Chapter 18

Storage Mechanisms
and Control in
Carbohydrate
Metabolism

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Chapter Outline
(18-1) How glycogen is degraded and produced
(18-2) Gluconeogenesis produces glucose from
pyruvate
(18-3) Control of carbohydrate metabolism
(18-4) Glucose is sometimes diverted through the
pentose phosphate pathway

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Glycogen
• Found primarily in liver and muscle
• Structure is optimized for its ability to store and
deliver energy quickly and for the longest amount of
time
• Key to this optimization is the average chain length of
the branches (13 residues)

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Glycogen Breakdown
• Liver
• Liver glycogen breaks down to glucose-6-phosphate,
which is hydrolyzed to give glucose

• Muscle
• Glucose-6-phosphate obtained from glycogen
breakdown enters the glycolytic pathway directly rather
than being hydrolyzed to glucose and then exported to
the bloodstream

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Glycogen Breakdown: First Reaction
• Each glucose residue cleaved from glycogen reacts
with phosphate to give glucose-1-phosphate
• Cleavage reaction is one of phosphorolysis rather
than hydrolysis
• Catalyzed by glycogen phosphorylase
• Cleaves the α(1 → 4) linkages in glycogen
Glycogen
Glycogen + Pi 
 Glucose-1-phosphate + Remainder of
phosphorylase

glycogen

• No ATP is hydrolyzed

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Glycogen Breakdown: Second Reaction
• Glucose-1-phosphate isomerizes to give glucose-6-
phosphate
• Catalyzed by phosphoglucomutase
Glucose-1-phosphate 
Phosphoglucomutase
 Glucose-6-phosphate

• Complete breakdown requires debranching

enzymes that degrade α(1 → 6) linkages

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Debranching of Glycogen
• Debranching enzyme:
• Transfers a limit branch
of three glucose residues
to the end of another
branch, where they are
removed by glycogen
phosphorylase
• Hydrolyzes the α(1 → 6)
glycosidic bond of the last
glucose residue
remaining at the branch
point

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Glycogen Production
• Glycogen synthesis requires energy, which is
provided by the hydrolysis of UTP
• Stage 1
• Glucose-1-phosphate reacts with UTP to produce
uridine diphosphate glucose (UDPG or UDP-glucose)
and pyrophosphate (PPi)
• Catalyzed by UDP-glucose pyrophosphorylase

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Glycogen Production (continued)
• Stage 2
• UDPG is added to a growing chain of glycogen
• Each step involves the formation of a new α(1 → 4)
glycosidic bond in a reaction catalyzed by glycogen
synthase
• Glycogen synthase must add to an existing chain with
α(1 → 4) glycosidic linkages
• Branching enzyme: Catalyzes the reactions needed
to introduce a branch point during the synthesis of
glycogen
• Transfers a segment (7 residues long) from the end of a
growing chain to the branch point where it catalyzes the
formation of the required α(1 → 6) glycosidic linkage
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Glycogen Production: Energy Release

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Figure 18.7 - Reaction Catalyzed by Glycogen
Synthase

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Figure 18.8 - Mode of Action of the Branching Enzyme
in Glycogen Synthesis

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Control of Glycogen Metabolism
• Glycogen phosphorylase is a major controlling factor
in the synthesis and breakdown of glycogen
• Enzyme is subject to allosteric control and covalent
modification

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Control of Glycogen Metabolism (continued 1)
• Glycogen synthase
• Activity is subject to the same type of covalent
modification as glycogen phosphorylase, but the
response is opposite
• Inactive form is the phosphorylated form, and the
active form is unphosphorylated
• Phosphorylation is stimulated by hormonal signals
(glucagon or epinephrine) via the enzyme cAMP-
dependent protein kinase
• Becomes inactive after phosphorylation at the same
time the hormonal signal is activating phosphorylase

