Formation of Acetyl Coenzyme-A

by Nickolaos D. Skouras, PhD.
Summary: Pyruvate is degraded and combined with Coenzyme-A to form acetyl coenzyme A; hydrogens are released; and carbon dioxide is released.

The pyruvic molecules formed in glycolosis enter the mitochondria, where they are converted to acetyl Coenzyme-A (acetyl-CoA). In this complex series of reactions, pyruvate undergoes oxidative decarboxylation. First, a carboxyl group is removed as carbon dioxide, which diffuses out of the cell. Then the two-carbon fragment remaining is oxidized, and the hydrogens that were removed during the oxidation are accepted by NAD+. Finally, the oxidized two-carbon fragment, an acetyl group, is attached to Coenzyme-A, which is manufactured in the cell from one of the B vitamins, pantothenic acid. The reaction is catalyzed by a multienzyme complex that contains several copies of each of three different enzymes. The overall reaction for the formation of acetyl Coenzyme-A can be stated as follows:

2 pyruvate + 2 NAD+ + 2 CoA ----> 2 acetyl-CoA + 2 NADH + 2 carbon dioxide

Note that the original glucose molecule has now been oxidized to two acetyl groups and two carbon dioxide molecules. The hydrogens removed have reduced NAD+ to NADH. At this point in aerobic respiration, four NADH molecules have been formed from a single starting glucose molecule, two during glycolosis and two during the formation of acetyl-CoA from pyruvate.

Lipid Metabolism

Three important cofactors that assist the enzymes are:

Coenzyme-A is a "helper" molecule important in many metabolic processes. The reactive end of the molecule is the sulfhydryl group (-SH) which acts as a nucleophile.

FAD / FAD-H2 is used as an oxidizing / reducing agent in the transfer of two hydrogen atoms, analogous to the catalytic hydrogenation of simple alkenes.

NAD+ / NADH is another oxidizing / reducing agent, for the transfer of a hydride ion (H-), NAD acts like a biochemical version of NaBH4.

The first step in the metabolism of triacyl glycerols is the hydrolysis of the tri-ester to yield glycerol and three fatty acid molecules.

At this stage, the two hydrolysis products are subject to two different metabolic pathways. The glycerol is metabolized by glycolysis - the same pathway that is used for carbohydrates. The fatty acid is broken down through the beta-oxidation pathway, as outlined below.

Once the fat has been hydrolized, the fatty acid is combined with Coenzyme-A as a thioester.

The CoA serves as a molecular "handle" for the enzymes in the following reactions. After forming the thioester, a double bond is introduced using FAD as the oxidizing agent.

The double bond is then hydrated, in much the same way that simple alkenes react with acid in water to form an alcohol, to form a beta-hydroxy compound.

The alcohol is then oxidized to the corresponding ketone with NAD.

The final step involves a reverse-aldol reaction to break the bond between the alpha and beta carbons.

The two products of this last step are acetyl-CoA and a second CoA that is attached to the original fatty acid molecule which has been shortened by two carbons. This smaller fatty acid-CoA molecule then goes through the whole sequence again, - starting at the FAD step. This removes two more carbons from the fatty acid, in the form of acety-CoA. The process continues until all the carbons of the fatty acid are converted to 2-carbon chunks in the form of acetyl-CoA.