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BIOCHEM 405 > Lecture 25 > Flashcards

Lecture 25 Flashcards

1
Q

what is glycogen

A

polymer of glucose

“Starch for Animals & Fungi”

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2
Q

Advantage of a polymer?

A

0.01 µM glycogen(insoluble) = 400 mM glucose(soluble)

→ Can store lots of glucose with little effect on osmotic pressure

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3
Q

Glycogen granules

A

Mini-compartments containing 20-40 glycogen molecules, and enzymes for glycogen synthesis & degradation.

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4
Q

Why glycogen but not fat?

A

Fat
• Synthesis & breakdown is slow
• Contributes to long-term energy homeostasis during starvation

Glycogen
• Synthesis & breakdown is rapid
• Helps maintain constant blood glucose level when fasting

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5
Q

Glycogen – Where is it?

A

Glycogen is stored in liver and skeletal muscle; has multiple functions.

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6
Q

glycogen to blood glucose

A

Glycogen –> Glucose-1-P –> Glucose-6-P –>Glucose –>Blood Glucose

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7
Q

glycogen in liver

A
  • glycogen = up to10% of wet weight
  • Exportable glucose reservoir
  • Exhausted in 12-24 h
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8
Q

glycogen to energy

A

Glycogen
Glucose-1-P
Glucose-6-P
Energy

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9
Q

glycogen in skeletal muscle

A
  • glycogen - 1-2% of wet weight
  • usable energy reservoir
  • exhausted in ~1h
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10
Q

Glycogen Structure

A

Glycogen uses two kinds of glycosidic bonds.

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11
Q

no reducing ends

A

• Glycogen degradation and synthesis occurs

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12
Q

branching occurs where

A

Branching occurs every 8-14 units at α-1,6 linkages.
plants: starch —> α-amylose (not branched)
amylopectin (branched every 24-30 units)

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13
Q

Why is glycogen so highly branched?

A

~2,000 non-reducing ends per glycogen molecule available for degradation
= rapid release of glucose !

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14
Q

Glycogen Breakdown aka glycogenolysis

A

look at power point

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15
Q

Glycogen Breakdown Overview of 3 Key Enzymes

1. Glycogen phosphorylase

A

Cleaves (α-1,4) linkages from non-reducing ends until it
reaches four units from a branch point

Cleaves (α-1,4) linkages:
glycogenn + Pi —> glucose-1-P + glycogenn-1

Glycogen phosphorylase does NOT use H2O to cleave (hydrolyze) the glycosidic bond. It uses phosphate to generate a phosphorylated product, AKA: phosphorolysis

Why use phosphorolysis?
→ Pi is abundant & no ATP required
→ glucose-1 phosphate can’t exit cell

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16
Q

Glycogen Breakdown Overview of 3 Key Enzymes

2. Debranching enzyme

A
  • Transfers a block of three units to the non-reducing end of the chain
  • Cleaves the last remaining (a-1,6)–linked glucose

3 units of one branch are transferred onto another

α-1,6 linkage hydrolyzed to yield unphosphorylated glucose

open for phosphorolysis

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17
Q

Glycogen Breakdown Overview of 3 Key Enzymes

3. Phosphoglucomutase

A

Converts glucose-1-P into glucose-6-P

A phosphorylated serine on the enzyme participates in phosphate exchange.

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18
Q

cofactor for glycogen phosphorylase

A

Pyridoxal-5- phosphate (PLP) is an essential
cofactor for glycogen phosphorylase.

PLP, a derivative of vitamin B6

PLP serves as a prosthetic group. The phosphate of PLP is involved in acid/base catalysis by glycogen phosphorylase.

PLP is covalently bound to glycogen phosphorylase via a Schiff base at Lys 680.

19
Q

glycogen phosphorylase inhibitor

A

1,5-Gluconolactone

Mimics structure of the intermediate

20
Q

[G6P] determines reaction direction

A

(fasted state)

21
Q

Glycogen Breakdown in summary

A

3 enzymes
2 products

Glucose units obtained from glycogen:
~ 92% glucose-1-phosphate
~ 8% glucose (Must be phosphorylated before use!)

22
Q

Glycogen Synthesis (AKA glycogenesis)

A

3 steps, 3 enzymes - Not just the opposite of breakdown!

23
Q

synthesis overview

A
  1. Activation of glucose
    Glucose-1-P + UTP —> UDP-Glucose + PPi
    UDP-glucose-pyrophosphorylase
  2. Formation of an α-1,4 bond
    UDP-Glucose + glycogenn —> glycogenn+1 + UDP
    glycogen synthase
  3. Formation of an α-1,6 bond
    branching enzyme
24
Q
  1. Activation of Glucose with UDP
A

Glucose-1-P + UTP —> UDP-Glucose + PPi
UDP-glucose-pyrophosphorylase
∆G ~ 0

PPi –(H2O)–> 2Pi
pyrophosphatase
ΔG = -19 kJ/mol

25
Q

Where does glucose-1-P come from?