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Control of Glycogen Metabolism (continued 2)
• Phosphorylated by several other enzymes, including
phosphorylase kinase and glycogen synthase kinases
• Dephosphorylated by phosphoprotein phosphatase
• Under allosteric control
• Inhibited by ATP, which can be overcome by glucose-6-
phosphate, an activator
• Modifying enzymes are themselves subject to
covalent modification and allosteric control

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Glycogen Production and Degradation:
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 control

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Gluconeogenesis
• Process by which pyruvate is converted to glucose
• Not the exact reversal of glycolysis, which involves
three irreversible steps
• Production of pyruvate and ATP from
phosphoenolpyruvate
• Production of fructose-1,6-bisphosphate from fructose-
6-phosphate
• Production of glucose-6-phosphate from glucose
• Net result of gluconeogenesis is reversal of the three
steps of glycolysis, but the pathway is different, with
different reactions and different enzymes

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Figure 18.10 - Pathways of Gluconeogenesis
and Glycolysis

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Conversion of Pyruvate to Phosphoenolpyruvate
• Step 1 - Pyruvate is carboxylated to oxaloacetate
• Requires energy, which is available from the hydrolysis
of ATP
• Catalyzed by pyruvate carboxylase, which is activated
by acetyl-CoA, an allosteric effector
• Reaction requires biotin, which is a CO2 carrier, and
Mg2+

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Figure 18.12 - Structure of Biotin and Its Mode of
Attachment to Pyruvate Carboxylase

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Conversion of Pyruvate to Phosphoenolpyruvate
(continued)

• Step 2 - Conversion of oxaloacetate to

phosphoenolpyruvate
• Catalyzed by phosphoenolpyruvate carboxykinase
(PEPCK)
• Involves the hydrolysis of GTP

• Net reaction
Pyruvate + ATPis+as follows:
GTP  Phosphoenolpyruvate + ADP + GDP + Pi
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Figure 18.13 - Two Stages of the Pyruvate
Carboxylase Reaction

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Fates of the Oxaloacetate Formed in the
Mitochondria
• Oxaloacetate can continue to form PEP
• PEP can leave the mitochondria via a specific
transporter to continue gluconeogenesis in the cytosol
• Oxaloacetate can be turned into malate via
mitochondrial malate dehydrogenase
• Reaction uses NADH
• Malate can then leave the mitochondria and have the
reaction reversed by cytosolic malate dehydrogenase

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Figure 18.15 - Pyruvate Carboxylase Catalyzes
a Compartmentalized Reaction

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Role of Sugar Phosphates in Gluconeogenesis
• Two reactions in which gluconeogenesis differs from
glycolysis are ones in which a phosphate-ester bond
to a sugar-hydroxyl group is hydrolyzed
• Reaction 1 - Hydrolysis of fructose-1,6-bisphosphate to
produce fructose-6-phosphate and phosphate ion
• ΔG°′ = –16.7 kJ mol–1 = –4.0 kcal mol–1
• Catalyzed by fructose-1,6-bisphosphatase, an allosteric
enzyme strongly inhibited by adenosine monophosphate
(AMP) but stimulated by ATP
• Control point in the pathway because of allosteric
regulation

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Figure 18.16 - Hydrolysis of Fructose-1,6-
Bisphosphate to Fructose-6-Phosphate

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Role of Sugar Phosphates in Gluconeogenesis
(continued)

• Reaction 2 - Hydrolysis of glucose-6-phosphate to

glucose and phosphate ion
• ΔG°′ = –13.8 kJ mol–1 = –3.3 kcal mol–1
• Catalyzed by glucose-6-phosphatase
• Hydrolysis of glucose-6-phosphate to glucose occurs in the
endoplasmic reticulum

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Reciprocal Regulation in Glucose Metabolism
• Different enzymes
catalyze opposing
reactions in glycolysis
and gluconeogenesis
pathways

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Reciprocal Regulation in Glucose Metabolism
(continued)

