BIO462

Storage Mechanisms and Control in

Carbohydrate Metabolism

• Gluconeogenesis
• Pentose Phosphate Pathway
Outline
1 How Glycogen is Produced and Degraded

2 Gluconeogenesis Produces Glucose from Pyruvate

3 Control of Carbohydrate Metabolism

4 Glucose is Sometimes Diverted Through the Pentose

Phosphate Pathway
Introduction
• When we digest a meal high in carbohydrates 
supply of glucose  (exceeds our immediate needs)
• Hence, extra glucose is stored as a polymer 
Glycogen.
• In the degradation of glycogen, several glucose
residues can be released simultaneously; one from
each end of a branch.
• It is useful for in short-term demands for energy (by
increasing glucose supply as quickly as possible.
• What will happen if you have excess glucose?
 Glucose is converted to glycogen in the liver
 Glycogen is then stored in liver and muscle
Polysaccharides
● Glycogen is a branced-chain polymer of α-D-
glucose like amylopectin
● It also consist of a chain of α-1,4-glycosidic
bonds and branches created by α-1,6-
glycosidic bonds
● The difference is that glycogen is more
branched than amylopectins
Polysaccharides
How does Glycogen Breakdown take
place?
• Glycogen is cleaved by phosphate to give a-D-
glucose-1-phosphate
• Cleavage reaction is phosphorlysis and not
hydrolysis
• No ATP is involved in reaction
• Reaction is catalyzed by glycogen phosphorylase
How does Glycogen Breakdown take
place? (Cont’d)
• In the second reaction, glucose-1-phosphate is
isomerized to glucose-6-phosphate
• This reaction is catalyzed by phosphoglucomutase

• Complete breakdown requires debranching

enzymes to degrade the a(1->6) linkages
Mode of Action of Debranching Enzyme in
Glycogen Breakdown
How is Glycogen formed from Glucose?
• Not exact reversal of glycogen
breakdown to glucose
• Glycogen synthesis requires
energy
• Energy supplied by hydrolysis
of UTP
• Glucose-1-phosphate reacts
with UTP to make UDPG
• Pyrophosphate is also formed
• UDPG is then added to a
growing chain of glycogen,
catalyzed by glycogen
synthase
How is Glycogen formed from Glucose?
(Cont’d)
• Coupling of UDPG formation with hydrolysis of
pyrophosphate drives formation of UDPG to
completion
Branching EnzymeMode of Action
Control of Glycogen Metabolism
• Glycogen phosphorylase is a major control point in
the synthesis and breakdown of glycogen
• Glycogen phosphorylase activity can be allosterically
controlled, as well as, controlled through covalent
modification
Control of Glycogen Metabolism (Cont’d)
• The activity of glycogen synthase is subject to the
same type of covalent modification as glycogen
phosphorylase, however, the response is opposite
• In addition:
• Hormonal signals (glucagon or epinephrine) stimulate
its phosphorylation
• After phosphorylation, glycogen synthase becomes
inactive at the same time the hormonal signal is
activating phosphorylase
• Glycogen synthase can be phosphorylated by several
other enzymes including phosphorylase kinase
• Dephosphorylation is by phosphoprotein phosphatase
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 Produces Glucose from
Pyruvate
• Gluconeogenesis: The conversion 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
• Three irreversible steps in glycolysis
- Phosphoenolpyruvate to pyruvate + ATP
- Fructose-6-phosphate to fructose-1,6-bisphosphate
- Glucose to glucose-6-phosphate
• Net result of gluconeogenesis is reversal of these
three steps, but by different reactions and using
different enzymes
Oxaloacetate is an Intermediate
• In first step, Pyruvate is carboxylated to oxaloacetate
• Requires biotin (CO2 carrier)
• Pyruvate carboxylase is subject to allosteric control; it
is activated by acetyl-CoA
Gluconeogenesis (Cont’d)
• Next, decarboxylation of oxaloacetate is coupled with
phosphorylation by GTP to give PEP

• The net reaction of carboxylation/decarboxylation is

Pyruvate + ATP +GTP ---> Phosphenolpyruvate + ADP + GDP + Pi

The Structure of Biotin and Its Mode of
Attachment to Pyruvate Carboxlyase
Pyruvate Carboxlyase Reaction
Role of Sugar Phosphates
• Other different reactions in gluconeogenesis relative to
glycolysis involve phosphate-ester bonds bound to sugar-
hydroxyl groups being hydrolyzed

