Acetyl-CoA Carboxylase and Fatty Acid Synthase

Acetyl-CoA Carboxylase

Acetyl-CoA is converted to malonyl-CoA by an ATP-dependant acetyl-CoA carboxylase (ACC). This reaction is the rate-limiting step for long chain fatty acid synthesis. ACC is a biotin dependent enzyme. 5-(tetradecyloxy)-2furoic acid (TOFA) inhibits ACC. AMP-Activated Kinase (AMPK) catalyzes inactivates acetyl-CoA carboxylase in peripheral tissues, but a decrease in AMPK activity decreases ACC activity in the hypothalamus.

Diagram 2. Acetyl-CoA Carboxylase reaction.

acetyl-CoA is converted to Malonyl CoA by ACC

Figure 5a. Coenzyme-A (CoA).

co-enzyme a

Figure 5b. Acetyl-CoA and malonyl-CoA.

acetyl-Co and Malonyl-CoA

acetyl-coa carboxylase carboxyl transferase

ACC has three functional domains; the biotin carrier protein, biotin carboxylase and the transcarboxylase protein.

Figure 5c. ACC biotin carboxylase subunit (left) ACC carboxyl transferase domain (right).Courtesy of RCSB protein databank.

Fatty Acid Synthase

Fatty Acid Synthase concerts seven malonyl-CoA and one acetyl-CoA to a 16 carbon fatty acid called palmitate. Cerulenin and C75 inhibit this enzyme by preventing the binding of malonyl-CoA.

Diagram 3. FAS reaction.

malonyl-coa to palmitate by fas

The mechanism involves 4 repeating steps.

Condensation of a malonyl and an acetyl group releasing carbon dioxide.
Reduction of the beta-keto group to a beta-hydroxy group by NADPH
Dehydration of the beta-carbon making a double bond between the alpha an beta carbons and releasing water.
Reduction of that double bond by another NADPH.

FAS is a large enzyme complex consisting of several proteins.

Figure 5d. FAS acyltransferase protein (left), E. coli-Ketoacyl-ACP Synthase III synthase with malonyl-CoA , pink, bound. .Courtesy of RCSB protein databank.