Chapter 17

Pyruvate
Dehydrogenase and
the Citric Acid Cycle

© 2023 W. H. Freeman and Company

 CHAPTER 17
Pyruvate Dehydrogenase and the
Citric Acid Cycle
 Ch.17 Learning Goals
By the end of this chapter, you should be able to:

1. Explain why the reaction catalyzed by the pyruvate

dehydrogenase complex is a crucial juncture in metabolism.
2. Identify the means by which the pyruvate dehydrogenase
complex is regulated.
3. Identify the primary catabolic purpose of the citric acid
cycle.
4. Explain the efficiency of using the citric acid cycle to oxidize
acetyl CoA.
5. Describe how the citric acid cycle is regulated.
6. Describe the role of the citric acid cycle in biosynthesis.
7. Identify the biochemical advantages that the glyoxylate cycle
provides.
 Ch.17 Outline
• 17.1 The Citric Acid Cycle Harvests High-Energy
Electrons
• 17.2 The Pyruvate Dehydrogenase Complex Links
Glycolysis to the Citric Acid Cycle
• 17.3 The Citric Acid Cycle Oxidizes Two-Carbon Units
• 17.4 Entry to the Citric Acid Cycle and Metabolism
Through It Are Controlled
• 17.5 The Citric Acid Cycle Is a Source of Biosynthetic
Precursors
• 17.6 The Glyoxylate Cycle Enables Plants and Bacteria
to Grow on Acetate
 Section 17.1 The Citric Acid Cycle
Harvests High-Energy Electrons
• citric acid cycle (CAC) = series of oxidation–reduction
reactions that result in the oxidation of an acetyl group to
two molecules of CO2
– the final pathway for the oxidation of fuel molecules
– oxidation generates high-energy electrons used to power
ATP synthesis
– important sources of precursors for biosynthesis
– also called the tricarboxylic acid (TCA) cycle or Krebs cycle
 Acetyl CoA

• Most fuel molecules enter the citric acid cycle as acetyl

CoA (acetyl coenzyme A).
 The Pyruvate Dehydrogenase
Complex and the Citric Acid Cycle
• pyruvate dehydrogenase complex = a large enzyme
complex that oxidatively decarboxylates pyruvate to
acetyl CoA under aerobic conditions
• Acetyl CoA enters the citric acid cycle where all
remaining carbons are completely oxidized to CO2.
• Reactions of the pyruvate dehydrogenase complex and
the citric acid cycle take place in the mitochondrial
matrix.
 Mitochondria Have Distinct
Compartments Defined by Two
Membranes
An Overview of the Citric Acid Cycle
• The citric acid
cycle removes
electrons from
acetyl CoA and
uses these
electrons to
reduce NAD+
and FAD to
form NADH
and FADH2.
 The Electron-Transport Chain

• electron-transport chain = a series of membrane proteins

that electrons released in the reoxidation of NADH and
FADH2 flow through to generate a proton gradient
across the inner mitochondrial membrane
• Protons flow through ATP synthase to generate ATP from
ADP and inorganic phosphate.
Cellular Respiration Removes High-
Energy Electrons from Carbon Fuel
Molecules to Generate ATP
 Section 17.2 The Pyruvate
Dehydrogenase Complex Links
Glycolysis to the Citric Acid Cycle
• The pyruvate dehydrogenase complex:
– is a highly integrated unit of three distinct enzymes in the
mitochondrial matrix.
– oxidatively decarboxylates pyruvate to acetyl CoA.

