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FHB Exam 3 > Metabolism: Glycogen Storage & Degradation > Flashcards

Metabolism: Glycogen Storage & Degradation Flashcards

1
Q

Describe the structure of glycogen.

A
  • highly hydrated
  • highly branched
    => alpha-1,4 linkages are horizontal/side by side
    => alpha-1,6 linkages are vertical/branching
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2
Q

Differentiate between the uses of glycogen in muscle vs. liver.

A

muscle: used for energy during exercise
liver: used to produce glucose during hypoglycemia

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3
Q

Describe oscillations in glycogen storage throughout the day.

A
  • highest times of glycogen storage are after breakfast (8am) and after dinner
  • lowest times of glycogen storage (or higher use of glycogenolysis) are between breakfast and dinner, and past midnight
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4
Q

Compare the amount of glycogen stored in muscles vs. liver.

A

muscle: 400g
liver: 100g

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5
Q

Why doesn’t the muscle generate glucose during hypoglycemia?

A

muscles don’t express G6Pase. Therefore, G6P is trapped inside the cell and is used for ATP production

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6
Q

Compare synthesis of glycogen in liver and muscle.

A

Liver

  • insulin independent uptake of post-prandial BG via GLUT2
  • Glu => G6P
  • insulin stimulates glycogen synthesis, fatty acid synthesis, or glycolysis

Muscle

  • insulin dependent uptake of post-prandial BG via GLUT4
  • Glu => G6P
  • majority of G6P is stored into glycogen; some enters glycolysis and TCA
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7
Q

Compare glycogen breakdown in liver and muscle.

A

Liver

  • low BG stimulates glucagon
  • glucagon promotes glycogenolysis and release of glucose via GLUT2

Muscle

  • during exercise or high epi, promotion of glycogenolysis
  • G6P enters glycolysis to generate ATP
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8
Q

Describe the energy sources during exercise and at what time they’re utilized.

A
  • 1st minute = stored ATP and CP
  • next 5 minutes = glycogen stores in muscle (anaerobic)
  • muscle and liver glycogenolysis (aerobic)
  • once sustained, fatty acid and TAG degradation
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9
Q

What is the mechanism of glycogen synthesis?

A
  1. glucose => G6P (hexokinase/glucokinase)
  2. G6P => G1P
  3. G1P => UDP-Glucose
  4. UDP-Glucose => glycogen (glycogen synthase adds glucosyl units in a 1,4 fashion; requires branching enzyme activity to add in 1,6 fashion)
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10
Q

What is the mechanism of glycogen breakdown?

A
  1. glycogen => G1P (glycogen phosphorylase and debranching enzyme)
  2. G1P => G6P
  3. G6P => glucose (G6Pase) (only in liver)
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11
Q

Describe the mechanism of glycogen synthase.

A
  1. synthase domain adds glucose in alpha-1,4 linkages

2. branching domain cleaves newly added glucose and adds it in alpha-1,6 linkages on another branch

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12
Q

What 3 enzymes are required for glycogen degradation?

A
  1. glycogen phosphorylase
  2. debranching enzyme
  3. kinases to activate glycogen phosphorylase
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13
Q

Describe the mechanism of glycogen phosphorylase.

A
  1. glycogen phosphorylase removes glucose from alpha-1,4 linkages
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14
Q

Describe the mechanism of debranching enzyme.

A
  1. transferase domain adds alpha-1,4 linkages cleaved by glycogen phosphorylase on another branch
  2. glucosidase domain cleaves remaining glucose molecules on the branch
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15
Q

What is the effect of second messenger systems on glycogen metabolism?

A
  • activate glycogen degradation by phosphorylating glycogen phosphorylase
  • inhibit glycogen synthesis by phosphorylating glycogen synthase
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16
Q

What are the second messenger systems used for glycogen metabolism?

A
  • cAMP
  • IP3/DAG
  • intracellular Ca2+
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17
Q

What activates glycogen phosphorylase?

A

Active glycogen phosphorylase is phosphorylated

  • glucagon/epi => cAMP
  • Ca2+
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18
Q

Describe the mechanism for how glucagon/cAMP activates glycogen phosphorylase?