• G° = -16.7•kJ mol-1

• Fructose-1,6-bisphosphatase is an allosteric enzyme, inhibited
by AMP and activated by ATP fructose-1,6-bisphosphatase is an
allosteric enzyme, inhibited by AMP and activated by ATP
Role of Sugar Phosphates (Cont’d)
• Another reaction is the hydrolysis of glucose-6-
phosphate to glucose and Pi

• Reaction also spontaneous (G°’ = -13.8 kJ mol-1)

• Reaction catalyzed by glucose-6-phosphatase
Control of Carbohydrate Metabolism
• Different enzymes
are responsible for
catalyzing
opposing reactions
of Glycolysis and
Gluconeogenesis
Control of Carbohydrate Metabolism
• Allosteric control: fructose-2,6-bisphosphate
(F2,6P)
• An allosteric activator of phosphofructokinase (PFK)
• An allosteric inhibitor of fructose bisphosphate
phosphatase (FBPase)
• 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)
• Each enzyme is controlled by
phosphorylation/dephosphorylation
Synthesis and Breakdown of F2,6P
Hormonal-Activation of Glycogen
Phosphorylase
The Adenylyl Cyclase Reaction
Binding of Insulin to Membrane Receptors
Triggers Protein Kinase Cascades
Mechanisms of Metabolic Control
Substrate Cycling
• Substrate cycling
• opposing reactions can be catalyzed by different
enzymes and each opposing enzyme or set of
enzymes can be regulated independently

Fructose-6-Phosphate + ATP ---> Fructose-1,6,-bisphosphate + ADP

Fructose-1,6,-bisphosphate + ADP---> Fructose-6-Phosphate + Pi

Both Reactions are exergonic, and the net reaction is

ATP +H2O <---> ADP + Pi

The Cori Cycle: How Different Organs
Share Carbohydrate Metabolism

• 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

• The liver shares the stress of vigorous exercise

The Cori Cycle
The Cori cycle. Lactate produced
in muscles by glycolysis is transported
by the blood to the liver.

Gluconeogenesis in the liver converts

the lactate back to glucose, which
can be carried back to the muscles by
the blood. Glucose can be stored as
glycogen until it is degraded by
glycogenolysis.

(NTP stands for

nucleoside triphosphate.)
Cori’s Cycle
• The Cori Cycle is the cycling of Lactate produced by red
blood cells during anaerobic respiration in the muscles
back into glucose.

• The lactate produced by the anaroebic glycolisis is cycled

into the liver through the blood.

• In the liver it is converted to pyruvate by lactate

dehydrogenase.

• The pyruvate is then cycled back into glucose by

glycogenesis and recycled back into the blood for use by
red blood cells and muscles.

Question: Write short notes on Cori’s cycle. (Mac 2016)

Glucose is Sometimes Diverted through the
Pentose Phosphate Pathway
• The Pentose Phosphate Pathway (PPP) is an alternative to
glycolysis, and differs in several ways
• In glycolysis, ATP production is important, in PPP, this is not
the case
• As the name implies, five-carbon sugars, including ribose, are
produced from glucose
• Oxidizing agent is NADP+; it is reduced to NADPH, which is a
reducing agent in biosyntheses
• Begins with two oxidation steps (NADP+) to give ribulose-5-
phosphate
• Following this, a series of carbon-shuffling steps occur during
which three-, four-, five-, six-, and seven-carbon
monosaccharide phosphates are produced
The Pentose Phosphate Pathway

Oxidative

Nonoxidative
Control of the PPP
• The carbon-shuffling reaction are catalyzed by:
• Transketolase for the transfer of two-carbon units
and
• Transaldolase for the transfer of three-carbon
units
• Control of the pentose phosphate pathway is
maintained by:
• Glucose-6-phosphate (G6P) can be channeled into
either glycolysis or the pentose phosphate pathway
• G6P channeling into glycolysis, if ATP needed
• G6P channeling into the pentose phosphate pathway,
if NADPH or ribose-5-phosphate are needed
Group Transfer Reactions
How PPP is Controlled