Pyruvate  CoA  NAD  acetyl CoA  CO2  NADH  H

 The Pyruvate Dehydrogenase
Complex Connects Glycolysis to the
Citric Acid Cycle
• The reaction catalyzed by the
pyruvate dehydrogenase
complex is an irreversible link
between glycolysis and the citric
acid cycle.
 Pyruvate Dehydrogenase Complex
of E. coli
TABLE 17.1 Pyruvate dehydrogenase complex of E. coli
Enzyme Abbreviation Prosthetic group Reaction catalyzed
Pyruvate E1 TPP Oxidative
dehydrogenase decarboxylation of
component pyruvate
Dihydrolipoyl E2 Lipoamide Transfer of acetyl
transacetylase group to CoA
E3 FAD Regeneration of the
Dihydrolipoyl oxidized form of
dehydrogenase lipoamide
Mechanism: The Synthesis of Acetyl
Coenzyme A from Pyruvate Requires
Three Enzymes and Five Coenzymes
• The catalytic cofactors are thiamine pyrophosphate
(TPP), lipoic acid, and FAD.
• The stochiometric cofactors (cofactors that function as
substrates) are CoA and NAD+.
 The Conversion of Pyruvate into
Acetyl CoA Consists of Three Steps,
Plus a Regeneration Step
• Steps must be coupled because the free energy from the
decarboxylation step drives the formation of NADH and
acetyl CoA.
 The Decarboxylation Step
• Pyruvate combines with the coenzyme TPP and is
decarboxylated to yield hydroxyethyl-TPP.
– the rate-limiting step in acetyl CoA synthesis
– catalyzed by the pyruvate dehydrogenase component (E1)
of the multienzyme complex
– TPP is the prosthetic group of E1
 The Mechanism of the
Decarboxylation Step
• Step 1: the carbon center of TPP ionizes to form a
carbanion
• Step 2: the carbanion readily adds to the carbonyl group
of pyruvate
• Step 3: decarboxylation of pyruvate
– the positive charged ring of TPP stabilizes the negative
charge resulting from the decarboxylation

• Step 4: protonation yields hydroxyethyl-TPP

 The Mechanism of the E1
Decarboxylation Reactions Uses a
Critical Thiamine-Derived Prosthetic
Group
 The Oxidation Step
• lipoamide = a derivative of lipoic acid that is linked to the
side chain of a Lys residue by an amide linkage
• the hydroxyethyl group attached to TPP oxidizes to form
an acetyl group while being simultaneously transferred to
lipoamide, yielding acetyllipoamide
– forms an energy-rich thioester bond
– the disulfide group of lipoamide is reduced
– catalyzed by E1
 The Formation of Acetyl CoA Step

• The acetyl group is transferred from acetyllipoamide to

CoA to form acetyl CoA.
– preserves the energy-rich thioester bond
– catalyzed by dihydrolipoyl transacetylase (E2)
 The Regeneration of Oxidized
Lipoamide Step
• flavoproteins = proteins tightly associated with FAD or
flavin mononucleotide (FMN)
• Dihydrolipoamide must be oxidized to lipoamide to
regenerate the active enzyme.
– two electrons are transferred to an FAD prosthetic group of
the enzyme and then to NAD+
– catalyzed by dihydrolipoyl dehydrogenase (E3)
 The Structure and Function of
Lipoamide
• The lipoamide arm of the E2
subunit carries substrates from
active site to active site.
– increases the overall reaction
rate
– minimizes side reactions
Flexible Linkages Allow Lipoamide to
Move Between Different Active Sites
• The core of the pyruvate dehydrogenase complex is
formed by 60 molecules of E2, the transacetylase.
• Transacetylase consists of 20 catalytic trimers
assembled to form a hollow cube.
• each trimer has three major domains:
– lipoamide domain = small domain containing a bound
flexible lipoamide cofactor attached to a Lys
– domain interacting with E3
– transacetylase domain
 The Structure of the Pyruvate
Dehydrogenase Complex from Bacteria
Reveals a Massive Protein Complex
• The core (60 molecules
of E2) is surrounded in a
shell of:
– ~45 copies of E1.
– ~10 copies of E3.
 The Transacetylase (E2) Core Is
Made Up of Three Distinct Domains
 The Pyruvate Dehydrogenase
Complex in Mammals
• E1 is an α2β2 tetramer.
• E3 is an αβ dimer.
• E3-binding protein (E3-BP) = another core protein which
facilitates the interaction between E2 and E3
– Complex has reduced activity when missing.
 Steps in the Pyruvate
Dehydrogenase Mechanism
• Step 1: Pyruvate is decarboxylated at the active site of
E1, forming hydroxyethyl-TPP and releasing CO2.
• Step 2: E2 inserts the lipoamide arm of the lipoamide
domain into the channel in E1 leading to the active site.
• Step 3: E1 catalyzes the transfer of the acetyl group to
the lipoamide and the acetylated arm leaves E1 and
enters the E2 cube to access the E2 active site.
Steps in the Pyruvate Dehydrogenase
Mechanism, Continued
• Step 4: The acetyl moiety is transferred to CoA, acetyl
CoA leaves the cube, and the reduced lipoamide arm
swings to the active site of the E3 flavoprotein.
• Step 5: The lipoamide is oxidized by coenzyme FAD,
reactivating the lipoamide.
• Step 6: NADH is produced with the reoxidation of FADH2
to FAD.
Three Enzymes Cooperate in the Full
Reactions of the Pyruvate
Dehydrogenase Complex
Click on the lipoamide arm in the step
where E1 catalyzes the formation of the
acetyl–lipoamide complex. (1 of 2)

