Lecture 25 Flashcards
what is glycogen
polymer of glucose
“Starch for Animals & Fungi”
Advantage of a polymer?
0.01 µM glycogen(insoluble) = 400 mM glucose(soluble)
→ Can store lots of glucose with little effect on osmotic pressure
Glycogen granules
Mini-compartments containing 20-40 glycogen molecules, and enzymes for glycogen synthesis & degradation.
Why glycogen but not fat?
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
Glycogen – Where is it?
Glycogen is stored in liver and skeletal muscle; has multiple functions.
glycogen to blood glucose
Glycogen –> Glucose-1-P –> Glucose-6-P –>Glucose –>Blood Glucose
glycogen in liver
- glycogen = up to10% of wet weight
- Exportable glucose reservoir
- Exhausted in 12-24 h
glycogen to energy
Glycogen
Glucose-1-P
Glucose-6-P
Energy
glycogen in skeletal muscle
- glycogen - 1-2% of wet weight
- usable energy reservoir
- exhausted in ~1h
Glycogen Structure
Glycogen uses two kinds of glycosidic bonds.
no reducing ends
• Glycogen degradation and synthesis occurs
branching occurs where
Branching occurs every 8-14 units at α-1,6 linkages.
plants: starch —> α-amylose (not branched)
amylopectin (branched every 24-30 units)
Why is glycogen so highly branched?
~2,000 non-reducing ends per glycogen molecule available for degradation
= rapid release of glucose !
Glycogen Breakdown aka glycogenolysis
look at power point
Glycogen Breakdown Overview of 3 Key Enzymes
1. Glycogen phosphorylase
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
Glycogen Breakdown Overview of 3 Key Enzymes
2. Debranching enzyme
- 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
Glycogen Breakdown Overview of 3 Key Enzymes
3. Phosphoglucomutase
Converts glucose-1-P into glucose-6-P
A phosphorylated serine on the enzyme participates in phosphate exchange.
cofactor for glycogen phosphorylase
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.
glycogen phosphorylase inhibitor
1,5-Gluconolactone
Mimics structure of the intermediate
[G6P] determines reaction direction
(fasted state)
Glycogen Breakdown in summary
3 enzymes
2 products
Glucose units obtained from glycogen:
~ 92% glucose-1-phosphate
~ 8% glucose (Must be phosphorylated before use!)
Glycogen Synthesis (AKA glycogenesis)
3 steps, 3 enzymes - Not just the opposite of breakdown!
synthesis overview
- Activation of glucose
Glucose-1-P + UTP —> UDP-Glucose + PPi
UDP-glucose-pyrophosphorylase - Formation of an α-1,4 bond
UDP-Glucose + glycogenn —> glycogenn+1 + UDP
glycogen synthase - Formation of an α-1,6 bond
branching enzyme
- Activation of Glucose with UDP
Glucose-1-P + UTP —> UDP-Glucose + PPi
UDP-glucose-pyrophosphorylase
∆G ~ 0
PPi –(H2O)–> 2Pi
pyrophosphatase
ΔG = -19 kJ/mol
Where does glucose-1-P come from?
→ phosphoglucomutase
What other modifications are used to “activate” metabolites?
→ acetyl CoA ~ acetate
→ ATP ~ Pi
Glycogen Synthase
Forms α-1,4 bonds at non-reducing ends
Result: Linear enlargement of existing glycogen molecule …
Glycogenin:
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.
Branching Enyzme
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
Glycogen Synthesis summary
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…
von gierke’s disease
breakdown
enzyme deficiency: glucose-6-phosphatase
tissue: liver
andersen’s disease
synthesis
enzyme deficiency: amylo-(1,4-1,6)-transg.. (branching enzyme)
tissue: liver, probably all organs
McArdle’s disease
breakdown
enzyme deficiency: glycogen phosphorylase
tissue: muscle
hers’ disease
breakdown
enzyme deficiency: glycogen phosphorylase
tissue: liver
Type I: Von Gierke’s disease
- 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
Type IV: Andersen’s disease - Branching enzyme deficiency
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
Type V: McArdle’s disease
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
Type VI: Hers’ disease –
LIVER glycogen phosphorylase deficiency
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
Two phosphorylase genes, two phosphorylase deficiencies:
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
Key Points Glycogen Overview
– 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
Key Points Glycogen breakdown (Glycogenolysis)
– Phosphorylase (Uses phosphate for phosphorolysis; cleave α-1,4 )
– Debranching enzyme (Transferase and hydrolyze α-1,6)
– Phosphoglucomutase (The fate of G-6-P)
Key Points (Glycogenesis)
– 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 = ?)
Key Points Glycogen Storage diseases
– Deficiencies in glucose-6-P phosphatase, branching enzyme,
glycogen phosphorylase in liver and muscle
