Pyruvate oxidation

Among the four stages of cellular respiration, pyruvate oxidation is kind of the odd one out; it’s relatively short in comparison to the extensive pathways of glycolysis or the citric acid cycle. But that doesn’t make it unimportant! On the contrary, pyruvate oxidation is a key connector that links glycolysis to the rest of cellular respiration.

At the end of glycolysis, we have two pyruvate molecules that still contain lots of extractable energy. Pyruvate oxidation is the next step in capturing the remaining energy in the form of $\text{ATP}$‍, although no $\text{ATP}$‍ is made directly during pyruvate oxidation.

In eukaryotes, this step takes place in the matrix, the innermost compartment of mitochondria. In prokaryotes, it happens in the cytoplasm. Overall, pyruvate oxidation converts pyruvate—a three-carbon molecule—into acetyl $\text{CoA}$‍—a two-carbon molecule attached to Coenzyme A—producing an $\text{NADH}$‍ and releasing one carbon dioxide molecule in the process. Acetyl $\text{CoA}$‍ acts as fuel for the citric acid cycle in the next stage of cellular respiration.

Pyruvate is produced by glycolysis in the cytoplasm, but pyruvate oxidation takes place in the mitochondrial matrix (in eukaryotes). So, before the chemical reactions can begin, pyruvate must enter the mitochondrion, crossing its inner membrane and arriving at the matrix.

In the matrix, pyruvate is modified in a series of steps:

Step 1. A carboxyl group is snipped off of pyruvate and released as a molecule of carbon dioxide, leaving behind a two-carbon molecule.

Step 2. The two-carbon molecule from step 1 is oxidized, and the electrons lost in the oxidation are picked up by ${\text{NAD}}^{+}$‍ to form $\text{NADH}$‍.

Step 3. The oxidized two-carbon molecule—an acetyl group, highlighted in green—is attached to Coenzyme A ($\text{CoA}$‍), an organic molecule derived from vitamin B5, to form acetyl $\text{CoA}$‍. Acetyl $\text{CoA}$‍ is sometimes called a carrier molecule, and its job here is to carry the acetyl group to the citric acid cycle.

The steps above are carried out by a large enzyme complex called the pyruvate dehydrogenase complex, which consists of three interconnected enzymes and includes over 60 subunits. At a couple of stages, the reaction intermediates actually form covalent bonds to the enzyme complex—or, more specifically, to its cofactors. The pyruvate dehydrogenase complex is an important target for regulation, as it controls the amount of acetyl $\text{CoA}$‍ fed into the citric acid cycle${}^{1,2,3}$‍.

If we consider the two pyruvates that enter from glycolysis (for each glucose molecule), we can summarize pyruvate oxidation as follows:

Why make acetyl $\text{CoA}$‍? Acetyl $\text{CoA}$‍ serves as fuel for the citric acid cycle in the next stage of cellular respiration. The addition of $\text{CoA}$‍ helps activate the acetyl group, preparing it to undergo the necessary reactions to enter the citric acid cycle.