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Click on the lipoamide arm in the step
where E1 catalyzes the formation of the
acetyl–lipoamide complex. (2 of 2)

© Macmillan Learning, 2023

 Section 17.3 The Citric Acid Cycle
Oxidizes Two-Carbon Units
• Citrate synthase catalyzes the addition of acetyl CoA and
oxaloacetate, yielding citrate and CoA.
– reaction is an aldol addition and a hydrolysis
– proceeds through energy-rich citryl CoA
 Mechanism: The Mechanism of
Citrate Synthase Prevents
Undesirable Reactions
• It minimizes the hydrolysis of acetyl CoA to acetate and
CoA side reaction
• Mammalian citrate synthase is a dimer of identical
subunits, each containing a small and large domain.
– Active sites are in a cleft between the domains of a
subunit.

• Citrate synthase exhibits sequential, ordered kinetics.

– Oxaloacetate binds first, followed by acetyl CoA.
– Oxaloacetate induces a structural rearrangement that
creates an acetyl CoA-binding site
The Ordered Binding of Substrates
by Citrate Synthase Is Explained by
Conformational Changes Upon
Binding Oxaloacetate
 Steps in the Citrate Synthase
Mechanism
• Step 1: His 274 donates a proton to acetyl CoA to
promote the removal of a methyl proton by Asp 375 to
form the enol intermediate.
• Step 2: Oxaloacetate is activated by the transfer of a
proton from His 320 to its carbonyl carbon atom.
• Step 3: Acetyl CoA attacks oxaloacetate to form a
carbon–carbon double bond, His 274 is reprotonated,
and citryl CoA is formed.
• Step 4: His 274 participates as a proton donor to
hydrolyze the thioester, yielding citrate and CoA.
The First Part of the Citrate Synthase
Mechanism Forms Citryl CoA
 Citrate Is Isomerized into Isocitrate
• iron-sulfur protein (nonheme iron protein) = protein that
contains iron that is not bonded to heme
– example: aconitase

• Aconitase catalyzes the isomerization of citrate into

isocitrate through a dehydration step and a hydration
step.
 Citrate Binds Directly to the Iron–
Sulfur Complex of Aconitase
• Four iron atoms
are complexed to
four inorganic
sulfides and
three cysteine
sulfur atoms.
• One iron atom is
available to bind
citrate.
 Isocitrate Is Oxidized and
Decarboxylated to Alpha-Ketoglutarate
• Isocitrate dehydrogenase catalyzes the oxidative
decarboxylation of isocitrate, forming α-ketoglutarate and
the high transfer-potential electron carrier NADH.
– proceeds through the unstable oxalosuccinate
– CO2 is released from oxalosuccinate to yield α-
ketoglutarate
 Succinyl Coenzyme A Is Formed by
the Oxidative Decarboxylation of
Alpha-Ketoglutarate
• The α-ketoglutarate dehydrogenase complex catalyzes
the oxidative decarboxylation of α-ketoglutarate to
succinyl CoA, yielding NADH.
The α-Ketoglutarate Dehydrogenase
Complex Is Homologous to the
Pyruvate Dehydrogenase Complex
• The E3 component is identical in both enzymes.
• Both α-ketoglutarate and pyruvate are α-ketoacids.
• Both reactions include the decarboxylation of an α-
ketoacid and the formation of a thioester linkage with
CoA that has a high transfer potential.
• The reaction mechanisms are entirely analogous.
Pyruvate  CoA  NAD 
Pyruvate dehydrogenase complex

