Control Mechanism for Carbon‐Chain Length in Polyunsaturated Fatty‐Acid Synthases

Polyunsaturated fatty acids (PUFAs) such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are essential fatty acids. PUFA synthases are composed of three to four subunits and each create a specific PUFA without undesirable byproducts. However, detailed biosynthetic mechanisms for controlling final product profiles have been obscure. Here, the bacterial DHA and EPA synthases were carefully dissected by in vivo and in vitro experiments. In vitro analysis with two KS domains (KS_A and KS_C) and acyl‐acyl carrier protein (ACP) substrates showed that KS_A accepted short‐ to medium‐chain substrates while KS_C accepted medium‐ to long‐chain substrates. Unexpectedly, condensation from C₁₈ to C₂₀, the last elongation step in EPA biosynthesis, was catalyzed by KS_A domains in both EPA and DHA synthases. Conversely, condensation from C₂₀ to C₂₂, the last elongation step for DHA biosynthesis, was catalyzed by the KS_C domain in DHA synthase. KS_C domains therefore determine the chain lengths.