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8/13/2019 Biochemistry Lect 7 2011 colour 2 slides per page.pdf
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LECTURE 7: Glucose: eat it or make it.
LECTURE 7: Glucose: eat it or make it.
KeyKey Concepts:Concepts:
Certain tissues of the body, highly dependent on glucose (brain!)
blood glucose constant ~ 80 mg/dl (~ 5 mM)
excess glucose stored in liver and muscle as glycogen
when blood glucose levels drop, liver glycogen is the glucose
source
during fasting the liver synthesizes glucose to maintain blood
glucose levels
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WHAT YOU NEED TO KNOW!! You should:WHAT YOU NEED TO KNOW!! You should:
understand glycogens structure
understand different roles of liverand muscle
glycogen stores
understand glycogen synthesis and degradation
understand roles of glycogen synthase and glycogen
phosphorylase
glycogen storage diseases
understand how the liver synthesizes glucose
Reading: (for onReading: (for on--line testing)line testing)
Campbell et al., Biology, 6th/7th ed Benjamin/Cummings
Chapter 5, The Structure and Function o f Macromolecules
Sugars, the smallest carbohydrates, serve as fuel and
carbon sources
Polysaccharides, the polymers of sugars, have storage
Relevant material in Chapter Reviews; including Self
Quizzes; Interactive Study Partner (CD)
----------------------------------
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GlycogenGlucose storage in the cytosol, in many tissues
Rapidly accessed & water soluble, efficiently accessedBut its heavy (associated H20)
Onl liver & some kidne l co en is accessible to other
tissues
Liver can store 8-10% of wet mass as glycogen
Muscles 1-2% (space limits in muscle)?
George Palade
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There are different pathways for
glycogen synthesis and degradation
diseases (more on this later)
(briefly) Mc Ardles disease (glycogen in
muscle but severe muscle cramps, due to a
,
phosphorylase in muscle)
Normal person
rest
Light exercise
McArdles
patients
Heavy exercise till exhaustion
Second wind effect
0 50 100 150 200
[ADP] uM
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Figure 7.1: Glycogen Structure
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Glycogen synthesis - Glycogenesis
Hepatic
portal vein
Hexokinase, or glucokinase (liver only)
Km 0.1 mM Km 10 mM
Glucose 6-phosphate
Hepatocyte
Hexokinase 1 mM Km
Glucokinase 10 mM Km
[Glucose] mM
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Glycogen synthesis - Glycogenesis
Phosphoglucomutase
G6P G1P
UTP + UDPG pyrophosphorylase
Endergonic (i.e. loss of energy)
Glycogen synthase
glycogenin
= UMP (a phosphate from UTP and the phosphate on the G1P makes the
bond)
GS is associated with glycogenin, controls size of granules
= reducing end
Glycogenesis
Glucose added to reducing ends, -1-4 glycosidic bonds
and -1-6 glycosidic bonds
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Glycogen synthesis - Glycogenesis
6-7 x UDP glucose& glycogen synthase
Branchin enz me
Permits denseconstruction of glycogen
Branching makes many
termini
97% efficient storage
Amylo(1,41,6)-transglycosylase
Branches are created by the transfer of ~7 glycosyl residues
Each branch must grow to 11 residues before transfer
New branches are 4 residues away, & move into the core
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ycogen rea own
= glocogenolysis
3 enzymes
1) Glycogen Phosphorylase
2) Glycogen de-branching enzyme
3) Phosphoglucomutase
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= non reducing end
Glycogen breakdown = glycogenolysis
From the non-reducing ends
Glycogen breakdown Glycogenolysis
Glycogen phosphorylasephosphorylysis
Glucose 1 phosphate
Glycogen phosphorylase only works to 5 glycosyl residues
Inhibited by ATP, glucose, and G6P
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Phosphorylyisis?
Why not hydrolysis?
