[2] Lecture 8: Glycogen Metabolism Flashcards
Osmotically inactive, readily mobilized form of glucose.
12 layers of glu. W/ approx. 55,000 glucose residues.
Linked w/ alpha-1,4 glycosidic bonds and branched w/ alpha-1,6 glycosidic bonds.
Structure of glycogen
Glycogen End that contain a terminal glucose w/ a free hydroxyl group at C4
Non-reducing end
Glycogen end Has glucose monomer connected to a protein called glycogenin
Reducing end
This protein is connected to the reducing end of glycogen:
Glycogenin
Glycogenin helps to make a ________, which is crucial for glycogen synthesis.
Primer
Enzyme involved in converting glucose to glycogen.
Acts as a primer.
Glycogenin
Where is glycogen stored?
Liver
And
Muscle
Liver stores 10% by weight and muscle stores 2% by weight, which holds more?
Muscle! More SA of muscle than liver
What doesglycogen look like on photomicrogrpah?
Granules
Glycogen granules
Glycogen contains what for its own metabolism?
Enzymes…more accurate timing
Regulates overall BG levels
Crucial for brain function
Liver glycogen
Provides reservoir of fuel [glucose] for physical activity for muscle
Muscle glycogen
Regulated storage and release of glycogen
Synthesis and degradation of glycogen involve diff. Pathways
Both pathways regulated independently
Glycogen metabolism
3 regulating factors for glycogen metabolism
Allosteric control-modulators
Covalent modification-P’s
Hormonal control
Glycogen broken down to release G-1-P-glycogen remnant-remodeled to allow further degradation->
Then, G-1-P converted to G-6-P
Glycogenolysis
3 fates of glycogenolysis:
glycolysis
Free glucose for release into bloodstream
Pentose phosphate pathway-NADPH and ribose derivative
Catalyzes the cleavage of glycogen- rate limiting step
Chain shortening occurs at the non-reducing end
Adds an orthophosphate and releases a glucose residue as G-1-P
Uses a pyridoxal phosphate (vitB-6) as a cofactor
Glycogen phosphorylase (GP)
When does phosphorylation cease?
When GP gets w/in 4 Residues of the alpha-1,6 linkage of a branch point
Transfers a block of 3 of the remaining 4 glucose to the non-reducing end of the main chain forming an alpha-1,4 bond
Which enzyme is this involved in glycogenolysis?
Transferase
Cleaves the alpha-1,6 bond of the single remaining glucose residue to release free glucose.
Which enzyme is this involved in glycogenolysis?
Alpha-1,6 glucosidase
Debranching enzyme
Whic 2 enzymes are responsible for converting branched glycogen into a linear structure for further action by glycogen phosphoylase?
Transferase
Alpha-1,6 glucosidase
What enzyme converts G-1-P to G-6-P?
Phosphoglucomutase
A phosphorylation group is transferred from the enzyme to the substrate, and a different phosphoryl group is transferred back to restore the enzyme to its initial state
Which enzyme?
Phosphoglucomutase
How is G-6-P converted to glucose?
It is shipped to the liver b/c it is the only place where you can find g-6-phosphatase
What’re the 2 ways glycogen phosphoryloase is regulated?>
Allosteric factors: energy signals of the cell
Reversible phosphorylation (hormones)
Glycogen phosphorylase exists in 2 forms
A and B
Liver GP is predominantly which form of GP?
Liver is phosphyrlase A and it exists mostly in R relaxed state
Muscle GP is predominantly which form?
Phosphorylase B mostly exists in T tense state
Liver and muscle forms of GP are products of seperate genes. What is this called?
Isozymes
Form A=
Form B=
A=relaxed
B=tense
Liver GP is inactivated and moves to tense states under what conditions?
Fed-state
Major inactivator of Liver (a) GP?
Glucose!
Glu binds to active site and stabilizes conformation in the inactive T state.
Makes sense…when BG levels are high, there’s no need for glycogen breakdown.
Muscle GP (b) is activated under what conditions?
Low energy states
Activated by AMP…
This makes sense b/c muscle contraction ATP converted to AMP by myosin and adenylate kinase signaling the GP to breakdown glycogen
AMP GPb activator mechanism:
Binds to active site and stabilizes conformation of the b in the active R state
What are 2 negative allosteric regulator (inhibitors) of GP b (muscle)?
ATP and gluc-6-phosphate
Under norm physiological conditions GP inactive b/c of inhibitory effect of ATP and Gluc-6-phosphate
What role does phosphorylation play in glycogen phosphorylase?
How is it initiated?
Phosphorylation of a single serine residue converts GP b to GP a
Conversion initiated by hormones
Phosphorylation of GP is carried out by what enzyme,?
Phosphorylase kinase (PK)
How is phosphorylase kinase partially activated?
Fully activated?
4 Ca++ ions partially activate PK
4 Ca++ ions and 8 Phosphates fully activates PK
What results when Pohsphoylase kinase is fully active?
Phosophorylase b converts to phosphorylase a
But requires 2 ATP
Wha hormone is released under low [BG] conditions
Glucagon
Muscle activity releases what hormone?
Epinephrine
Glucagon and epinephrine are mediated via:
Both of these hormones signal:
via G protein coupled receptors (GPCR)
Signal glycogen breakdown
Glucagon and epinephrine, can they pass the plasmalemma?
No they are peptide hormones that act on the GPCR’s
When does glycogen breakdown stop?
When the hormone (glucagon or Epi) shuts down
PK and GP are DEphosphorylated =inactivated
When synthesis of glycogen is promoted
Liver and muscle forms of GP are products of separate genes what is this term called?