A

→ phosphoglucomutase

26
Q

What other modifications are used to “activate” metabolites?

A

→ acetyl CoA ~ acetate

→ ATP ~ Pi

27
Q

Glycogen Synthase

A

Forms α-1,4 bonds at non-reducing ends

Result: Linear enlargement of existing glycogen molecule …

28
Q

Glycogenin:

A

a primer for glycogen synthase

auto-catalytic tyrosine glycosyl-transferase –
The enzyme IS the substrate!

After glycogenin “seeds” itself with glucose chains, glycogen synthase can bind & polymerize non-reducing ends.

29
Q

Branching Enyzme

A

α-1,4 linkage is cleaved to yield a 7-unit chain

α-1,6 bond forms between 7-unit chain & another glycosyl unit

∆G of hydrolysis (kJ/mol)
α-1,4 = -15.5
α-1,6 = - 7.1

30
Q

Glycogen Synthesis summary

A

2 branches per chain, ~13 units in a branch

  • Enough non-reducing ends to provide lots of glucose rapidly
  • Long chains provide enough glucose to sustain escape response…
31
Q

von gierke’s disease

A

breakdown
enzyme deficiency: glucose-6-phosphatase
tissue: liver

32
Q

andersen’s disease

A

synthesis
enzyme deficiency: amylo-(1,4-1,6)-transg.. (branching enzyme)
tissue: liver, probably all organs

33
Q

McArdle’s disease

A

breakdown
enzyme deficiency: glycogen phosphorylase
tissue: muscle

34
Q

hers’ disease

A

breakdown
enzyme deficiency: glycogen phosphorylase
tissue: liver

35
Q

Type I: Von Gierke’s disease

A
  • Glucose-6-phosphatase deficiency
  • Most common GSD

Clinical Signs
• Glycogen accumulation in the liver and kidneys
• Liver enlargement
• Hypoglycemia

Treatment & Prognosis
• Feed cornstarch to maintain blood glucose
• Avoid sugars that → glucose-6-P
• Prognosis good if diagnosed before damage occurs

RECALL: muscle lacks glucose 6- phosphatase

Glycogen	
Glucose-1-P	
Glucose-6-P (problem in this step going to next)
Glucose
blood glucose
36
Q

Type IV: Andersen’s disease - Branching enzyme deficiency

A

Very long unbranched chains have impaired solubility

Symptoms & Prognosis
• Long unbranched glycogen precipitates in liver and heart
• Liver cirrhosis, muscle weakness
• Most succumb in early childhood; one cause of miscarriage

37
Q

Type V: McArdle’s disease

A

MUSCLE glycogen phosphorylase deficiency

Symptoms & Prognosis
• Glycogen accumulates in muscle
• Poor acute exercise tolerance, cramping
• Prognosis OK with exercise training
 & sucrose supplementation

Glycogen (problem in this step going to next)
Glucose-1-P
Glucose-6-P

38
Q

Type VI: Hers’ disease –

LIVER glycogen phosphorylase deficiency

A

Symptoms & Prognosis
• Can be asymptomatic
• Mild liver enlargement, hypoglycemia, low muscle tone, elevated ketone bodies (less fat more glucose)
• Prognosis good; symptoms usually stabilize by adulthood

Glycogen (problem in this step going to next)	
Glucose-1-P	
Glucose-6-P 
Glucose
blood glucose
39
Q

Two phosphorylase genes, two phosphorylase deficiencies:

A

Type V: McCardle’s Disease
• Muscle glycogen phosphorylase deficiency
• Exercise intolerance, muscle pain, fatigue, cramps
• Associated with nearly 100 mutations in the muscle phosphorylase gene

Type VI: Hers’ Disease
• Liver glycogen phosphorylase deficiency
• Enlarged liver, hypoglycemia, elevated ketone bodies
• Associated with >17 mutations in the liver phosphorylase gene

40
Q

Key Points Glycogen Overview

A

– A polymer provides glucose and energy (G-1-P)
– α-1,4 and α-1,6 linkages; non-reducing end
– Different roles in liver and skeletal muscle

41
Q

Key Points Glycogen breakdown (Glycogenolysis)

A

– Phosphorylase (Uses phosphate for phosphorolysis; cleave α-1,4 )
– Debranching enzyme (Transferase and hydrolyze α-1,6)
– Phosphoglucomutase (The fate of G-6-P)

42
Q

Key Points (Glycogenesis)

A

– Activating glucose (UDP-G pyrophosphorylase; requires UTP)
– Glycogen Synthase (Extension of existing chain; – Branching enzyme (Cleave α-1,4 to form α-1,6)
– 1 chain, two branches, ~13 units per branch (advantage = ?)

43
Q

Key Points Glycogen Storage diseases

A

– Deficiencies in glucose-6-P phosphatase, branching enzyme,

glycogen phosphorylase in liver and muscle

BIOCHEM 405 (25 decks)

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