Metabolism 5: Glycogen Flashcards
What is glycogen composed of?
Glycosyl residues mostly of a-1,4 glycosidic linkages and branching a-1.6 glycosidic linkages
What happens to hepatic glycogen concetration as meal time varies?
Increases after meals
Decreases in between meals
What’s the difference between muscle glycogen and liver glycogen interms of function
Muscle glycogen is fuel reserve for ATP production within that muscle
Liver glycogen serves as a reserve for maintainig blood glucose
What’s the limit that liver can store for glycogen? What happens to excess glucose?
100 g of glycogen
Excess glucose is redirected to fatty acid synthesis
What does glycogen synthase do?
key enzyme that adds glucose-1-phosphate to growing glycogen chains
What does glycogen phosphorylase do?
remove glucose moieties from glycogen
Why can liver contribute its glucose from glycogen directly to blood?
Liver has glucose 6 phosphatase that converts G6P to glucose and allows it to exit the liver and enter circulation
Why can’t the muscle glycogen contribute to blood glucose levels?
muscle does not express glucose 6 phosphatase, so G6P cannot leave the cell and is thus used for ATP production
How much glycogen can muscle store and what happens to excess glucose?
400 g of glycogen
Excess converted to FAs and stored as TGs
When is muscle glycogen mobilized?
During exercise
What is the sequence of events after a meal for hepatic glycogen synthesis?
Glucose from blood enters liver via GLUT2 -> converted to G6P -> Insulin stimulate glycogen formation, fatty acid biosynthesis , or glycolysis to use as fuel
What is the sequence of events during a fast for hepatic glycogen
Glucagon released by pancreas -> stimulates liver to undergo glycogenolysis -> release G6P -> glucose-6-phosphatase converts it to glucose -> glucose leaves liver via GLUT-2 into blood
What is the sequence of events for muscle glycogen after a meal?
Insulin stimulates glucose uptake by muscle via GLUT4 from blood -> converts to G6P -> forms glycogen or undergoes glycolysis and CAC
What is the sequence of events for muscle glycogen during exercise?
Epinephrine stimulates glycogenolysis via beta receptors -> convert glucose to G6P -> use in glycolysis and CAC for energy
What energy source is used during exercise at the beginning?
ATP + Creatine phosphate —> Anaerobic Glycolysis (Muscle Glycogen)
What energy source is used in prolonged exercise?
Aerobic Oxidation
Muscle glycogen, plasma glucose, liver glycogen
Much later, start using plasma FFA and adipose tissue triglycerides
What enzymes are required for glycogen synthesis?
Glycogen synthase: adds glucosyl units in a-1,4 links
Branching enzyme: adds glucosyl units in a-1,6 links
What enzymes are required for glycogen degradation?
Glycogen Phosphorylase: removes glucosyl units from a-1,4-links
Debranching Enzyme: transferase activity and removes a-1,6 links (glucosidase activity)
Kinases to activate Glycogen Phosphorylase
What is Glycogenin?
Polypeptide primer used for glycogen synthesis
Osmotically, what’s the difference between glucose and glycogen?
Glycogen is not osmotically active while glucose is
Why are secondary messenger systems pertinent for glycogen equilibrium?
Can activate glycogen degradation or inhibit glycogen syntehsis by activating or inhibiting glycogen phosphorylase and glycogen synthase, respectively
What are some of the secondary messengers regulating glycogen formation/degradation?
cAMP ->PKA -> activate phosphorylkinase
PI -> DAG and IP3 -> Ca2+ -> activate Phosphorylkinase
Ca2+ -> activate phosphoryl kinase
What does activating phosphoryl kinase do?
Phosphorylates glycogen phosphorylase to convert it from its inactive b form to active a form
Promotes glycogen degradation
What does cAMP do for glycogen equilibrium?
Activate PKA or inhibit phosphoprotein phosphatase to promote glycogen degradation
How does insulin regulate glycogen synthesis/degradation?
Inhibits glycogen phosphorylase by stimulating phosphoprotein phosphatase which dephosphorylates the glycogen phosphorylase, inactivating it
Which hormone promotes glycogen storage/degradation?
Storage: insulin
Degradation: glucagon
When would you have high levels of AMP?
During exercise
How does AMP regulate glycogen levels?
Directly binds to the b form of glycogen phosphorylase to activate it regardless of phosphorylation status
Overrides inhibitory effect of ATP
Promotes glycogen degradation
What happens to glycogen levels when glucose and ATP are high?
Glucose and ATP bind directly to the active form of glycogen phosphorylase to inactivate its activity
What activates glycogen synthase?
Dephosphorylation; Leads to glycogen synthesis
Phosphorylation inactivates glycogen synthase and thus inhibits glycogen sythesis
What does insulin promote with regards to glycogen synthase?
Insulin activates phosphoprotein phosphatase to dephosphorylate glycogen synthase -> promotes glycogen synthesis
What do the secondary messengers cAMP, Ca2+ and DAG do on glycogen synthase?