acetyl CoA  CO2  NADH  H
 -Ketoglutarate dehydrogenase complex
 -Ketoglutarate  CoA  NAD  
succinyl CoA  CO2  NADH
A Compound with High Phosphoryl-
Transfer Potential Is Generated from
Succinyl Coenzyme A
• Succinyl CoA synthetase catalyzes the cleavage of a
thioester linkage of succinyl CoA, yielding succinate.
– coupled to the phosphorylation of ADP or GDP because
the ∆G°′ for the hydrolysis is comparable to that of ATP
– The reaction is readily reversible.
 ATP or GTP Formation May Be
Coupled to the Formation of Succinate
• Mammals have two isozymic forms of the enzyme:
– The GDP-requiring enzyme predominates in tissues
performing anabolic reactions (e.g., liver), and the GTP is
used to power succinyl CoA synthesis,
– The ADP-requiring enzyme predominates in tissues
performing large amounts of cellular respiration (e.g.,
skeletal and heart muscle).
 Nucleoside Diphosphokinase
• nucleoside diphosphokinase = catalyzes the transfer of
the γ phosphoryl group from any nucleotide triphosphate
to any other nucleotide diphosphate
– allows for the adjustment of concentrations to meet the
cell's needs
– keeps concentrations in the cell near equilibrium with one
another
 Mechanism: Succinyl Coenzyme A
Synthetase Transforms Types of
Biochemical Energy
• Clear example of an energy transformation: Energy
inherent in the thioester molecule is transformed into
phosphoryl-group-transfer potential.
• The reaction is readily reversible with a ∆G°′ of −3.4 kJ
mol−1.
• The formation of ATP at the expense of succinyl CoA is
an example of substrate-level phosphorylation.
 The Mechanism of Succinyl CoA
Synthetase Allows the Formation of a
Phosphoanhydride Through a
Phosphorylated Enzyme Intermediate
 Steps in the Succinyl Coenzyme A
Synthetase Mechanism
• Step 1: Orthophosphate attacks succinyl CoA, displacing
coenzyme A and generating succinyl phosphate, an
energy-rich compound.
• Step 2: A His residue acts as a moving arm that removes
the phosphoryl group, forming phosphohistidine and
releasing succinate.
• Step 3: The phosphohistidine swings over to a bound
ADP.
• Step 4: The phosphohistidine transfers the group to ADP
to form ATP.
 Two carbon atoms from acetyl CoA
leave the citric acid cycle as CO2 in
two successive decarboxylations
catalyzed by isocitrate
dehydrogenase and α-ketoglutarate
dehydrogenase, resulting in the
formation of what compound? (1 of 2)

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 Two carbon atoms from acetyl CoA
leave the citric acid cycle as CO2 in
two successive decarboxylations
catalyzed by isocitrate
dehydrogenase and α-ketoglutarate
dehydrogenase, resulting in the
formation of what compound? (2 of 2)

succinyl CoA

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 Oxaloacetate Is Regenerated by the
Oxidation of Succinate
• Succinate dehydrogenase, fumarase, and malate
dehydrogenase catalyze successive reactions of four-
carbon compounds to regenerate oxaloacetate.
• FADH2 and NADH are generated.
• Once regenerated, oxaloacetate can initiate another
cycle.
 Succinate Is Oxidized to Fumarate
by Succinate Dehydrogenase
• Succinate dehydrogenase:
– is an iron–sulfur protein.
– has the isoalloxazine ring of FAD covalently attached to a
histidine side chain.
– is embedded in the inner mitochondrial membrane.
– is directly associated with the electron-transport chain.

• FAD is the hydrogen acceptor because the free-energy

change is insufficient to reduce NAD+.
Fumarate Is Hydrated to L-Malate by
Fumarase
• Fumarase catalyzes the stereospecific trans addition of H+
and OH−, yielding only the L-isomer of malate.
 Malate Is Oxidized to Oxaloacetate
by Malate Dehydrogenase
• Malate dehydrogenase catalyzes the oxidation of malate,
yielding oxaloacetate and NADH.

• ∆G°′ is significantly positive (∆G°′= +29.7 kJ mol−1).

