Citric Acid Cycle

Citric acid cycle
Citric acid cycle

The metabolism of glucose to pyruvate in glycolysis, an anaerobic process,
harvests but a fraction of the ATP available from glucose. Most of the ATP
generated in metabolism is provided by the aerobic processing of glucose. This
process starts with the complete oxidation of glucose derivatives to carbon dioxide.
This oxidation takes place in a series of reactions called the citric acid cycle, also
known as the tricarboxylic acid (TCA) cycle or the Krebs cycle. The citric acid
cycle is the final common pathway for the oxidation of fuel molecules—
carbohydrates, fatty acids, and amino acids. Most fuel molecules enter the cycle as
acetyl coenzyme A.
Under aerobic conditions, the pyruvate generated from glucose is

oxidatively decarboxylated to form acetyl CoA. In eukaryotes, the reactions of the
citric acid cycle take place inside mitochondria (Figure 17.1), in contrast with
those of glycolysis, which take place in the cytoplasm.
The citric acid cycle harvests high-energy electrons
The citric acid cycle is the central metabolic hub of the cell. It is the gateway to the
aerobic metabolism of any molecule that can be transformed into an acetyl group
or a component of the citric acid cycle. The cycle is also an important source of
precursors for the building blocks of many other molecules such as amino acids,
nucleotide bases, and porphyrin (the organic component of heme). The citric acid
cycle component, oxaloacetate, is also an important precursor to glucose.
Pyruvate Dehydrogenase Links Glycolysis to the Citric Acid Cycle

Carbohydrates, most notably glucose, are processed by glycolysis into
pyruvate. Under anaerobic conditions, the pyruvate is converted into lactate or
ethanol, depending on the organism. Under aerobic conditions, the pyruvate is
transported into mitochondria by a specific carrier protein embedded in the
mitochondrial membrane. In the mitochondrial matrix, pyruvate is oxidatively
decarboxylated by the pyruvate dehydrogenase complex to form acetyl CoA.
The citric acid cycle is controlled at several points
The rate of the citric acid cycle is precisely adjusted to meet an animal cell’s
needs for ATP. The primary control points are the allosteric enzymes isocitrate
dehydrogenase and α-ketoglutarate dehydrogenase, the first two enzymes in the
cycle to generate high-energy electrons. The first control site is isocitrate
dehydrogenase. The enzyme is allosterically stimulated by ADP, which enhances
the enzyme’s affinity for substrates. The binding of isocitrate, NAD +, Mg2+, and
ADP is mutually cooperative. In contrast, ATP is inhibitory. The reaction product
NADH also inhibits isocitrate dehydrogenase by directly displacing NAD+. It is
important to note that several steps in the cycle require NAD + or FAD, which are
abundant only when the energy charge is low.
A second control site in the citric acid cycle is α ketoglutarate dehydrogenase.
Some aspects of this enzyme’s control are like those of the pyruvate
dehydrogenase complex, as might be expected from the homology of the two
enzymes. α-Ketoglutarate dehydrogenase is inhibited by succinyl CoA and NADH,
the products of the reaction that it catalyzes. In addition, α-ketoglutarate
dehydrogenase is inhibited by a high energy charge. Thus, the rate of the cycle is
reduced when the cell has a high level of ATP.
The use of isocitrate dehydrogenase and α-ketoglutarate dehydrogenase as control

points integrates the citric acid cycle with other pathways and highlights the central
role of the citric acid cycle in metabolism. For instance, the inhibition of isocitrate
dehydrogenase leads to a buildup of citrate, because the interconversion of
isocitrate and citrate is readily reversible under intracellular conditions. Citrate can
be transported to the cytoplasm, where it signals phosphofructokinase to halt
glycolysis and where it can serve as a source of acetyl CoA for fatty acid synthesis.
The α-ketoglutarate that accumulates when α-ketoglutarate dehydrogenase is
inhibited can be used as a precursor for several amino acids and the purine bases.
Defects in the citric acid cycle contribute to the development of cancer

Three enzymes crucial to cellular respiration are known to contribute to the
development of cancer: succinate dehydrogenase, fumarase, and pyruvate
dehydrogenase kinase. Mutations that alter the activity of all three of these
enzymes enhance aerobic glycolysis.
In aerobic glycolysis, cancer cells preferentially metabolize glucose to

lactate even in the presence of oxygen. Defects in all of these enzymes share a
common biochemical link: the transcription factor hypoxia inducible factor 1 (HIF-
1). Normally, HIF-1 up-regulates the enzymes and transporters that enhance
glycolysis only when oxygen concentration falls, a condition called hypoxia.
Under normal conditions, HIF-1 is hydroxylated by prolyl hydroxylase 2

and is subsequently destroyed by the proteasome, a large complex of proteolytic
enzymes. The degradation of HIF-1 prevents the stimulation of glycolysis.
Prolyl hydroxylase 2 requires α-ketoglutarate, ascorbate, and oxygen for

