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Carbohydrate

metabolism

Learning outcomes
Upon completion of this chapter,
students should;

Understand
Understand
Understand
Understand

glycogenolysis
glyconeogenesis
Cori cycle
pentose phosphate pathway

Short review
What will happen if you have excess
glucose?
Glucose is converted to glycogen in the
liver
Glycogen is then stored in liver and
muscle

Short review
What happens when you have less glucose?

Glycogen is cleaved by phosphate to give aD-glucose-1-phosphate


no ATP is involved in this phosphorylation
HO(Glucose) nOH + HO-PO3 2Glycogen

glycogen
phosphorylase

HO
HO
HO(Glucose) n-1OH + H2 O +

CH2 OH
O

OH
OPO32-D-Glucose-1-phosphate
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Glucose is needed in blood


In blood, amount of glucose needs to be
maintained at a certain concentration
Important for brains and erythrocytes

We know that excess glucose to


glycogenin liver (for storage)
This glycogen will be kept in both liver and
muscles
BUT what happens when blood glucose is
low?
Glycogen to glucose
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Glycogenolysis
The breakdown of stored glycogen to
glucose when the blood sugar is low.
Is glycogen actually broken down to
glucose?
Not really!!! It is broken down to glucose
-1-phosphate

This is done in several steps using


several enzymes
Lets understand each step
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Glycogenolysis
First enzyme that we should look at is the
glycogen phosphorylase
Breaks down the -(1-4)- glycosidic linkages
between the glucose molecule in glycogen
LIMITATION: cannot breaks down 4 or less
glucose residues.

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Glycogenolysis
The second enzyme will come to the rescue glycogen
debranching enzyme

This enzyme works in two ways:


1. Transfer three glucose residues to the end of another
branch
2. Break down -(1-6)-glycosidic bond

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Glycogenolysis
The end products from the break down

1. Glycogen phosphorylase : glucose-1phosphate


2. Glycogen debranching enzyme : glucose
Overall: 90% glucose-1-phosphate; 10% glucose
BUT glucose-1-phosphate is not such a useful molecule
for energy production
Thus, conversion of G1P to G6P is needed.

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Glycogenolysis
In muscle glucose-6-phosphate is used to produce
energy, whereas in the liver it is ultimately transported to
other tissues via the circulatory system

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Gluconeogenesis

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Gluconeogenesis
Gluconeogenesis: the synthesis of glucose from pyruvate

gluconeogenesis is not the exact reversal of


glycolysis; that is, pyruvate to glucose does not
occur by reversing the steps of glucose to
pyruvate
there are three irreversible steps in glycolysis
---phosphoenolpyruvate to pyruvate + ATP
---fructose-6-phosphate to fructose-1,6-bisphosphate
---glucose to glucose-6-phosphate

the net result of gluconeogenesis is reversal of


these three steps, but by different reactions and
using different enzymes
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Gluconeogenesis
Step 1: carboxylation of pyruvate
requires biotin
pyruvate carboxylase is subject to
allosteric control; it is activated by
acetyl-CoA
O
biotin

CH3 CCOO- + CO2 + ATP


Pyruvate

pyruvate
carboxylase
O
CH2 CCOO- + ADP + Pi + 2H+
COOOxaloacetate
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Biotin
Biotin is a carrier of carbon dioxide
O
HN

NH

1. H2 N-enzyme

2. CO2 + ATP
COO-

S
Biotin

O
-

NH

H
S

C
O

NH-enzyme
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Gluconeogenesis
decarboxylation of oxaloacetate is
coupled with phosphorylation by GTP to
give PEP
O
CH2 CCOO- + GTP
CO2Oxaloacetate

OPO32CH2 =CCOO- + CO2 + GDP


Phosphoenolpyruvate

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Gluconeogenesis
Second different reaction in
gluconeogenesis

CH2 OPO3 2fructose


CH2 OPO3 2O
1,6-bisphosphatase
H HO
+ H2 O
2+
Mg
H
OH
HO
H
-D-Fructose-1,6-bisphosphate
CH2 OPO3 2CH2 OH
O
H HO
+ Pi
H
OH
HO
H
-D-Fructose-6-phosphate
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Gluconeogenesis
Third different reaction in gluconeogenesis

HO
HO

CH2 OPO32O
+ H2 O

OH
OH
-D-Glucose-6-phosphate

glucose-6phosphatase

HO
HO

CH2 OH
O

OH
OH
-D-Glucose

+ Pi

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Glycogen metabolism
control

Glycogen synthesis and glycogenolysis


cannot happen simultaneously in the
same cell
Or else it would be a waste of chemical
energy by hydrolysis of UTP

The controlling factor is the enzyme


glycogen phosphorylase itself
Exist as a dimer in two forms
1. Phosphorylase a
2. Phosphorylase b
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Glycogen phosphorylase - a
major control point

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Glycogen metabolism
control

In liver, glucose is the allosteric


inhibitor for phosphorylase-a
Binds to active site and favors the
transition to the T state (inactive)

In muscle, the allosteric effectors are


ATP, AMP and G6P
When muscle use ATP, [AMP] increase
stimulate formation of of R-state of
phosphorylase-b (active)
When [ATP] and [G6P] is high
promotes formation of T-state (inactive) 30

Glycogen metabolism
control
Glycogen synthase also exist in two forms

Phosphorylated
synthase D

(inactive)

glycogen

Activated only by high conc. of G6P

Non-phosphorylated
synthase I

(active)

glycogen

Active even with low level of G6P


Glycogen synthase is also inhibited by ATP, but this
inhibition can be overcome by G6P

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Can glycogen synthesis


and gluconeogenesis
happen simultaneously?

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The Cori cycle


under vigorous anaerobic exercise, glycolysis
in muscle tissue converts glucose to pyruvate;
NAD+ is regenerated by reduction of pyruvate
to lactate
lactate from muscle is transported to the liver
where it is reoxidized to pyruvate and
converted to glucose
thus, the liver shares the stress of vigorous
exercise

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Glucose is sometimes diverted


to Pentose Phosphate Pathway

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Intro to PPP
The main purpose for this pathway is to
produce
NADPH provides reducing power for
biosynthesis
ribulose-5-phosphate to make nucleic acid

Divided into two phases:


1. Non-oxidative phase create only ribulose-5phosphate
2. Oxidative phase create both products of PPP
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Oxidative PPP
Involves two steps:
1. G6P ribulose-5-P + CO2 (irreversible)
2. 2NADP+ 2NADPH

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CHO
+
H
OH NADP
HO
H
H
OH
H
OH
CH2 OPO32 Glucose-6-phosphate

COO+
NADPH
H
OH NADP NADPH
HO
H
H
OH
H
OH
CH2 OPO326-Phosphogluconate

COOH
OH
C O
H
OH
H
OH
CH2 OPO32 -

CH2 OH
C O
+ CO2
H
OH
H
OH
CH2 OPO32 Ribulose-5-phosphate

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Non-oxidative pathway

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Pentose Phosphate Pathway


the carbon-shuffling reactions are catalyzed by
---transketolase for the transfer of two-carbon units and
---transaldolase for the transfer of three-carbon units

transketolase requires thiamine pyrophosphate


Control of the pentose phosphate pathway

glucose-6-phosphate (G6P) can be channeled


into either glycolysis or the pentose phosphate
pathway
if ATP needed, G6P is channeled into glycolysis
if NADPH or ribose-5-phosphate are needed,
G6P is channeled into the pentose phosphate
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pathway

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End of Lecture

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