– The reaction is driven by the use of the products:
oxaloacetate by citrate synthase and NADH by the
electron-transport chain.
 The Citric Acid Cycle Produces High
Transfer-Potential Electrons, ATP,
and CO2
• The net reaction of the citric acid cycle is

Acetyl CoA  3 NAD   FAD  ADP  Pi  2 H2O 

2 CO2  3 NADH  FADH2  ATP  2H  CoA

• The two carbon atoms that enter each cycle as acetyl

CoA are not the ones that leave as CO2 during the initial
two decarboxylation reactions.
 The Stoichiometry of the Citric Acid
Cycle
• Two carbon atoms enter in the form of acetyl CoA, and
two carbons leave in the form of CO2 molecules.
• Four pairs of hydrogen atoms leave in four oxidation
reactions (yielding three NADH and one FADH2).
• One compound with high phosphoryl-transfer potential
(usually ATP) is generated.
• Two water molecules are consumed.
 One Acetyl Unit Generates
Approximately 10 Molecules of ATP
• When oxidized via the electron-transport chain:
– each pair of electrons from NADH will generate ~2.5 ATP.
– each pair of electrons from FADH2 will generate ~1.5 ATP.

• Nine high transfer-potential phosphoryl groups are

generated from the oxidation of 3 NADH and 1 FADH2
molecules.
• One ATP is directly formed in one round of the citric acid
cycle.
 Eight Enzyme-Catalyzed
Reactions Make Up the Full Citric
Acid Cycle
• There is a physical
association of the
citric acid cycle
enzymes into a
supramolecular
complex.
– allows for
substrate
channeling
 Citric Acid Cycle
TABLE 17.2 Citric acid cycle
Prosthetic ∆G°′: kJ ∆G°′: kcal
Step Reaction Enzyme group Type* mol−1 mol−1
1 Acetyl CoA + oxaloacetate H2O Citrate synthase a −31.4 −7.5
→ citrate + CoA + H+
2a Aconitase Fe–S b +8.4 +2.0

2b Aconitase Fe–S c −2.1 −0.5

3 Isocitrate d+e −8.4 −2.0

dehydrogenase
4 α-Ketoglutarate Lipoic acid, d+e −30.1 −7.2
dehydrogenase FAD, TPP
complex
5 Succinyl CoA f −3.3 −0.8
synthetase
6 Succinate FAD, Fe–S e 0 0
dehydrogenase
7 Fumarase c −3.8 −0.9

8 Malate e +29.7 +7.1

dehydrogenase
*Reaction type; (a) condensation; (b) dehydration; (c) hydration; (d) decarboxylation; (e)
oxidation; (f) substrate-level phosphorylation.
 Starting with one molecule of
pyruvate, how many ATP are
produced as pyruvate is converted
to acetyl-CoA and proceeds through
the citric acid cycle. Assume NADH
and FADH2 are oxidized via the
electron-transport chain. (1 of 2)

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 Starting with one molecule of
pyruvate, how many ATP are
produced as pyruvate is converted
to acetyl-CoA and proceeds through
the citric acid cycle. Assume NADH
and FADH2 are oxidized via the
electron-transport chain. (2 of 2)
(4 NADH) (2.5 ATP per NADH) = 10 ATP
(1 FADH2) (1.5 ATP per FADH2) = 1.5 ATP
1 ATP
11.5 ATP

© Macmillan Learning, 2023

 Section 17.3 Entry to the Citric Acid
Cycle and Metabolism Through It
Are Controlled
• The formation of acetyl CoA from
pyruvate is irreversible in animal
cells.
• Acetyl CoA has two principal fates:
– metabolism by the citric acid cycle
– incorporation into lipids

• The activity of the pyruvate

dehydrogenase complex is tightly
controlled allosterically and by
reversible phosphorylation.
 The Pyruvate Dehydrogenase
Complex Is Regulated Allosterically
• High concentrations of reaction products inhibit the
reaction by informing the enzyme that there is no need to
metabolize pyruvate to acetyl CoA:
– Acetyl CoA inhibits the transacetylase component (E2).
– NADH inhibits the dihydrolipoyl dehydrogenase (E3).
 The Pyruvate Dehydrogenase
Complex Is Regulated by Reversible
Phosphorylation
• Pyruvate dehydrogenase kinase (PDK) phosphorylates
the pyruvate dehydrogenase component (E1).
– switches off the activity of the complex

• Pyruvate dehydrogenase phosphatase (PDP)

dephosphorylates E1.
• In mammals, both PDK and PDP are associated with the
E2-E3-BP core complex.
 The Activity of the Pyruvate
Dehydrogenase Complex Is Regulated
by Reversible Phosphorylation
The Pyruvate Dehydrogenase Complex
Responds to Changes in the Energy
Charge of the Cell
 Regulation in Biological Conditions