1) Ensures released glucose is charged and trapped in cells
2) Primed for use by glycolysis (e.g. by muscle)
3) It saves an ATP! (Pi is used)
-1,4 link
- 1,6-glucosidase
To core-1,6 link
transferase that transfers 3 units
and then hydrolyses the -1,6 link
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Glycogen breakdown - Glycogenolysis
Glycolysis
Pentose
phosphate
pathway
Glucose 1-phosphate Glucose 6- phosphate
Glycogen breakdown - Glycogenolysis
Glucose 6-phosphatase
Blood
Glucose 6-phosphate
G6Pase only in the liver and kidneys!
Glucose
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Animation: Scheme of glycogen
synthesis and degradation
UDPG
pyrophosphorylase
Maximum recorded speed 117 km/hr,
extremely active glycolysis in muscle
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Fig. 7.5 Coordinate control of glycogen metabolism
Stimulated/inhibited by glucagon or epinephrine (aka. adrenalin)
From: Biochemistry (5th edition) Berg, Tymoczico and Stryer
Active Inactive
Cascade
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Abnormal GlycogenMetabolism
, ,
Glycogen storage diseases
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Glycogen Storage Diseases
Incidence ~ 2.5 children / 100,000 births
7 result in muscle weakness or wastage
5 result in enlarged livers
-
I GSD) glucose 6-phosphatase mutation
von Gierkesdisease
H o l caemia
Excess G6P shunted to
triglycerides, hyperlipidaemia
Elevated lactate during
fasting
Gout (hyperuricaemia)
n arge ver an neys Treatment fructose and other
carbohydrates
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What happens when glycogen
runs out?
Glycogen depletion, athletes Hitting the
wall, caffeine and carbohydrates
In an average resting male Brain uses 120 g/day gluc
Stores 20 g blood gluc, 190g glycogen
90% gluc used / day, 57% by brain
n y e a e en o ay
Make glucose! Gluconeogenesis
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Sources of building blocks for
gluconeogenesis
Amino acids (except leucine and lysine)
Glycerol (remainder of fats cannot be used inanimals to make glucose)
TCA intermediates conversion tooxaloacetate/malate)
Fig 7.6: Gluconeogenic precursors
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Gluconeogenesis
Overall luconeo enesis:
2Pyr + 4ATP +2GTP+2NADH + 6H2O Glucose +4ADP +2GDP +2NAD+ + 2H+ + 6Pi
G = -15.6 kJ/mol
Using glyconeogenesis
G = + 83.7 kJ/mol
Enough to heat 250ml water to 100oC
Still expensive Investment of 6 ATP
If NADH is included~12 ATP equivalents*
* Assumes 3 ATP / NADH
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Parts ofl col sis
are
reversible
ome are
not!
Equilibrium versus non-equilibrium enzymes
Equilibrium
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Equilibrium versus Non-
Equilibrium enzymes
Non-Equilibrium
Three bypasses
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Fig. 7.7: The gluconeogenic pathway
Bypass 1 (PK)
Cytosol
Pyruvate Kinase
Mitochondrial
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Bypass 2 (PFK) & 3 (GK, HK)
Gluco/Hexokinase
Phosphofructokinase
ER
Important gluconeogenicenzymes
Phosphoenolpyruvate carboxykinase
(PEPCK) (bypass I)
Fructose 1,6-bisphosphatase (bypass II)
-
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Control of gluconeogensis and
glycolysis -
Glycolysis makes + 2 ATP
mis-match of - 4 ATP
Fructose 6-PhosphateF 2,6P +
AMP +
ATP -
-
F 2,6P -
AMP -
Citrate +
Fructose 1, 6-Phosphate
Fructose 1, 6-Phosphate
H+ -
F 2,6P +
AMP +
ADP -
Pyruvate
xa oace a eATP -Citrate -
H+ -
Modified from Stryer 4th edition
Acetyl CoA+
ADP -
Green means go
Red means stop
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Futile cycles canbe useful
Bumblebees can
fly on cold days
Honey Bees
cannot
Fructose 6-Phosphate
Fructose 1, 6-Phosphate
Heat
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Fuel utilization by a PEPCK-Cmus and control
mouse during strenuous exercise.