ТЕХНИЧЕСКИЙ ИНСТИТУТ ЁДЖУ В

ГОРОДЕ ТАШКЕНТ
YEOJU TECHNICAL INSTITUTE IN
TASHKENT
Department of Fundamental Medical Disciplines

Storage Mechanisms
and Control of
Carbohydrate
Metabolism
 Learning Objectives
1. How Is Glycogen Produced and Degraded?
2. How Does Gluconeogenesis Produce Glucose
from Pyruvate?
3. How Is Carbohydrate Metabolism Controlled?
4. Why Is Glucose Sometimes Diverted through
the Pentose Phosphate Pathway?
• Why do animals store any energy as
glycogen? Why not convert all excess fuel
into fatty acids?

• Why not store energy as free glucose?

 Adult Human 70 kg
Triacylglyceride: 100.000 kcal
Protein (muscle): 25.000 kcal
Glycogen: 600 kcal
Glucose: 40 kcal

Triacylglyceride: approx 11 kg
of body weight
glycogen storage instead of fat:
increase in weight: 55 kg!!
 Glycogen Breakdown ”glycogenolysis”

• Glycogen is cleaved by glycogen

phosphorylase by adding phosphate to give
a-D-glucose-1-phosphate (phosphorolysis)
– No ATP is involved in this phosphorolysis
– Occur in the liver maintains blood glucose
glycogen
2 -
phosphorylase
HO(Glucose) nOH + HO- PO3
Glycogen
CH2 OH
HO O
HO(Glucose) n-1OH + H2 O + HO
OH
OPO 3 2 -
-D-Glucose-1-phosphate
• Enzyme-catalyzed isomerization converts the
1-phosphate to the 6-phosphate
CH2 OH CH2 OPO 3 2 -
HO O phospho- HO O
HO glucomutase HO
OH OH
OPO 3 2 - OH
-D-Glucose-1-phosphate -D-Glucose-6-phosphate

Note: more ATP is glycolysis

produced from glucose of
glycogen
– Glycogen transferase enzyme transfers three
glucose residues from (limit branch) to another
branch, where they are removed by glycogen
phosphorylase

– Glycogen debranching enzyme then hydrolyzes

the a(1,6) glycosidic bond of the last glucose residue
remaining at the point of branching.
 Glycogenesis glycogenin
• Glucose 1-phosphate reacts with uridine
triphosphate to give UDPG and pyrophosphate
UDP-glucose
pyrophosphorylase
Glucose- 1-phosphate + UTP UDP G + PPi

C H2 O H O
HO O
HO HN
OH O O
O N
O - P- O - P O C H2
O
O - O -
H H
Uridine diphosphate glucose H H
(UDPG ) OH OH
• Coupling of UDPG formation with hydrolysis of
pyrophosphate drives formation of UDPG to
completion

G°'
(kJ•mol-1 )
Glucose-1-phosphate + UTP UDPG + PPi ­0
PPi + H2 O 2Pi -30.5

Glucose-1-phosphate + UTP + H2 O UDPG + 2Pi -30.5

– Uridine diphosphate glucose (UDPG) then adds its
glucose unit to the growing glycogen chain
glycogen
synthase
HO(Glucose) n OH + UDP G
Glycogen
HO-Glucose- O(Glucose) n OH + UDP
new glucose
unit added
α (1-4 bond)
– Exchange of phosphate from ATP regenerates UTP

nucleoside
phosphate kinase
UDP + ATP UTP + ADP
 Glycogenesis
• Branching enzyme
transfers about
seven glucose
residue-long
segment from
growing branch to
a new branch
point via α(1-6)
glycosidic bond
 Control of Glycogen Metab
Glycogen phosphorylase - a major control point

Glycogen Glycogen
(Dephosphorylated form( (Phosphorylated form)
 Coordinate Control of Glycogen Metabolism

Inactive forms are shown in red, and active ones in green.

 Control of Glycogen Metab
• The activity of glycogen synthase is subject to the
same type of covalent modification as glycogen
phosphorylase
– the response, however, is opposite
– hormonal signals (glucagon or epinephrine) stimulate its
phosphorylation
– once phosphorylated, glycogen synthase becomes inactive
at the same time the hormonal signal is activating glycogen
phosphorylase
– glycogen synthase can be phosphorylated by several other
enzymes including glycogen synthase kinase
– dephosphorylation is by phosphoprotein phosphatase
 Glycogen Loading ??
http://runnersconnect.net/running-nutrition-
articles/carbohydrate-loading-marathon/
 Glycogen storage diseases.
• Type I Von Gierke’s disease
• Deficiency of glucose-6-phosphatase
Liver cells and renal tubule cells loaded
with glycogen. Hypoglycemia, lactic acidemia,
ketosis, hyperlipemia.
 Summary
• Glycogen is the storage form of glucose in animals,
including humans. Glycogen releases glucose when
energy demands are high

