Mary K. Campbell
Shawn O. Farrell
http://academic.cengage.com/chemistry/campbell
Chapter 19
The Citric Acid Cycle
Paul D. Adams • University of Arkansas
The Central Role of the Citric Acid Cycle
3 processes play central roles in ________ metabolism
• The citric acid cycle (TCA cycle)
• Electron transport (Chapter 20)
• Oxidative phosphorylation (Chapter 20)
• Metabolism consists of
• Catabolism: the oxidative breakdown of nutrients
• Anabolism: the reductive synthesis of biomolecules
• The citric acid cycle is ______________________;
that is, it plays a role in both catabolism and
anabolism. It is the central metabolic pathway
Relationship of TCA Cycle to Catabolism
Where does the Citric Acid Cycle Take Place?
• In eukaryotes, cycle takes place in the mitochondrial matrix
Features of TCA Cycle
Pyruvate is Converted to Acetyl-CoA
• Pyruvate dehydrogenase complex is responsible for
the conversion of pyruvate to CO2 and the acetyl
portion of acetyl-CoA
• Five enzymes in complex: pyruvate
dehydrogenase, dihydrolipoyl transacetylase,
dihydrolipoyl dehydrogenase, pyruvate
dehydrogenase kinase, pyruvate dehydrogenase
phosphatase
Pyruvate is Converted to Acetyl-CoA
• First, pyruvate loses CO2 and hydroxyethylTPP (HETPP) is
formed
• In the second step, the active form of ____________ acid is
bound to the enzyme, dihydrolipoyl transacetylase, by an
amide bond to the -amino group of a lysine
• The hydroxyethyl group (HE) is oxidized and transferred to a
sulfur atom of the reduced form of lipoamide
• Lipoamide is reduced to dihydrolipoamide
• In step 3, the acetyl group is transferred to the ___________
group of coenzyme A
• Next, dihydrolipoamide is oxidized to lipoamide
Mechanism of the Pyruvate Dehydrogenase Complex
Summary
• The two-carbon unit needed at the start of the citric
acid cycle is obtained by converting pyruvate to
acetyl-CoA
• This conversion requires the three primary enzymes
of the pyruvate dehydogenase complex, as well as,
the cofactors TPP, FAD, NAD+, and lipoic acid
• The overall reaction of the pyruvate dehydogenase
complex is the conversion of pyruvate, NAD+, and
CoA-SH to acetyl-CoA, NADH + H+, and CO2
Individual Reactions of the Citric Acid Cycle
• In step 1, there is a condensation of acetyl-CoA with
oxaloacetate to form _______________
• G°’ = -32.8 kJ•mol-1, therefore, the reaction is ___________
• Reaction is catalyzed by citrate _____________, an allosteric
enzyme that is inhibited by NADH, ATP, and succinyl-CoA
Individual Reactions of the Citric Acid Cycle
• In step 2, citrate is isomerized to isocitrate.
The reaction is catalyzed by _____________
• Citrate is achiral; it has no stereocenter
• Isocitrate is chiral; it has 2 stereocenters,
so 4 possible stereoisomers
• _____________ of the 4 stereoisomers of
isocitrate is formed in the cycle
Individual Reactions of the Citric Acid Cycle
Individual Reactions of the Citric Acid Cycle
• In step 3, there is an
oxidation of isocitrate
followed by decarboxylation
to form ________________
and CO2
• The reaction is catalyzed by
isocitrate ______________,
an allosteric enzyme, which
is inhibited by ATP and
NADH, and activated by
ADP and NAD+
Individual Reactions of the Citric Acid Cycle
• In step 4, there is an oxidative decarboxylation of
-ketoglutarate to _____________________
• This reaction is catalyzed by the -ketoglutarate
dehydrogenase complex, which is, like pyruvate
dehydrogenase, a multienzyme complex and requires
_________________________________________________
Individual Reactions of the Citric Acid Cycle
• Next, the thioester bond of succinyl-CoA if hydrolyzed in the
formation of succinate
• The two CH2-COO- groups of succinate are equivalent
• This is the first __________________________ step of the cycle
• The overall reaction is slightly exergonic
Individual Reactions of the Citric Acid Cycle
• Next, there is an oxidation of succinate to _____________
• Then, the hydration of fumarate to _____________________
Individual Reactions of the Citric Acid Cycle
• Then, malate is oxidized to __________________________
Oxidation of Pyruvate Forms CO2 and ATP
Summary
• In the citric acid cycle and the pyruvate
dehydrogenase reaction, one molecule of
