Regulation of Substrate Transport in the Early Stages of Fatty Acid Synthesis

The fungal type 1 fatty acid synthase (FAS) is a complex multienzyme system that plays a crucial role in the synthesis of saturated fatty acids. The progression of the intricate reaction cycle relies on the transfer of reaction intermediates between catalytic domains, facilitated by an acyl carrier domain. The initial step of the reaction involves the transfer of acetyl to the carrier, necessitating a substantial conformational change that is stabilized by the binding of a regulatory $$\gamma $$ γ -subunit. This study aims to elucidate the molecular mechanism underlying the induction of the conformational change and the stabilization of the initiation complex. To achieve this, all-atom molecular dynamics simulations were performed on the FAS in the initiation conformation. A comprehensive model of the full-length 2.6 MDa FAS complex was reconstructed, serving as the basis for the simulations conducted in the presence and absence of the $$\gamma $$ γ -subunit, as well as by relocating the carrier to different catalytic domains. The results demonstrate that the binding of the $$\gamma $$ γ -subunit is essential for stabilizing the conformational change, whereas the binding of the carrier protein did not exert a significant effect. These findings support the hypothesis that the initiation of fatty acid synthesis is regulated through conformational selection, rather than solely relying on the binding and dynamics of the carrier protein.