• Glucose polymerizes to form glycogen when the

organism has no immediate need for the energy
derived from glucose breakdown

• Glycogen metabolism is subject to several different

control mechanisms, including covalent modification
and allosteric effects
Gluconeogenesis
 Gluconeogenesis
• The synthesis of glucose from none carbohydrate
sources like lactate, glycerol and amino acids.
– gluconeogenesis is not the exact reversal of
glycolysis; that is, pyruvate to glucose does not occur
by reversing the steps of glucose to pyruvate
– It is impossible to reverse any kinase reaction under
physiological conditions.
– gluconeogenesis occur in the cytosol & mitochondria
– gluconeogenesis takes place in the liver 90%
and in kidneys 10%
 Gluconeogenesis
– 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 (bypassing)
+ 2 ATP - 6 ATP
 Gluconeogenesis
• Step 1: carboxylation of pyruvate (1st bypass)
– requires biotin
– pyruvate carboxylase is subject to allosteric
control; it is activated by acetyl-CoA
O
-
biotin
CH3 CCOO + CO 2 + A TP
pyruvate
Pyruvate carboxylase
O
CH2 CCOO - + A DP + P i + 2 H+
COO-
Oxaloacetate
 Biotin
• Biotin is a carrier of CO2 (carboxylation)
O

HN NH 1 . H2 N- e n z y m e
H H
2 . CO 2 + A TP
S COO-
Biotin O O
C
-
O N NH
H H
N H-e n z y me
S C
O
 Gluconeogenesis
– decarboxylation of oxaloacetate is coupled with phosphorylation
by GTP to give PEP
O OPO 3 2 -
CH2 CCOO - + GTP CH2 = CCOO - + CO 2 + GD P
CO 2 -
Oxaloacetate Phosphoenolpyruvate

– the net reaction of carboxylation/decarboxylation is

Pyruvate + ATP + GTP

Phosphoenolpyruvate + ADP + GDP + P i + 2 H+

– net reaction is close to equilibrium: DG0’ = 2.1 kJ•mol-1

 Gluconeogenesis
• Second different reaction (2nd bypass) in gluconeogenesis

CH2 OPO 3 2 -
CH2 OPO 3 2 - fructose
O
1,6-bisphosphatase
H HO + H2 O
2 +
H OH Mg
HO H
-D-Fructose-1,6-bisphosphate
CH2 OPO 3 2 -
O CH2 OH
H HO + Pi
H OH
HO H
-D-Fructose-6-phosphate

– G° = -16.7•kJ mol-1

– fructose-1,6-bisphosphatase is an allosteric enzyme, inhibited by
AMP and F2,6P and activated by ATP
 Gluconeogenesis
• Third different reaction (3rd bypass) in
gluconeogenesis
CH2 OPO 3 2 - CH2 OH
HO O glucose-6- HO O
HO phosphatase HO
+ H2 O + Pi
OH OH
OH OH
-D-Glucose-6-phosphate -D-Glucose

G°’ = -13.8 kJ•mol-1

 The Cori Cycle
• 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
The Cori Cycle
Control of carbohydrate metabolism

How ?
 Control of carbohydrate metabolism

• Allosteric: fructose-2,6-bisphosphate (F2,6P)

– high concentration of F2,6P stimulates glycolysis; a low
concentration stimulates gluconeogenesis
– concentration of F2,6P in a cell depends on the balance
between its synthesis (catalyzed by
phosphofructokinase-2) and its breakdown (catalyzed
by fructose bisphosphatase-2)
– AMP inhibits FBPase and stimulates PFK
– each enzyme is controlled by phosphorylation/
dephosphorylation
 Fructose-2,6-bisphosphate

Fructose-2,6-bisphosphate is an allosteric activator of

phosphofructokinase (a glycolytic enzyme) and an allosteric
inhibitor of fructose bisphosphate phosphatase (an enzyme in
the pathway of gluconeogenesis).

p. 520
Reciprocal Regulation of Gluconeogenesis and
Glycolysis in the Liver
 Control of carbohydrate metabolism

Allosteric Effectors (substrates, products, or coenzymes)

of a pathway inhibit or activate an enzyme
Covalent Inhibition or activation of an enzyme
modification depends on formation or breaking of a
covalent bond, often by phosphorylation or
dephosphorylation
Substrate Two opposing reactions (such as formation
cycles or breakdown of a substance) are catalyzed
by different enzymes, which are activated or
inhibited separately
Genetic The amount of enzyme present is
increased by protein synthesis
 Control of carbohydrate metabolism

