Fatty Acid Synthesis and Modification

by Nickolaos D. Skouras, PhD.

"Acetyl Coenzyme-A" The Center of Lipid MetabolismTM"

Coenzyme-A is a commonly used carrier for activated acyl groups (acetyl, fatty acyl and others). The thioester bond, which links the acyl group to Coenzyme-A, has a large negative standard free energy of hydrolysis (-7.5 kcal/mole). This qualifies it as a high energy bond, and explains why an acyl group attached to Coenzyme-A in this manner is considered to be activated.

The fatty acid (1) obtained from fat digestion is converted into the thioester of Coenzyme-A (2) by an acyl CoA synthetase enzyme. The complete structure of Coenzyme-A is shown above and is commonly abbreviated as HSCoA. The first step of the b-oxidation cycle involves dehydrogenation of 2 to give the ab-unsaturated thioester 3. This reaction is catalyzed by acyl coenzyme-A dehydrogenases. In this reaction, the tricyclic isoalloxazine portion of flavin adenine dinucleotide (FAD) is reduced to give FADH2 (see scheme 3), while the fatty acid is oxidized from the alkane to the corresponding alkene. In the next step, water is added to the alkene of 3 to produce b-hydroxy thioester 4. This hydration reaction is catalyzed by enoyl coenzyme-A hydratase. In the next step the b-hydroxy thioester (4) is oxidized to the corresponding b-keto thioester (5). This reaction is catalyzed by 3-hydroxyacyl coenzyme-A dehydrogenase and the oxidizing agent is nicotinamide adenine dinucleotide (NAD+), which is reduced to NADH (see scheme 3). The final step of this cycle involves a retro-Claisen reaction of the b-ketothioester 5 with Coenzyme-A to give 6 and Acetyl Coenzyme-A. In this process the acyl unit has been shortened by two carbons.