• In gluconeogenesis, hydrolysis of fructose-1,6-

bisphosphate to fructose-6-phosphate is catalyzed by
fructose-1,6-bisphosphate
• Fructose-1,6-bisphosphate is subject to allosteric
inhibition by fructose-2,6-bisphosphate and AMP
• In glycolysis, phosphofructokinase (PFK) catalyzes
the phosphorylation of fructose-6-phosphate to
fructose-1,6-bisphosphate
• Enzyme is activated by fructose-2,6-bisphosphate and
AMP and is inhibited by ATP and citrate

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Fructose-2,6-Bisphosphate (F2,6BP)
• Important allosteric activator of PFK, key enzyme of
glycolysis
• Inhibitor of fructose bisphosphate phosphatase
(FBPase)
• High concentration stimulates glycolysis, and low
concentration stimulates gluconeogenesis

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Fructose-2,6-Bisphosphate (F2,6BP) (continued)
• Concentration in a cell depends on the balance
between its synthesis, catalyzed by
phosphofructokinase-2 (PFK-2), and its breakdown,
catalyzed by fructose-2,6-bisphosphatase-2
(FBPase-2)
• PFK-2 and FBPase are controlled by a
phosphorylation/dephosphorylation mechanism

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Reciprocal Regulation in the Breakdown and
Synthesis of Glycogen
• Glycogen synthase and glycogen phosphorylase are
controlled by covalent modification as well as by
allosteric control
• This enzyme system is responsible for the modification
of both the synthase and the phosphorylase
• Hormonal control is essential in the synthesis and
breakdown of glycogen
• Enzymatic cascade triggers the activation of
glycogen phosphorylase
• First reaction in the cascade is the adenylate cyclase
reaction

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Figure 18.22 - Hormone-Activated Enzymatic Cascade
That Leads to Activation of Glycogen Phosphorylase

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Figure 18.23 - Adenylyl Cyclase Reaction

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Reciprocal Regulation in the Synthesis of Glycogen
• Enzymatic cascade triggered by insulin binding to
receptors on the cell surface starts a series of
covalent modifications, eventually activating glycogen
synthase kinase
• Glycogen synthase kinase phosphorylates glycogen
synthase to produce glycogen synthase D
• Phosphoprotein phosphatase, which plays a role in
glycogen breakdown, dephosphorylates glycogen
synthase I

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Hormone Control of Glycogen Metabolism
• Insulin is secreted in response to increased blood
glucose levels
• Uptake of insulin by cells as a result of insulin binding
to receptors on the surface triggers the protein kinase
cascade that leads to glycogen synthesis
• Another protein kinase cascade triggered by insulin
binding to receptors stimulates the action of GLUT4

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Figure 18.24 - Binding of Insulin to Plasma
Membrane Receptors

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Hormone Control of Glycogen Metabolism
(continued)

• Glucagon and epinephrine play important roles when

blood glucose levels decrease
• Binding of either of these hormones initiates a cascade
that activates glycogen phosphorylase and inhibits
glycogen synthase
• In both cases, phosphorylase cascade amplifies the
original signal of hormone binding

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Figure 18.25 - Glucagon and Epinephrine
Activate a Cascade of Reactions

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Table 18.1 - Mechanisms of Metabolic Control

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Substrate Cycling
• Control process in which opposing reactions are
catalyzed by different enzymes
• Opposing reactions can be independently regulated
and can have different rates
• Hydrolysis of ATP is the energetic price paid for
independent control of the opposing reactions

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Substrate Cycling: Example
• Conversion of fructose-6-phosphate to fructose-1,6-
bisphosphate and then back to fructose-6-phosphate
• Both reactions are highly exergonic under
physiological conditions

Fructose-6-phosphate + ATP  Fructose-1,6-bisphosphate + ADP

G =  25.9 kJ mol 1 =  6.2 kcal mol1

Fructose-1,6-bisphosphate + H 2O  Fructose-6-phosphate + Pi
G =  8.6 kJ mol 1 =  2.1 kcal mol1


 ADP + Pi
Net reaction: ATP + H 2 O 


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The Cori Cycle
• Involves cycling of glucose due to glycolysis in
muscle and gluconeogenesis in liver
• Glycolysis in fast-twitch skeletal muscle produces
lactate in conditions of O2 debt
• Gluconeogenesis recycles the lactate to glucose after
it is first oxidized to pyruvate
• Occurs in the liver
• Glucose is transported back to skeletal muscle by the
blood

