The Citric Acid Cycle

The Citric Acid Cycle
the citric cycle is a central driver of cellular respiration. It takes acetyl CoA-produced by
the oxidation of pyruvate and originally derived from glucose as its starting material and,
in a series of redox reactions, harvests much of its bond energy in the form of NADH,
FADH2 and ATP molecules. The reduced electron carriers NADH and FADH2 generated
in the TCA cycle will pass their electrons into the electron transport chain and, through
oxidative phosphorylation, will generate most of the ATP produced in cellular
respiration.
Overview of the citric acid cycle
In eukaryotes, the citric acid cycle takes place in the matrix of the mitochondria, just like
the conversion of pyruvate to acetyl CoA. In prokaryotes, these steps both take place in
the cytoplasm. The citric acid cycle is a closed loop; the last part of the pathway reforms
the molecule used in the first step. The cycle includes eight major steps.
Dr. C. Grant
In the first step of the cycle, acetyl CoA combines with a four-carbon acceptor molecule,
oxaloacetate, to form a six-carbon molecule called citrate. After a quick rearrangement,
this six-carbon molecule releases two of its carbons as carbon dioxide molecules in a
pair of similar reactions, producing a molecule of NADH. The enzymes that catalyze
these reactions are key regulators of the citric acid cycle, speeding it up or slowing it
down based on the cell’s energy needs.
The remaining four-carbon molecule undergoes a series of additional reactions, first

making an ATP molecule or, in some cells, a similar molecule called GTP then reducing
the electron carrier FAD to FADH2, and finally generating another NADH. This set of
reactions regenerates the starting molecule, oxaloacetate, so the cycle can repeat.
Overall, one turn of the citric acid cycle releases two carbon dioxide molecules and
produces three NADH, one FADH2 and one ATP or GTP. The citric acid cycle goes
around twice for each molecule of glucose that enters cellular respiration because there
are two pyruvates and thus, two acetyl CoA made per glucose.
Steps of the citric acid cycle

Step 1. In the first step of the citric acid cycle, acetyl CoA joins with a four-carbon
molecule, oxaloacetate, releasing the CoA group and forming a six-carbon molecule
called citrate.
Step 2. In the second step, citrate is converted into its isomer, isocitrate. This is actually
a two-step process, involving first the removal and then the addition of a water
molecule, which is why the citric acid cycle is sometimes described as having nine steps
rather than the eight listed here.
Dr. C. Grant
Step 3. In the third step, isocitrate is oxidized and releases a molecule of carbon
dioxide, leaving behind a five-carbon molecule α-ketoglutarate. During this step, NAD+,
is reduced to form NADH. The enzyme catalyzing this step, isocitrate dehydrogenase,
is important in regulating the speed of the citric acid cycle.
Step 4. The fourth step is similar to the third. In this case, it’s α-ketoglutarate that’s
oxidized, reducing NAD to NADH and releasing a molecule of carbon dioxide in the
process. The remaining four-carbon molecule picks up Coenzyme A, forming the
unstable compound succinyl CoA. The enzyme catalyzing this step, α-ketoglutarate
dehydrogenase, is also important in regulation of the citric acid cycle.
Step 5. In step five, the CoA succinyl CoA is replaced by a phosphate group, which is
then transferred to ADP to make ATP. In some cells, GDP—guanosine diphosphate—is
Dr. C. Grant
used instead of ADP, forming GTP—guanosine triphosphate—as a product. The four-
carbon molecule produced in this step is called succinate.
Step 6. In step six, succinate is oxidized, forming another four-carbon molecule called
fumarate. In this reaction, two hydrogen atoms—with their electrons—are transferred
to FAD, producing FADH2. The enzyme that carries out this step is embedded in the
inner membrane of the mitochondrion, so FADH2 can transfer its electrons directly into
the electron transport chain.
Step 7. In step seven, water is added to the four-carbon molecule fumarate, converting
it into another four-carbon molecule called malate.
Step 8. In the last step of the citric acid cycle, oxaloacetate—the starting four-carbon
compound—is regenerated by oxidation of malate. Another molecule of NAD+ is
reduced to NADH in the process.
Products of the citric acid cycle
In a single turn of the cycle,
 two carbons enter from acetyl CoA, and two molecules of carbon dioxide are released;
 three molecules of NADH and one molecule of FADH2 are generated; and
 one molecule of ATP or GTP is produced.
These figures are for one turn of the cycle, corresponding to one molecule of
acetyl CoA. Each glucose produces two acetyl CoA molecules, so we need to multiply
these numbers by 2 if we want the per-glucose yield.
Dr. C. Grant
Two carbons from acetyl CoA enter the citric acid cycle in each turn, and two carbon
dioxide molecules are released. However, the carbon dioxide molecules don’t actually
contain carbon atoms from the acetyl CoA that just entered the cycle. Instead, the
carbons from acetyl CoA are initially incorporated into the intermediates of the cycle and
are released as carbon dioxide only during later turns. After enough turns, all the carbon
atoms from the acetyl group of acetyl CoA will be released as carbon dioxide.
Where’s all the ATP ?
It’s true that the citric acid cycle doesn’t produce much ATP directly. However, it can
make a lot of ATP indirectly, by way of the NADH and FADH2 it generates. These
electron carriers will connect with the last portion of cellular respiration, depositing their
electrons into the electron transport chain to drive synthesis of ATP molecules
through oxidative phosphorylation.
Dr. C. Grant

The Citric Acid Cycle

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The Citric Acid Cycle

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The Citric Acid Cycle

Overview of the citric acid cycle

The remaining four-carbon molecule undergoes a series of additional reactions, first

Steps of the citric acid cycle

Products of the citric acid cycle

In a single turn of the cycle,

Where’s all the ATP ?

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