pyruvate is oxidized to three molecules of CO2
as a result of oxidative decarboxylation
• The oxidations are accompanied by reductions
involving NAD+ to NADH & FAD to FADH2
• GDP is phosphorylated to GTP
Control of the Citric Acid Cycle
• There are 3 points of control within the cycle:
• Citrate synthase: inhibited by ATP, NADH, and
succinyl CoA; also product inhibition by citrate
• Isocitrate dehydrogenase: activated by ADP and
NAD+, inhibited by ATP and NADH
• -ketoglutarate dehydrogenase complex: inhibited
by ATP, NADH, and succinyl CoA; activated by ADP
and NAD+
• There is one control point outside the cycle
• Pyruvate dehydrogenase: inhibited by ATP and
NADH; also product inhibition by acetyl-CoA
Control of the Citric Acid Cycle
Energetics of the Citric Acid Cycle
Control of the Citric Acid Cycle (Cont’d)
The Glyoxylate Cycle
• In plants and some bacteria, there may be a
modification of the citric acid cycle to produce
4-carbon dicarboxylic acids & eventually glucose
• The glyoxylate cycle bypasses the two oxidative
decarboxylations of the citric acid cycle
• Instead, it routes isocitrate via glyoxylate to malate
• Key enzymes in this cycle are _______ _________
and _______________ _______________
The Glyoxylate Cycle
The Glyoxylate Cycle
The Glyoxylate Cycle
The Glyoxylate Cycle
• The glyoxylate cycle takes place:
• In _______: in glyoxysomes, specialized organelles
devoted to this cycle
• In _______and _______: in the cytoplasm
• Helps plants grow in the dark:
• Seeds are rich in lipids, which contain fatty acids
• During germination, plants use the acetyl-CoA
produced in fatty acid oxidation to produce
oxaloacetate and other intermediates for
carbohydrate synthesis
• Once plants begin photosynthesis and can fix CO2,
glyoxysomes disappear
The Citric Acid Cycle in Catabolism
• The catabolism of _______, _______, and _______ _______
all feed into the citric acid cycle at one or more points
Summary
• All metabolic pathways are related, and all of them
operate simultaneously
• In catabolic pathways, nutrients, many of which
are macromolecules, are broken down to smaller
molecules, such as sugars, fatty acids, and amino
acids
• Small molecules are processed further, and the
end products of catabolism frequently enter the
citric acid cycle, which plays a key role in
metabolism
The Citric Acid Cycle in Anabolism
• The citric acid cycle is the source of starting
materials for the biosynthesis of other compounds
• If a component of the citric acid cycle is taken out
for biosynthesis, it must be replaced
• Oxaloacetate, for example, is replaced by the
______________ ____________ _____________
• A reaction that replenishes a citric acid cycle
intermediate is called an _________________
reaction
The Citric Acid Cycle in Anabolism
The Citric Acid Cycle in Anabolism
Lipid Anabolism
• Lipid anabolism begins with acetyl-CoA and takes
place in the ______________
• acetyl-CoA is produced mainly in mitochondria from
catabolism of fatty acids and carbohydrates
• an indirect transfer mechanism exists involving citrate
Citrate + CoA-SH + ATP
Acetyl-CoA + Oxaloacetate + ADP + Pi
• the oxaloacetate thus formed provides a means for
the production of the NADPH needed for biosynthesis
Lipid Anabolism
Oxaloacetate + NADH + H+ Malate + NAD+
Malate + NADP+ Pyruvate + CO2 + NADPH + H+
• The net effect of these two reactions is
replacement of NADH by NADPH
• While there is some NADPH produced by this
means, its principal source is the pentose
phosphate pathway
• The anabolic reactions that produce amino acids
and many other biomolecules begin with TCA
cycle molecules that are transported into the
cytosol
Summary of Anabolism in the Citric Acid Cycle
Summary
• The citric acid cycle plays a central role in anabolic
pathways as well as in catabolism
• Pathways that give rise to sugars, fatty acids, and
amino acids all originate with components of the
citric acid cycle
The Link To Oxygen
• The citric acid cycle is considered part of the
aerobic metabolic process because of its link to
the _______________ and _______________
• NADH and FADH2, two important cofactors
generated by the citric acid cycle, ultimately
pass their electrons to _____________