page_title: Fatty acid synthase
section_title: Substrate shuttling mechanism
hierarchical_section_title: Fatty acid synthase / Substrate shuttling mechanism
caption_attribution_description: English: Fatty acid synthase (FAS) 'head-to-tail' model with positions of polypeptides, three catalytic domains and their corresponding reactions, designed and produced by Kosi Gramatikoff user:kosigrim.
context_page_description: Fatty acid synthase 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 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, dehydratase, and enoyl reductase. The growing fatty acid chain is carried between these active sites while attached covalently to the phosphopantetheine prosthetic group of an acyl carrier protein, and is released by the action of a thioesterase upon reaching a carbon chain length of 16.
context_section_description: The solved structures of yeast FAS and mammalian FAS show two distinct organizations of highly conserved catalytic domains/enzymes in this multi-enzyme cellular machine. Yeast FAS has a highly efficient rigid barrel-like structure with 6 reaction chambers which synthesize fatty acids independently, while the mammalian FAS has an open flexible structure with only two reaction chambers. However, in both cases the conserved ACP acts as the mobile domain responsible for shuttling the intermediate fatty acid substrates to various catalytic sites. A first direct structural insight into this substrate shuttling mechanism was obtained by cryo-EM analysis, where ACP is observed bound to the various catalytic domains in the barrel-shaped yeast fatty acid synthase. The cryo-EM results suggest that the binding of ACP to various sites is asymmetric and stochastic, as also indicated by computer-simulation studies
caption: FAS 'head-to-tail' model with positions of polypeptides, three catalytic domains and their corresponding reactions, visualization by Kosi Gramatikoff.
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