Fatty acid synthase

Fatty acid synthase (FAS) is an enzyme that in humans is encoded by the FASN gene.

Fatty acid synthase is a multi-enzyme protein that catalyzes fatty acid synthesis. It is not a single enzyme but a whole enzymatic system composed of two identical 272 kDa multifunctional polypeptides, in which substrates are handed from one functional domain to the next.

Its main function is to catalyze the synthesis of palmitate (C16:0, a long-chain saturated fatty acid) from acetyl-CoA and malonyl-CoA, in the presence of NADPH.

The fatty acids are synthesized by a series of decarboxylative Claisen condensation reactions from acetyl-CoA and malonyl-CoA. Following each round of elongation the beta keto group is reduced to the fully saturated carbon chain by the sequential action of a ketoreductase (KR), dehydratase (DH), and enoyl reductase (ER). The growing fatty acid chain is carried between these active sites while attached covalently to the phosphopantetheine prosthetic group of an acyl carrier protein (ACP), and is released by the action of a thioesterase (TE) upon reaching a carbon chain length of 16 (palmitic acid).

There are two principal classes of fatty acid synthases.

The mechanism of FAS I and FAS II elongation and reduction is the same, as the domains of the FAS II enzymes are largely homologous to their domain counterparts in FAS I multienzyme polypeptides. However, the differences in the organization of the enzymes - integrated in FAS I, discrete in FAS II - gives rise to many important biochemical differences.

The evolutionary history of fatty acid synthases are very much intertwined with that of polyketide synthases (PKS). Polyketide synthases use a similar mechanism and homologous domains to produce secondary metabolite lipids. Furthermore, polyketide synthases also exhibit a Type I and Type II organization. FAS I in animals is thought to have arisen through modification of PKS I in fungi, whereas FAS I in fungi and the CMN group of bacteria seem to have arisen separately through the fusion of FAS II genes.

Mammalian FAS consists of a homodimer of two identical protein subunits, in which three catalytic domains in the N-terminal section (-ketoacyl synthase (KS), malonyl/acetyltransferase (MAT), and dehydrase (DH)), are separated by a core region (known as the interdomain) of 600 residues from four C-terminal domains (enoyl reductase (ER), -ketoacyl reductase (KR), acyl carrier protein (ACP) and thioesterase (TE)). The interdomain region allows the two monomeric domains to form a dimer.