[2] Lecture 8: Glycogen Metabolism Flashcards by John Pate

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

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Glycogen End that contain a terminal glucose w/ a free hydroxyl group at C4

Non-reducing end

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Glycogen end Has glucose monomer connected to a protein called glycogenin

Reducing end

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This protein is connected to the reducing end of glycogen:

Glycogenin

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Glycogenin helps to make a ________, which is crucial for glycogen synthesis.

Primer

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Enzyme involved in converting glucose to glycogen.

Acts as a primer.

Glycogenin

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Where is glycogen stored?

Liver
And
Muscle

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Liver stores 10% by weight and muscle stores 2% by weight, which holds more?

Muscle! More SA of muscle than liver

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What doesglycogen look like on photomicrogrpah?

Granules

Glycogen granules

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Glycogen contains what for its own metabolism?

Enzymes…more accurate timing

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Regulates overall BG levels

Crucial for brain function

Liver glycogen

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Provides reservoir of fuel [glucose] for physical activity for muscle

Muscle glycogen

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Regulated storage and release of glycogen

Synthesis and degradation of glycogen involve diff. Pathways

Both pathways regulated independently

Glycogen metabolism

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3 regulating factors for glycogen metabolism

Allosteric control-modulators

Covalent modification-P’s

Hormonal control

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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

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3 fates of glycogenolysis:

glycolysis

Free glucose for release into bloodstream

Pentose phosphate pathway-NADPH and ribose derivative

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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)

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When does phosphorylation cease?

When GP gets w/in 4 Residues of the alpha-1,6 linkage of a branch point

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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

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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

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Whic 2 enzymes are responsible for converting branched glycogen into a linear structure for further action by glycogen phosphoylase?

Transferase

Alpha-1,6 glucosidase

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What enzyme converts G-1-P to G-6-P?

Phosphoglucomutase

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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

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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

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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:

1. Trapping and activating of glucose. 2. Elongation of glycogen polymer 3. 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

What are the 2 reasons for branching of glycogen?

1. Increases solubility 2. 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

[2] Lecture 8: Glycogen Metabolism Flashcards

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