Isozymes
Liver vs. muscle GP
DIFFER: in their sensitivities to regulatory molecules
Both are activated by phosphorylation by phosphorylase kinase and inhibited by ATP and G6P
Muscle GP is allosterically activated by
AMP
Liver GP is inactivated by:
Unaffected by:
Inactivated by glucose and unaffected by AMP
Mutations in liver GP causes
Hers disease
Mutaiton in muscle GP causes:
McArdle syndrome
3 key events in glycogenesis:
- Trapping and activating of glucose.
- Elongation of glycogen polymer
- Branching of glycogen chains.
In the cytosol of hepatocytes and muscle cells catalyze phosphorylation of glucose to glucose-6-phosphate.
This traps glucose in theses cells.
Glucokinase / hexokinase
Reversible isomerizes G-6-P to G-1-P
Phosphoglucomutase
Transfers the G-1-P to uridine triphosphate which generates UDP-glucose
Uridine diphosphate (UDP)-glucose pyrophosphorylase
Active form of glucose
UDP-glucose
What is the significance of the Breakdown of pyrophosphate to Pi w/ UTP and glycogenesis?
generates energy and drives the RXN forward
Preexisting short glycogen polymer serves as a primer to which glucose units are added
Primer formation done by glycogenin
This is completed by the transfer of glucose from UDP-glucose onto a non-reducing end of glycogen chain. What enzyme comlpletes this?
Glycogen synthase
Rate limiting rx of glycogenesis
Glycogen synthase
Forms alpha-1,4-glycosidic bonds btw glucose molecules.
Glycogen synthase
Glycogenin requires
Manganese-Mn
whenglycogen reaches 11 residues, a fragment of the chain [about 7 residues long] is broken off at an alpha-1,4 link and reattached elsewhere through an alpha-1,6 link by activity of what enzyme?
Glucosyl (4:6) transferase
The new branching point must be at least ___ residues away from a preexisting branch
4
What are the 2 reasons for branching of glycogen?
- Increases solubility
- Increases number of terminal non-reducing ends
Increases rate at which glycogen can be synthesized and degraded
Key enzyme in glycogen synthesis
Glycogen synthase
2 forms of glycogen synthase
One form in the liver
One form in the muscles and other tissues
Active [non-phosphorylated] form = a form
Inactive [phosphorylated] b form
Interconversion mediated by covalent modifications [fine-tuning role]. What is this regulation?
Regulation of glycogen synthesis
Glycogen synthesis is regulated by what enzyme that phosphorylates?
Glycogen synthase kinase
-GSK
What hormones affect GSK?
Allosteric regulation?
Insulin and PKA
Allosteric: glucose-6-phosphate [powerful activator]- stabilizes the R state
Synthesis and degradation of glycogen pathways are:
Independent
Allows for independent regulation.
The 2 key enzymes to glycogen metabolism:
Glycogen phosphorylase (GP)
Glycogen synthase
Both are the rate limiting steps of degradation/synthesis
Both enzymes are regulated by reversible phosphorylation but effects are in opposite directions
How do glucagon and epi control both glycogen breakdown and synthesis?
Via PKA!
What is the centerpiece intermediate in glycogen metabolism?
PKA
GP function
Stimulate glycogen breakdown
Glycogen synthase function:
Stimulate glycogen synthesis.
What is favored in fed state: glycogenolysis or glycogenesis:
Glycogenesis
B/c BG and insulin elevated and cellular ATP is high- signal of high energy
-when glycogen synthesis is favored, the DEPHOSPHO form of glycogen synthase (active) and glycogen phosphorylase(inactive) are predominant
What is favored in fasting state: glycogenolysis or glycogenesis:
Glycogenolysis
B/c BG levels are low and glucagon levels are high and cellular Ca++ and AMP are elevated -like exercise
-when glycogen degradation is favored PHOSPHORYLATED forms of glycogen synthase (inactive) and glycogen phosphoylase (active) are predominant
High BG
Release of _____ by beta cells of pancreas
Binding to its receptor tyrosine kinase
Activation of signaling cascade
Regulation by insulin; insulin
4 key proteins in Regulation by insulin:
- GLUT 4 [glu transporter]
- Protein kinase B [PKB]
- Protein phosphatase 1 [PP1]
- Glycogen synthase kinase 3 [GSK3]
Net result of insulin
Activation of glycogen synthase and inactivation of glycogen phosphorylase
Formation of insulin receptor complex i activated by:
Protein kinase B
[PKB]
This also translocates GLUT to membrane
What phosphorylates PP1 (active) and GSK3 (inactive)
PKB
What is function of PP1
Active PP1 dephosphorylates glycogen synthase (activates it)
And
Dephosphorylates glycogen phosphorylase (GP-deactivating it)
- Reduced sensitivity to insulin
- Called insulin resistance
- Mutations in insulin receptor and/or downstream signaling proteins
-Down-regulation in receptor levels triggered by elevated insulin [leading 2 endocytosis and degradation of the insulin receptor].notreplaced by translation
What type disorder is this?
Type II diabetes
What is the glucose sensor in the liver cells?
Glycogen phosphorylase
Glucose has what effect when bound to liver GP (a)?
Deactivates it and allows glycogen synthase to begin storing energy…b/c it is in fed state or high energy
McArdle syndrome is a disease of:
Muscle GP
Limited ability to perform strenuous exercise b/c of painful muscle cramps; otherwise patient is normal.
Hers disease is:
Liver GP issue
Milder form of liver enlargement, FTT, hypoglycemia, ketosis, hyperuricemia, hyperlipidemia
