhibits glycogen phosphorylase in liver but not in muscle
How is calcium an allosteric regulator of epinephrine?
Activates glycogen phosphorylase kinase
How is AMP an allosteric regulator of epinephrine? When is this especially relevant?
Activates glycogen phosphorylase; Especially relevant during periods of exercise
When does glycogen metabolism stop?
When secretion of hormone stops
What happens to glycogen metabolism after the secretion of hormone stops?
PK and GP are dephosphorylated and inactivated, breakdown of glycogen stops, synthesis of glycogen promoted
What is the fate of liver Glu1P?
Glu1P is converted to glu6P and then to glucose by G6P; Glucose released into the blood stream
What is the fate of muscle glu1P?
Use glu6P to generate energy via glycolysis and the TCA cycle
What can’t myocytes hydrolyze glu6P?
Lack G6P
What enzymes is the glucose sensor in liver cells?
Glycogen phosphorylase
What is the defective enzyme in Von Gierke (type I) disease?
Glucose 6-phosphatase or the transport system
What is the organ affected in Von Gierke (type I) disease?
Liver and kidney
How is glycogen affected in the organ in Von Gierke (type I) disease?
Increased amount, but normal structure
What is the defective enzyme in Pompe (type II) disease?
alpha-1,4-glucosidase (lysosomal)
What is the organ affected in Pompe (type II) disease?
All organs
How is glycogen affected in the organ in Pompe (type II) disease?
Massive increase in amount, but normal structure
What is the defective enzyme in Cori (type III) disease?
alpha-1,6-glucosidase
What is the organ affected in Cori (type III) disease?
Muscle and liver
How is glycogen affected in the organ in Cori (type III) disease?
Increased amount and short outer branches
What is the defective enzyme in Andersen (type IV) disease?
GLucosyl (4:6) transferase (branching enzyme)
What is the organ affected in Andersen (type IV) disease?
Liver and spleen
How is glycogen affected in the organ in Andersen (type IV) disease?
Normal amount, but very long outer branches
What is the defective enzyme in McArdle (type V) disease?
Phosphorylase
What is the organ affected in McArdle (type V) disease?
Muscle
How is glycogen affected in the organ in McArdle (type V) disease?
Moderately increased amount and normal structure
What is the defective enzyme in Hers (type VI) disease?
Phosphorylase
What is the organ affected in Hers (type VI) disease?
Liver
How is glycogen affected in the organ in Hers (type VI) disease?
Increased amount
What is the defective enzyme in Type VII glycogen storage disease?
Phosphofructokinase
What is the organ affected in Type VII glycogen storage disease?
Muscle
How is glycogen affected in the organ in Type VII glycogen storage disease?
Increased amount and normal structure
What is the defective enzyme in Type VIII glycogen storage disease?
Phosphorylase kinase
What is the organ affected in Type VIII glycogen storage disease?
Liver
How is glycogen affected in the organ in Type VIII glycogen storage disease?
Increased amount and normal structure
Which of the glycogen storage diseases are inherited in an autosomal recessive manner?
Types I-VII
How is type VIII glycogen storage disease inherited?
Sex-linked
T or F: Types III-VIII glycogen storage diseases are inherited in an autosomal dominant manner.
False. Types I-VII are inherited in an autosomal recessive manner, while type VIII is sex-linked.
In GSD type 0, what is the defective enzyme?
Glycogen synthase
How is glycogen affected in GSD 0 disease?
Patients cannot synthesize glycogen
What is the presentation and treatment of GSD 0?
Patients have muscle cramps due to lack of glycogen in muscle; Rely on glucose in diet, vulnerable to hypoglycemia when fasting (during sleep), must eat frequently
What is the clinical presentation of GSD type III (Cori)?
Light hypoglycemia and heptomegaly
What is the life expectancy of a patient with GSD type IV (Andersen)?
5 years
Which GSD is a result of a deficiency in the rate-limiting step of glycogen breakdown?
GSD V (McArdle)
What is the clinical presentation of GSD type V (McArdle)?
Patients are unable to supply muscles with enough glucose, have weakness, muscle cramps, exercise intolerance, myoglobinuria; Tolerance by reducing strenuous exercise
Describe blood glucose levels in patients with GSD VI (Hers)?
Low blood glucose levels
What can be used to treat GSD type II (Pompe)?
Enzyme replacement therapy (ERT)
Describe ERT to treat GSD II.
Recombinant human alpha-glucosidase delivered via IV infusion in babies/young children
What is the clinical presentation of GSD II?
Progressive muscle weakness and myopathy (including heart and skeletal muscle)
What do patients typically die of with GSD II?
Heart failure
