Fatty Acid Synthesis

Carboxylation is ATP-dependent: energy input

Malonyl-CoA upon condensation with the growing fatty acid looses CO₂

The spontaneous decarboxylation drives the condensation reaction

The input: acetyl-CoA, which is then carboxylated: malonyl-CoA.

As with other carboxylation reactions, the enzyme prosthetic group is biotin 

ATP-dependent carboxylation of the biotin, carried out at one active site 1 , is followed by transfer of the carboxyl group to acetyl-CoA at a second active site 2 .

Acetyl-CoA Carboxylase catalyzes the 2-step reaction by which acetyl-CoA is carboxylated to form malonyl-CoA

Fatty acid synthesis from acetyl-CoA & malonyl-CoA occurs by a series of reactions that:

• in bacteria catalyzed by 6 different enzymes plus a separate acyl carrier protein (ACP)
• in mammals catalyzed by individual domains of a very large polypeptide that includes an ACP domain

NADPH serves as electron donor in the two reactions involving substrate reduction

The NADPH is produced mainly by the Pentose Phosphate Pathway

The condensation reaction involves decarboxylation of the malonyl moiety, followed by attack of the resultant carbanion on the carbonyl carbon of the acetyl moiety

Product release:

When the fatty acid is 16 carbon atoms long, a Thioesterase domain catalyzes hydrolysis of the thioester linking the fatty acid to phosphopantetheine.

The 16-C saturated fatty acid palmitate is the final product of the Fatty Acid Synthase complex.

Desaturases introduce double bonds at specific positions in a fatty acid chain.

Mammalian cells are unable to produce double bonds at certain locations, e.g., Δ¹².

Thus some polyunsaturated fatty acids are dietary essentials, e.g., linoleic acid, 18:2 cis Δ^9,12 (18 C atoms long, with cis double bonds at carbons 9-10 & 12-13).