A

cAMP activates phosphorylase kinases that phosphorylate glycogen phosphorylase => activated
cAMP also inhibits phosphoprotein phosphatases, preventing the dephosphorylation of glycogen phosphorylase and of phosphorylase kinases

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19
Q

What deactivates glycogen phosphorylase?

A

inactive glycogen phosphorylase = dephosphorylated

  • insulin
  • high BG
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20
Q

Describe the mechanism of how insulin effects glycogen phosphorylase?

A

insulin promotes phosphoprotein phosphatases => dephosphorylate glycogen phosphorylase
dephosphorylate phosphorylase kinases

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21
Q

Describe allosteric regulation of glycogen phosphorylase

A

activation
- AMP (muscle exercise) changes phosphorylase conformation to active form

inactivation - necrosis, inflammation, liver injury

  • ATP
  • glucose
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22
Q

How does allosteric regulation of glycogen phosphorylase differ from covalent modification?

A

phosphorylation of glycogen phosphorylase occurs in a more systemic pattern due to hormonal induction of second messenger system. Allosteric regulation occurs in localized area, such as muscles during exercise or injured cells

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23
Q

What activates glycogen synthase?

A

active = dephosphorylated

  • insulin
  • glucose
24
Q

What is the mechanism for insulin and its effect on glycogen synthase?

A

promotes phosphoprotein phosphatases => dephosphorylates glycogen synthase and protein kinases
=> active glycogen synthase => glycogen synthesis

25
Q

What deactivates glycogen synthase?

A

inactive = phosphorylate

  • glucagon/epi
  • cAMP
  • Ca2+
26
Q

What is the mechanism for glucagon and its effect on glycogen synthase?

A
  • glucagon => cAMP => promotes protein kinases and inhibits phosphoprotein phosphatases => phosphorylates glycogen synthase => inactive => prevents glycogen synthesis
27
Q

How does Ca2+ effect glycogen synthase?

A

Ca2+ promotes protein kinases => phosphorylation => inactive

28
Q

Describe allosteric regulation of glycogen synthase.

A
  • G6P binds to glycogen synthase inactive and causes a conformational change to the active form => promotes glycogen synthesis
29
Q

Summarize glycogen homeostasis during starvation.

A

low BG = glucagon is active => promotes glycogen phosphorylase (glycogen degradation) and inhibits glycogen synthase

  • glycogen phosphorylase gets phosphorylated = active
  • glycogen synthase gets phosphorylated = inactive
30
Q

Summarize glycogen homeostasis during fed state.

A

high BG => inhibits glucagon and promotes insulin => inhibits glycogen phosphorylase and promotes glycogen synthase (glycogen synthesis)

  • glycogen phosphorylase gets dephosphorylated => inactive
  • glycogen synthase gets dephosphorylated => active
31
Q

Which allosteric regulators promote glycogen synthesis?

A
  • ATP (phosphorylase)
  • glucose (phosphorylase)
  • G6P (synthase)
32
Q

Which allosteric regulators promote glycogen degradation?

A
  • AMP (phosphorylase)
33
Q

Compare cAMP effects in the liver vs muscle.

A

Liver

  • promotes glycogen degradation
  • inhibits glycolysis
  • produces glucose and exports it into the bloodstream

Muscle

  • promotes glycogen degradation
  • activates glycolysis (G6P => pyruvate => TCA)
  • lactate gets exported to the liver
34
Q

Describe the effect of epinephrine.

A

epi => IP3 => releases Ca2+ from the ER => activates PKC => promotes glycogen degradation

same in muscles

35
Q

What are the 3 things that GSDs can affect?

A
  • tissue concentration of glucose
  • fasting BG levels (can’t access glycogen for glucose)
  • fatty acid metabolism (low BG promotes fatty acid metabolism => FFA in blood)
36
Q

What are general symptoms of all GSDs?

A
  • poor growth
  • poor tolerance of low BG
  • swollen belly
  • muscle cramps
  • enlarged liver
  • abnormal blood tests
37
Q

Describe GSD Type 1 (Von Gierke’s Disease).

  • enzyme
  • location
  • glycogen homeostasis
  • clinical features
A
  • enzyme: G6Pase
  • liver and kidney
  • increased glycogen, normal structure
  • hepatomegaly (glycogen accumulation), FTT, hypoglycemia, hyperuricemia, gout/arthritis, hyperlipidemia, mental retardation, lactic acidosis
38
Q

Describe GSD Type 2 (Pompe Disease).