Activates phosphoryl kinase, calmodulin depdendent protein kinase, and PKC to promote phosphorylation of glycogen synthase -> inhibits glycogen synthesis
What happens to glycogen synthase when G6Plevels are high?
G6P can bind to the inactivated (phosphorylated) form of glycogen synthase and allosterically activate it to promote glycogen synthesis (seen in GSDs)
What is the overall effect of increased cAMP in liver?
Promote glycogen degradation
Inhibit glycolysis
Inhibit glycogen synthesis
What is the overall effect of increased cAMP in heart and skeletal muscle
Promote glycogen degradation
Activate glycolysis
Inhibit glycogen syntehsis
How does the phosphoinositide mechanism proceed?
Epi binds to a-adrenergic receptor -> PIP2 cut by PLC -> IP3 and DAG released -> IP3 binds to ER to promote Ca2+ release and DAG activates PKC -> Ca2+ activates Ca2+ dependent PK -> stimulate glycogenolysis
How does insulin affect glycogen levels
Insulin promotes glycogen synthesis in both the muscle and liver
What is the sequence for forming and degrading glycogen?
synthesis: Glucose ->G6P ->G1P ->UDP-glucose -> glycogen
Degradation: Glcyogen -> G1P -> G6P -> glucose
What can inherited glycogen storage disease affect?
Tissue levels of glycogen
Fasting blood glucose levels
lipid metabolism
GSDs: Type 1 Von Gierke’s Disease
Defective G6Phosphatase
Organs: Liver and kidney
Glycogen: increased normal structure
Clinical: hepatomegaly, failure to thrive, hypoglycemia, increased lactate, hyperuricemia, hyperlipidemia, gouty arthritis, mental retardation, hyperlipidemia
GSDs: Type II Pompe’s Disease
Defective 1,4-glucosidase
Organs: all
Glycogen: Massive increase in normal structure
Clinical: Cardiorespiratory failure, Death usually before 2yo
GSDs: Type III Cori’s Disease
Defective amylo-1,6 debranching enzyme
Organs: Muscle and liver
Glycogen: increased short outer
Clinical: Similar to type 1 Von Gierke’s but milder
GSDs: Type IV Anderson’s Disease
Defective Branching Enzyme
Organs: Liver and Spleen
Glycogen: Normal amount with long branches
Clinical: Cirrhosis of liver, liver death before 2 yo leads to death
GSDs: Type V McArdle’s Disease
Defective Phosphorylase
Organs: Muscle
Glycogen: Moderate amount of normal structure
Clinical: Can’t perform strenuous exercise, painful muscle cramps
GSDs: Type VI Hers’ Disease
Defective phosphorylase
Organ: Liver
Glycogen: Increased amount
Clinical: Like Von Gierke’s but milder
GSDs: Type VII
Defective PFK-1
Organ: Muscle
Glycogen: Increased
clinical: Like Type V McArdle’s
GSDs: Type VIII
Defective Phosphorylase Kinase
Organ: Liver
Glycogen: Increased normal
Clinical: Mild hepatomegaly, mild hypoglycemia
What effects do glucagon and epinephrine have on glucose homeostasis
Raise blood glucose Promote hepatic gluconeogenesis Promote hepatic glycogen degradation Inhibit hepatic glycolysis Inhibit hepatic glycogen synthesis Block hepatic use of glucose
How does glucagon/epi block hepatic glycolysis?
Inhibit PFK-2 -> dec F26bisphophate -> inhib PFK-1
Inhibit pyruvate kinase
How does glucagon/epi promote hepatic gluconeogenesis?
Inhibit PFK-2 -> dec F26 bisphosphate -> promote F16phosphatase
Inhibit Pyruvate kinase
What does the Pentose Phosphate Pathway do?
Generate NADPH for lipid biosynthesis
Generate Ribose-5-phosphate for biosynthesis of purine (DNA, RNA, etc)
Intermediates for glycolysis
What is the rate limiting enzyme in the pentose phosphate pathway
Glucose-6-phosphate dehydrogenase
Deficiency leads to hemolytic anemia due to inability of RBCs to maintain adequate levels of NADPH necessary to reduce glutathione that reduces SH on proteins
What are some glycolytic intermediates produced by the pentose phosphate pathway
glyceraldehyde 3 phosphate, F6P
How much of glucose is used for the pentose phosphate pathway?
Only a small portion is diverted in this way
What can lead to drug induced hemolytic anemia
Deficiency in G6PDH leads to hemolytic anemia due to inability of RBCs to maintain adequate levels of NADPH necessary to reduce glutathione that reduces SH on proteins and thus protect RBCs from oxidative damage
What is necessary to maintain glutathione in its reduced state? Why is this necessary?
NADPH. REduced GSH (glutathione) necessary to detoxify hydrogen peroxide (H2O2) and other reactive oxygen species
What happens when NADPH levels are low in RBC?
Decreased in reduced form of glutathione (GSH) and thus increased levels of hydrogen peroxide and levels of oxidative damage
