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After emerging from glycolysis, the two pyruvate are transported into the mitochondria. There, the pyruvate undergo a transition stage before entering the actual citric acid cycle. In this phase the pyruvate is transformed into acetyl-coenzyme A (acetyl-CoA), the starting product in the citric acid cycle. ;

2 Pyruvate + 2 coenzyme A + 2NAD+ -> 2 acetyl-CoA +2CO2 + 2 NADH
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Formation of Acetyl-CoA

Acetyl-CoA is a common product of carbohydrate, lipid, and protein breakdown. It consists of an acetyl group attached to a coenzyme A molecule. Coenzyme A is a large molecule that contains a molecule of ADP with two side chain groups stemming from its phosphate arms. Acetyl groups attach to the end of these side chains. In this way, the coenzyme A acts as a carrier of acetyl groups. When it is broken down by water, large amounts of energy are released, which, as we shall see, drive the citric acid cycle. The most common way that acetyl-CoA is derived in the metabolic pathway is with the help of the pyruvate dehydrogenase multienzyme complex.

The pyruvate dehydrogenase multienzyme is a complex of three distinct enzymes that together convert pyruvate into acetyl-CoA with the help of a molecule of coenzyme A and NAD. The mechanism for the formation of acetyl-CoA is complex, as seen below. Generally, in reaction 1, the enzyme pyruvate dehydrogenase pulls a carbon dioxide molecule off the pyruvate. This is accomplished with the help of a molecule called TPP that forms a temporary bond with the pyruvate molecule. The carbon dioxide removal reaction is similar to that of the yeast pyruvate decarboxylase in alcoholic fermentation.

Figure %: Pyruvate Metabolism to form Acetyl-CoA.

In reaction 2, the enzyme dihydrolipoyl transacetylase helps to attach another temporary molecule called a lipoamide. With this bond formation, the TPP molecule from the first step is released leading to the formation of an acetyl group. In the third step, this lipoamide group is reduced and released as a molecule of CoA attacks the acetyl group. We now have acetyl-CoA. The third enzyme, dihydrolipoyl dehydrogenase, is responsible for restoring the lipoamide to its original, oxidized state so that it can be reused in the cycle in a fourth step. The molecule of NAD asserts itself at this point, helping to reoxidize the lipoamide.

At this point, we have acetyl-CoA and are ready to enter the citric acid cycle.