• At rest, the ratios of NADH/NAD+, acetyl CoA/CoA, and

ATP/ADP are high.
– promotes phosphorylation and inactivation of the complex
by activating PDK

• During activity:
– high ADP and pyruvate activate the complex by inhibiting
the kinase.
– Ca2+ stimulates the phosphatase, enhancing pyruvate
dehydrogenase activity.
In Some Tissues, the Phosphatase Is
Regulated by Hormones
• In liver tissue, epinephrine binds to the α-adrenergic
receptor, causing an increase in Ca2+ concentration that
activates the phosphatase.
• In liver and adipose tissue, insulin stimulates the
phosphatase.
 Pyruvate Dehydrogenase
Phosphatase Deficiency
• Individuals with pyruvate dehydrogenase phosphatase
deficiency have a pyruvate dehydrogenase complex that
is always phosphorylated (i.e., inactive).
• In these individuals, glucose is processed to lactate
rather than to acetyl CoA.
– resulting in lactic acidosis
– many tissues malfunction in the acidified environment,
including the central nervous system
 Diabetic Neuropathy May Be Due to
Inhibition of the Pyruvate
Dehydrogenase Complex
• diabetic neuropathy = numbness, tingling, or pain in the
hands, arm, fingers, toes, feet, and legs
– common complication (~50% of patients) of both type 1
and type 2 diabetes
– can be treated with painkillers, but cannot be cured
– overproduction of lactic acid by cells in the dorsal root
ganglion may be a significant contributor
Diabetic Neuropathy May Be Due to
Inhibition of the Pyruvate
Dehydrogenase Complex, Continued
• hyperglycemia (high glucose concentration) = the
defining feature of diabetes
– increases PDK activity in the cells of the dorsal root
ganglion, leading to inhibition of the pyruvate
dehydrogenase complex

• Inhibition of the complex leads to pyruvate being

processed to lactate.
• Excess lactate leads to an increase in acid-sensing
nociceptors (pain receptors), a type of G-protein-coupled
receptor, resulting in diabetic neuropathy.
The Citric Acid Cycle Is Regulated at
Several Points
• Isocitrate dehydrogenase and
α-ketoglutarate
dehydrogenase are allosteric
enzymes that primarily
regulate the rate of cycling.
– These are the first two
enzymes that harvest high-
energy electrons in the cycle.
Which is a means by which the citric
acid cycle is allosterically
controlled? (1 of 2)
a. The pyruvate dehydrogenase complex is allosterically
inhibited by NADH.
b. Isocitrate dehydrogenase is allosterically stimulated by
ATP.
c. The α-ketoglutarate dehydrogenase complex is
allosterically stimulated by NADH.
d. Succinate dehydrogenase is allosterically stimulated by
FADH2.
e. Succinyl CoA synthase is allosterically inhibited by
succinyl CoA.

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Which is a means by which the citric
acid cycle is allosterically
controlled? (2 of 2)
*a. The pyruvate dehydrogenase complex is allosterically
inhibited by NADH.
b. Isocitrate dehydrogenase is allosterically stimulated by
ATP.
c. The α-ketoglutarate dehydrogenase complex is
allosterically stimulated by NADH.
d. Succinate dehydrogenase is allosterically stimulated by
FADH2.
e. Succinyl CoA synthase is allosterically inhibited by
succinyl CoA.

© Macmillan Learning, 2023

Section 17.5 The Citric Acid Cycle Is
a Source of Biosynthetic Precursors
• The citric acid cycle integrates many of the cell's other
metabolic pathways, including those of carbohydrates,
fats, amino acids, and porphyrins.
• Many citric acid cycle components are precursors for
biosynthesis of key biomolecules.
 The Citric Acid Cycle Plays an
Important Role in Biosynthesis
The Citric Acid Cycle Must Be Capable
of Being Rapidly Replenished
• Citric acid cycle intermediates must be replenished if any
are used for biosyntheses.
• Mammals lack the enzymes for the net conversion of
acetyl CoA into oxaloacetate or other cycle intermediate.
• anaplerotic reaction = a reaction that leads to the net
synthesis, or replenishment, of pathway components
• Pyruvate carboxylase catalyzes the formation
carboxylation of pyruvate to oxaloacetate.
– This reaction is used in gluconeogenesis and is dependent
on the presence of acetyl CoA.