  • enzyme
  • location
  • glycogen homeostasis
  • clinical features
A
  • enzyme: (1,4)-alpha-glucosidase
  • all organs
  • massive increase in glycogen, normal structure
  • cardiorespiratory failure, death before age 2
39
Q

Describe GSD Type 3 (Cori’s Disease).

  • enzyme
  • location
  • glycogen homeostasis
  • clinical features
A
  • enzyme: glycogen debranching enzyme
  • muscle and liver
  • increased short outer branch
  • similar to Von Gierke’s (Type 1) but milder
40
Q

Describe GSD Type 4 (Anderson’s Disease).

  • enzyme
  • location
  • glycogen homeostasis
  • clinical features
A
  • enzyme: glycogen branching enzyme
  • liver and spleen
  • normal amount; longer branches
  • progressive cirrhosis, liver failure, death before age 2
41
Q

Describe GSD Type 5 (McArdle Disease).

  • enzyme
  • location
  • glycogen homeostasis
  • clinical features
A
  • enzyme: phosphorylase
  • muscle
  • moderate amount, normal structure
  • limited ability to perform strenuous exercise, painful muscle cramps

(liver is compensating for systemic glucose)

42
Q

Describe GSD Type 6 (Hers Disease).

  • enzyme
  • location
  • glycogen homeostasis
  • clinical features
A
  • enzyme: phosphorylase
  • liver
  • increased amount
  • similar to Von Gierke’s (Type 1) but milder
43
Q

Describe GSD Type 7 (Tarui Disease).

  • enzyme
  • location
  • glycogen homeostasis
  • clinical features
A
  • enzyme: PFK1
  • muscle
  • increased amount
  • similar to McArdle Disease (Type 5)
44
Q

Describe GSD Type 8.

  • enzyme
  • location
  • glycogen homeostasis
  • clinical features
A
  • enzyme: phosphorylase b kinase
  • liver
  • increased amount, normal structure
  • mild liver enlargement, mild hypoglycemia
45
Q

Describe GSD of glycogen synthase deficiency.

  • enzyme
  • location
  • glycogen homeostasis
  • clinical features
A
  • enzyme: glycogen synthase
  • liver
  • decreased glycogen
  • hypoglycemia, postprandial lactic acidemia, fasting ketosis
46
Q

How do glucagon/epinephrine affect hepatic glycolysis?

A
  • inhibit glycolysis
  • inhibit PFK2 (indirectly inhibits PFK1)
  • inhibit pyruvate kinase
47
Q

What are the general products of PPP?

A
  • NADPH
  • ribose-5-phosphate intermediate (used for purine biosynthesis)
  • glycolysis intermediates
48
Q

What is the rate-limiting enzyme of PPP?

A

G6P dehydrogenase

49
Q

What is a genetic deficiency in G6PDH associated with?

A

drug induced hemolytic anemia

50
Q

Describe effects of G6PDH deficiency.

A
  • X linked dominant
  • increased bilirubin
  • decreased Hb
  • increased hemolytic anemia
51
Q

What is the mechanism of hemolytic anemia due to G6PDH deficiency?

A
  • NADPH generated by PPP is used to sequester enough glutathione
  • glutathione is an antioxidant
  • without PPP generating NADPH, there is not enough glutathione in the RBC
    ==> oxidative stress causes cell lysis
52
Q

Describe the purpose of glutathione.

A
  1. GSH is used to detoxify H2O2 to H2O
  2. now you are left with oxidized GSSG
  3. you need NADPH to return GSSG to its reduced GSH form
53
Q

What are the most common precipitating factors of hemolytic anemia due to G6PDH deficiency?

A
  • oxidative drugs
  • infection (produces ROS)
  • fava bean diet
54
Q

What parts of the world are most affected by G6PDH deficiency?

A
  • mediterranean
55
Q

How can G6PDH be protective?

A
  • protective against malaria because the virus requires RBCs in order to proliferate
  • with hemolytic anemia, you don’t have enough cells for the virus to amplify

FHB Exam 3 (23 decks)

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