Fatty Acid Synthase

How Fatty Acids are Made

Whether existing as one complex or as independent enzymes, the reactions catalysed by types I and II fatty acid synthases are the same. Both systems are primed with acetyl-CoA, and then add 2-carbon units to the growing chain using malonyl-CoA as substrate. Type I FAS (EC 2.3.1.85) has seven different catalytic activities. Acyl carrier protein (ACP) shuttles the substrate around.

Activation/Priming

In type I FAS, the enzyme must first be activated by attaching the pantheine arm of CoA to the acyl carrier protein (ACP) domain, which is accomplished by the phosphopantetheinyl transferase (PPT) domain.

The first committed step of fatty acid synthesis in both systems is the carboxylation of acetyl-CoA to malonyl-CoA. This is achieved by the type II enzyme acetyl-CoA carboxylase (ACC), or by the equivalent type I acetyltransferase (AT; EC 2.3.1.38) domain. In type II systems, ACC is the major site of regulation that controls the rate of fatty acid synthesis, since ACC requires polymerisation to be active.

The AT domain of type I FAS loads the acetate primer from acetyl-CoA onto the ACP pantheine arm, while in type II FAS the acetate primer is directly transferred from acetyl-CoA to the enzyme beta-ketoacyl-ACP synthase III (bacterial FabH), which catalyses the first condensation reaction in the chain elongation cycle.

Elongation

The elongation cycle begins with the transfer of the acetate primer by ACP to the ketoacyl synthase (KS; EC 2.3.1.41) domain in type I. The empty ACP then moves to the malonyl transacylase (MPT; EC 2.3.1.39) domain to acquire the elongation substrate malonyl-CoA, which it delivers to the KS domain for chain elongation. The intermediate is then processed three times to produce a saturated fatty acid - this involves the ketoacyl reductase (KR; EC 1.1.1.100) domain, the dehydratase (DH; EC 4.2.1.61) domain, and the enoyl reductase (ER; EC 1.3.1.10) domain, with ACP shuttling the intermediates between active sites, before returning the substrate to the KS domain. The two reduction reactions require NADPH oxidation to NADP⁺. This reaction cycle is repeated, adding two-carbon units to the growing chain using malonyl-CoA as substrate, to produce a saturated fatty acid of the desired length. The final enzyme, thioesterase (EC 3.1.2.14), catalyses the removal of the ACP from the fatty acid chain.

Type II FAS employ four individual enzymes for each of these steps.

Termination

The process is terminated when the fatty acid reaches 16 (palmitic acid) or 18 (stearic acid) carbons in length. The fatty acid is then released from the enzyme and can undergo separate additional elongation and/or unsaturation to yield other fatty acid molecules.

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