• Substrate cycling
– opposing reactions can be catalyzed by different
enzymes and each opposing enzyme or set of enzymes
can be regulated independently
G0'
phosphofructo-
kinase (kJ•mol -1)
Fructose-6-phosphate + ATP
Fructose 1,6-bisphosphate + ADP -25.9

fructose-1,6-
bisphosphatase
Fructose 1,6-bisphosphate + H2 O
Fructose-6-phosphate + Pi -8.6
 Major Control Points in Carbohydrate
Metabolism
• Three steps in glycolysis are major control points in glucose
metabolism
• Hexokinase
– Inhibited by high levels of glucose 6-phosphate
Phosphofructokinase,
– When glycolysis is inhibited through glucose 6-phosphate builds up, shutting
down hexokinase
• Pyruvate kinase (PK) is an allosteric enzyme
– Inhibited by ATP and alanine
– Activated by fructose-1,6-bisphosphate
• PK has 3 different isoenzymes
– M predominates in muscle, L in liver, and A in other tissues
– Native PK is a tetramer
– Liver isoenzymes are subject to covalent modification
Control of Pyruvate Kinase
 Summary
• A number of control mechanisms operate in
carbohydrate metabolism. These include
allosteric effectors, covalent modification,
substrate cycles, and genetic control

• In the mechanism of substrate cycling, the

synthesis and the breakdown of a given
compound are catalyzed by two different
enzymes
 Pentose Phosphate Pathway
– As the name implies, five-carbon sugars, including
ribose, are produced from glucose
– The oxidizing agent is NADP+; it is reduced to NADPH,
which is a reducing agent in biosyntheses e.g. lipid
– PPP is composed from two reactions:
1. Oxidative reactions: begins with two oxidation steps
(using NADP+) to give ribulose-5-phosphate
2. Non-oxidative reactions: a series of carbon-shuffling
steps during which three-, four-, five-, six-, and seven-
carbon monosaccharide phosphates are produced
– ATP production is not an important concern
 PPP
oxidative reactions
-
CHO CO O
+ +
H OH NADP NADPH H O H NADP NADPH
HO H HO H
H OH H OH
H OH H OH
CH 2 O PO 3 2 - CH 2 O PO 3 2 -
Glucose-6-phosphate 6-Phosphogluconate

CO O-
H OH CH 2 OH
C O C O
H OH H OH + CO 2
H OH H OH
CH 2 O PO 3 2 - CH 2 O PO 3 2 -
Ribulose-5-phosphate
 Non-oxidative reactionsCH2 OH
RNA C O
CHO HO H
H OH H OH
H OH H OH
CH2 OH H OH H OH
C O CH2 O PO 3 2 - CH 2 O PO 3 2 -
H OH Ribose-5-phosphate Sedoheptulose-
H OH 7-phosphate
CH2 O PO 3 2 - CH2 OH
Ribulose-5- C O
phosphate HO H CHO
H OH H OH
CH2 O PO 3 2 - CH2 O PO 3 2 -
Xylulose-5-phosphate Glyceraldehyde-
3-phosphate
 CH2 OH
C O
HO H
H OH CHO
H OH H OH
H OH H OH
CH2 OPO 3 2 - CH2 OPO 3 2 -
Sedoheptulose-7-phosphate Erythrose-4-phosphate
CH2 OH
C O
HO H
CHO H OH
H OH H OH
CH2 OPO 3 2 - CH2 OPO 3 2 -
Glyceraldehyde-3-phosphate Fructose-6-phosphate
 CH2 OH
C O
HO H CHO
H OH H OH
CH2 OPO 3 2 - CH2 OPO 3 2 -
Xylulose-5- Glyceraldehyde-
phosphate 3-phosphate

CH2 OH
C O To glycolysis
CHO HO H
H OH H OH
H OH H OH
CH2 OPO 3 2 - CH2 OPO 3 2 -
Erythrose- Fructose-6-
4-phosphate phosphate
Pentose Phosphate Pathway
 Pentose Phosphate Pathway

– the carbon-shuffling reactions are catalyzed by

---transketolase for the transfer of two-carbon units
requires thiamine pyrophosphate as a coenzyme
---transaldolase for the transfer of three-carbon units
• 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 pathway
 G-6-PD

• More than 400 variants of G-6-PD have been

characterized, which show less activity than
normal.
• G-6-PD is the most common human enzyme
deficiency in the world. It affect an estimated 400
million people.
• Hemolysis, abdominal pain, dizziness, headache,
dyspnea, palpitation, neonatal jaundice
 Precipitating Factors
• Infection & other ac. Illness(diabetic ketoacidosis)
• Drugs: Antimalarials, Antipyretics or Antibiotics
• Fava beans “favism”
• Neonatal jaundice : due to decrease hepatic
catabolism or increase production of bilirubin.
 Pentose Phosphate Pathway

• Summary of oxidative reactions

• Glucose-6-phosphate + 2 NADP
Ribulose-5-phosphate + CO2 + 2 NADPH

• Summary of non-oxidative reactions

Reactant Enzyme Products
Transketolase
C5 + C5 C7 + C3

Transaldolase
C7 + C3 C6 + C4

Transketolase
C5 + C4 C6 + C3

Net: 3 C5 2 C6 + C3
Relationship between PPP and Glycolysis
End
Chapter 18