Pyruvate  CO2  ATP  H2O  oxaloacetate  ADP  Pi  2 H

The Disruption of Pyruvate Metabolism
Is the Cause of Beriberi and Poisoning
by Mercury and Arsenic
• beriberi = a neurologic and cardiovascular disorder is
caused by a dietary deficiency of thiamine (vitamin B1)
• Thiamine is the precursor of the cofactor thiamine
pyrophosphate (TPP).
• TPP is the prosthetic group of:
– pyruvate dehydrogenase.
– α-ketoglutarate dehydrogenase.
– transketolase (a pentose phosphate pathway enzyme).

• Patients with beriberi have higher than normal levels of

pyruvate and α-ketoglutarate in the blood.
 Mercury and Arsenite Inhibit the
Pyruvate Dehydrogenase Complex
• Both mercury and arsenite (AsO33−) have a high affinity for
neighboring sulfhydryls.
• Binding of mercury or arsenite to the dihydrolipoyl groups of
the E3 component of the pyruvate dehydrogenase complex
inhibits the complex and leads to central nervous system
pathologies.
• Treatment is the administration of sulfhydryl reagents with
adjacent sulfhydryl groups to compete with the dihydrolipoyl
residues for binding.
Arsenite Inhibits the Pyruvate
Dehydrogenase Complex
 The Citric Acid Cycle Likely Evolved
from Preexisting Pathways
• The citric acid cycle was most likely assembled from
preexisting reaction pathways.
• Compounds such as pyruvate, α-ketoglutarate, and
oxaloacetate were likely present early in evolution for
biosynthetic purposes.
• The thermodynamically-favorable oxidative decarboxylation
of α-ketoacids likely formed the core of processes that
preceded the citric acid cycle evolutionarily.
 Which citric acid cycle intermediate
is NOT drawn off for biosynthesis
when the energy needs of the cell
are met? (1 of 2)
a. oxaloacetate
b. citrate
c. -ketoglutarate
d. succinyl CoA
e. fumarate

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 Which citric acid cycle intermediate
is NOT drawn off for biosynthesis
when the energy needs of the cell
are met? (2 of 2)
a. oxaloacetate
b. citrate
c. -ketoglutarate
d. succinyl CoA
*e. fumarate

© Macmillan Learning, 2023

 Section 17.6 The Glyoxylate Cycle
Enables Plants and Bacteria to Grow on
Acetate
• glyoxylate cycle = reaction sequence that converts acetyl
CoA from fat stores into glucose
– takes place in organelles called glyoxysomes
– prominent in oil-rich seeds (e.g. sunflower, cucumber)

• similar to the citric acid cycle, but bypasses the two

decarboxylation steps and two molecules of acetyl CoA
enter the cycle
 The Glyoxylate Cycle Reaction

• The sum of the reactions is

2 Acetyl CoA  NAD  2 H2 O 

succinate  2 CoA  NADH  2 H

• Succinate produced can be converted into

carbohydrates by a combination of the citric acid cycle
and gluconeogenesis.
The Glyoxylate Cycle Allows Plants
and Some Microorganisms to Grow
on Acetate
 New Treatments for Tuberculosis
May Be on the Horizon (1 of 2)
• tuberculosis (TB) = disease caused by the bacterium
Mycobacterium tuberculosis
– one of the leading causes of death worldwide
– transmitted by people with active lung infections by
coughing and sneezing
– commonly treated with the antibiotic rifampicin
– antibiotic-resistant strains are emerging

• M. tuberculosis are dependent on the glyoxylate cycle,

especially when they are in a latent state in the lungs.
 New Treatments for Tuberculosis
May Be on the Horizon (2 of 2)
• 2-vinyl-isocitrate = a suicide
inhibitor or mechanism-based
inhibitor for isocitrate lyase
– When isocitrate lyase reacts
with the inhibitor, succinate is
released but a thioether-linked
homopyruvoyl moiety remains
covalently linked to Cys191,
inhibiting the enzyme.

• Cys191 is conserved in all

strains of M. tuberculosis .
 Which enzymes are present in the
glyoxylate cycle that are not present
in the citric acid cycle? (1 of 2)

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 Which enzymes are present in the
glyoxylate cycle that are not present
in the citric acid cycle? (2 of 2)

isocitrate lyase and malate synthase

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Remember to complete your exit poll
tonight!

© Macmillan Learning, 2023