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Figure 18.26 - The Cori Cycle

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The Cori Cycle (continued)
• Requires the net hydrolysis of two ATP and two GTP
Glycolysis:
Glucose + 2NAD + + 2ADP + 2Pi 
2 Pyruvate + 2NADH + 4H + + 2ATP + 2H 2 O

Gluconeogenesis:
2 Pyruvate + 2NADH + 4H + + 4ATP + 2GTP + 6H 2 O 
Glucose + 2NAD + + 4ADP + 2GDP + 6Pi

Overall:
2ATP + 2GTP + 4H 2O  2ADP + 2GDP + 4Pi

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Pentose Phosphate Pathway
• Pathway in sugar metabolism that gives rise to:
• Five-carbon sugars, including ribose
• Nicotinamide adenine dinucleotide phosphate
(NADPH), which is a reducing agent in biosynthesis
• Begins with a series of oxidation reactions to produce
NADPH and five-carbon sugars and is followed by
nonoxidative reshuffling of the carbon skeletons of
the sugars involved

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Figure 18.28 - Pentose Phosphate Pathway

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Pentose Phosphate Pathway: Oxidative
Reactions
• Reaction 1 - Glucose-6-phosphate is oxidized to 6-
phosphogluconate
• Catalyzed by glucose-6-phosphate dehydrogenase
• Results in the production of NADPH
• Reaction 2 - Oxidative decarboxylation
• 6-phosphogluconate molecule loses its carboxyl group,
which is released as CO2
• Catalyzed by 6-phosphogluconate dehydrogenase
• Results in the production of the five-carbon ketose,
ribulose-5-phosphate

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Pentose Phosphate Pathway: Nonoxidative
Reactions
• Two different reactions are involved in which ribulose-
5-phosphate isomerizes
• First reaction
• Catalyzed by phosphopentose-3-epimerase
• Involves the inversion of configuration around carbon
atom 3, producing xylulose-5-phosphate, which is a
ketose
• Second reaction
• Catalyzed by phosphopentose isomerase
• Results in production of an aldose rather than a ketone
and isomerization of ribulose-5-phosphate to ribose-5-
phosphate

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Pentose Phosphate Pathway: Nonoxidative
Reactions (continued 1)
• Group-transfer reactions
• Link the pentose phosphate pathway with glycolysis
• Require the two five-carbon sugars produced by the
isomerization of ribulose-5-phosphate
• Two molecules of xylulose-5-phosphate and one
molecule of ribose-5-phosphate rearrange to give two
molecules of fructose-6-phosphate and one molecule of
glyceraldehyde-3-phosphate
• Aided by two enzymes that are responsible for
reshuffling carbon atoms of ribose-5-phosphate and
xylulose-5-phosphate in the remainder of the pathway
• Transketolase - Transfers a two-carbon unit
• Transaldolase - Transfers a three-carbon unit
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Table 18.2 - Group-Transfer Reactions in the
Pentose Phosphate Pathway

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Pentose Phosphate Pathway: Nonoxidative
Reactions (continued 2)
• Final reaction
• Xylulose-5-phosphate reacts with erythrose-4-
phosphate
• Catalyzed by transketolase
• Results in the production of fructose-6-phosphate and
glyceraldehyde-3-phosphate

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Pentose Phosphate Pathway: Regulation
• Reactions catalyzed by transketolase and
transaldolase are reversible, which allows the
pentose phosphate pathway to respond to the needs
of an organism
• If the need for NADPH is more than that for ribose-5-
phosphate, the reaction goes through the pentose
phosphate pathway
• If the need for ribose-5-phosphate is more than that for
NADPH, the nonoxidative reactions of the pentose
phosphate pathway operate in reverse to produce
ribose-5-phosphate

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Figure 18.29 - Relationships between the
Pentose Phosphate Pathway and Glycolysis

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