activity. Thus, when oxygen concentration falls, the prolyl hydroxylase 2 is
inactive, HIF-1 is not hydroxylated and not degraded, and the synthesis of proteins
required for glycolysis is stimulated. As a result, the rate of glycolysis is increased.
Defects in the enzymes of the citric acid cycle can significantly affect the
regulation of prolyl hydroxylase 2. When either succinate dehydrogenase or
fumarase is defective, succinate and fumarate accumulate in the mitochondria and
spill over into the cytoplasm. Both succinate and fumarate are competitive
inhibitors of prolyl hydroxylase 2. The inhibition of prolyl hydroxylase 2 results in
the stabilization of HIF-1, since HIF-1 is no longer hydroxylated.
Lactate, the end product of glycolysis, also appears to inhibit prolyl
hydroxylase 2 by interfering with the action of ascorbate. In addition to increasing
the amount of the proteins required for glycolysis, HIF-1 also stimulates the
production of pyruvate dehydrogenase kinase (PDK). The kinase inhibits the
pyruvate dehydrogenase complex, preventing the conversion of pyruvate into
acetyl CoA. The pyruvate remains in the cytoplasm, further increasing the rate of
aerobic glycolysis. Moreover, mutations in PDK that lead to enhanced activity
contribute to increased aerobic glycolysis and the subsequent development of
cancer. By enhancing glycolysis and increasing the concentration of lactate, the
mutations in PDK result in the inhibition of hydroxylase and the stabilization of
HIF-1.
These observations linking citric acid cycle enzymes to cancer suggest that
cancer is also a metabolic disease, not simply a disease of mutant growth factors
and cell cycle control proteins. The realization that there is a metabolic component
to cancer opens the door to new thinking about the control of cancer. Indeed,
preliminary experiments suggest that if cancer cells undergoing aerobic glycolysis
are forced by pharmacological manipulation to use oxidative phosphorylation, the
cancer cells lose their malignant properties. It is also interesting to note that the
citric acid cycle, which has been studied for decades, still has secrets to be revealed
by future biochemists.
The Citric Acid Cycle Is a Source of Biosynthetic Precursors
The citric acid cycle also produces CO2, the precursors for several amino acids (aspartate,
asparagine, glutamine, proline) and NADH – all of which are used in other important metabolic
pathways, such as amino acid synthesis and oxidative phosphorylation
Thus far, discussion has focused on the citric acid cycle as the major degradative
pathway for the generation of ATP. As a major metabolic hub of the cell, the citric
acid cycle also provides intermediates for biosyntheses (Figure 17.20). For
example, most of the carbon atoms in porphyrins come from succinyl CoA. Many
of the amino acids are derived from α ketoglutarate and oxaloacetate. The citric
acid cycle must be capable of being rapidly replenished. The important point now
is that citric acid cycle intermediates must be replenished if any are drawn off for
biosyntheses. Suppose that much oxaloacetate is converted into amino acids for
protein synthesis and, subsequently, the energy needs of the cell rise. The citric
acid cycle will operate to a reduced extent unless new oxaloacetate is formed,
because acetyl CoA cannot enter the cycle unless it condenses with oxaloacetate.
Even though oxaloacetate is recycled, a minimal level must be maintained to allow
the cycle to function. How is oxaloacetate replenished? Mammals lack the
enzymes for the net conversion of acetyl CoA into oxaloacetate or any other citric
acid cycle intermediate. Rather, oxaloacetate is formed by the carboxylation of
pyruvate, in a reaction catalyzed by the biotin-dependent enzyme pyruvate
carboxylase.
The Glyoxylate Cycle Enables Plants and Bacteria to Grow on Acetate
Acetyl CoA that enters the citric acid cycle has but one fate: oxidation to CO2 and
H2O. Most organisms thus cannot convert acetyl CoA into glucose, because
although oxaloacetate, a key precursor to glucose, is formed in the citric acid cycle,
the two decarboxylations that take place before the regeneration of oxaloacetate
preclude the net conversion of acetyl CoA into glucose. In plants and in some
microorganisms, there is a metabolic pathway that allows the conversion of acetyl
CoA generated from fats stores into glucose. This reaction sequence, called the
glyoxylate cycle, is similar to the citric acid cycle but bypasses the two
decarboxylation steps of the cycle. Another important difference is that two
molecules of acetyl CoA enter per turn of the glyoxylate cycle, compared with one
in the citric acid cycle. The glyoxylate cycle (Figure 17.23), like the citric acid
cycle, begins with the condensation of acetyl CoA and oxaloacetate to form citrate,
which is then isomerized to isocitrate. Instead of being decarboxylated, as in the
citric acid cycle, isocitrate is cleaved by isocitrate lyase into succinate and
glyoxylate. The ensuing steps regenerate oxaloacetate from glyoxylate. First,
acetyl CoA condenses with glyoxylate to form malate in a reaction catalyzed by
malate synthase, and then malate is oxidized to oxaloacetate, as in the citric acid
cycle. The sum of these reactions is In plants, these reactions take place in
organelles called glyoxysomes. This cycle is especially prominent in oil-rich seeds,
such as those from sunflowers, cucumbers, and castor beans. Succinate, released
midcycle, can be converted into carbohydrates by a combination of the citric acid
cycle and gluconeogenesis. The carbohydrates power seedling growth until the cell
can begin photosynthesis. Thus, organisms with the glyoxylate cycle gain a
metabolic versatility because they can use acetyl CoA as a precursor of glucose
and other biomolecules.

Citric Acid Cycle

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Citric Acid Cycle

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Citric acid cycle

Citric acid cycle

Under aerobic conditions, the pyruvate generated from glucose is

Pyruvate Dehydrogenase Links Glycolysis to the Citric Acid Cycle

The use of isocitrate dehydrogenase and α-ketoglutarate dehydrogenase as control

Defects in the citric acid cycle contribute to the development of cancer

In aerobic glycolysis, cancer cells preferentially metabolize glucose to

Under normal conditions, HIF-1 is hydroxylated by prolyl hydroxylase 2

Prolyl hydroxylase 2 requires α-ketoglutarate, ascorbate, and oxygen for

The Citric Acid Cycle Is a Source of Biosynthetic Precursors

The Glyoxylate Cycle Enables Plants and Bacteria to Grow on Acetate

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