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CITRIC ACID CYCLE
MS C
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• The acetyl groups are fed into the citric acid cycle, which enzymatically
oxidizes them to CO2
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• It is the final common pathway for the aerobic oxidation of carbohydrate,
lipid, and protein because glucose, fatty acids, and most amino acids are
metabolized to acetyl-CoA or intermediates of the cycle
...


Catabolism of proteins, fats, and carbohydrates in the
three stages of cellular respiration
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• This transport uses some of the energy stored in the mitochondrial inner
membrane electrical potential gradient
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• The overall reaction catalyzed by the pyruvate dehydrogenase complex is
an oxidative decarboxylation, an irreversible oxidation process in which
the carboxyl group is removed from pyruvate as a molecule of CO2 and the
two remaining carbons become the acetyl group of acetyl-CoA
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The Pyruvate Dehydrogenase Complex Consists of Three
Distinct Enzymes
• The PDH complex contains three enzymes—pyruvate dehydrogenase (E1),
dihydrolipoyl transacetylase (E2), and dihydrolipoyl dehydrogenase
(E3)—each present in multiple copies
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• The active site of E1 has bound TPP, E2 is the point of connection for the
prosthetic group lipoate, and that of E3 has bound FAD
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• Thiamine-deficient animals are unable to oxidize pyruvate normally
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• Beriberi, a disease that results from thiamine deficiency, is characterized
by loss of neural function
• Alcoholics can also develop thiamine deficiency, because much of their
dietary intake consists of the vitamin-free “empty calories” of distilled
spirits and impaired absorption
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Reactions of the Citric Acid Cycle

The Citric Acid Cycle Has Eight Steps
1
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2
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• Aconitase can promote the reversible addition of H2O to the double bond
of enzyme-bound cis-aconitate leading to isocitrate:

• Aconitase contains an iron-sulfur center, which acts both in the binding of
the substrate at the active site and in the catalytic addition or removal of
H2O
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Oxidation of Isocitrate to -Ketoglutarate and CO2: In the next step,
isocitrate dehydrogenase catalyzes oxidative decarboxylation of
isocitrate to form α-ketoglutarate
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4
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5
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The energy released in the breakage of this bond is used to
drive the synthesis of GTP or ATP
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• The GTP formed by succinyl-CoA synthetase can donate its terminal
phosphoryl group to ADP to form ATP, in a reversible reaction catalyzed by
nucleoside diphosphate kinase
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Oxidation of Succinate to Fumarate: The succinate formed from succinylCoA is oxidized to fumarate by the flavoprotein succinate
dehydrogenase:

• In eukaryotes, succinate dehydrogenase is tightly bound to the inner
mitochondrial membrane, and is the only enzyme of the citric acid cycle
that is membrane-bound
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7
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8
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Three NADH, one FADH2, one
GTP (or ATP), and two CO2 are released in oxidative decarboxylation
reactions
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Citric Acid Cycle Components Are Important Biosynthetic Intermediates
• α-Ketoglutarate and oxaloacetate can, for example, serve as precursors of
the amino acids aspartate and glutamate by simple transamination
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• Oxaloacetate is converted to glucose in gluconeogenesis
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• And the citrate produced in some organisms is used commercially for a
variety of purposes
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• When long chain fatty acids are available, and can provide acetyl-CoA via
β-oxidation, pyruvate oxidation is inhibited
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• The PDH complex is inhibited by reversible phosphorylation of a specific
Ser residue on one of the two subunits of E1
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The Citric Acid Cycle Is Regulated at Its Three Exergonic Steps
• Three factors govern the rate of flux through the cycle:
- substrate availability,
- inhibition by accumulating products, and
- allosteric feedback inhibition of the enzymes that catalyze early steps in the cycle
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• NADH, a product of isocitrate and α-ketoglutarate oxidation, accumulates
under some conditions, and at high [NADH] both dehydrogenase reactions
are severely inhibited by mass action
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• ADP is an allosteric activator of citrate synthase enzyme
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• Citrate, the product of the first step of the citric acid cycle, is an important
allosteric inhibitor of phosphofructokinase-1 in the glycolytic pathway

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