Coenzyme-A Technologies Inc. Fatty Acid Synthesis and Modification

Fatty Acid Synthesis and Modification

"Acetyl Coenzyme-A" The Center of Lipid Metabolism^TM"

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 a,b-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.