title: Conformational flexibility of metazoan fatty acid synthase enables catalysis.
abstract: The metazoan cytosolic fatty acid synthase (FAS) contains all of the enzymes required for de novo fatty acid biosynthesis covalently linked around two reaction chambers. Although the three-dimensional architecture of FAS has been mostly defined, it is unclear how reaction intermediates can transfer between distant catalytic domains. Using single-particle EM, we have identified a near continuum of conformations consistent with a remarkable flexibility of FAS. The distribution of conformations was influenced by the presence of substrates and altered by different catalytic mutations, suggesting a direct correlation between conformation and specific enzymatic activities. We interpreted three-dimensional reconstructions by docking high-resolution structures of individual domains, and they show that the substrate-loading and condensation domains dramatically swing and swivel to access substrates within either reaction chamber. Concomitant rearrangement of the beta-carbon-processing domains synchronizes acyl chain reduction in one chamber with acyl chain elongation in the other.
authors.affiliation: Department of Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Brignole
authors.forename: Stuart
authors.initials: S
authors.lastname: Smith
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Asturias
mesh_terms: D000818:Animals; D002384:Catalysis; D064429:Fatty Acid Synthases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D008854:Microscopy, Electron; D008958:Models, Molecular; D017354:Point Mutation; D051381:Rats
chemical_list: D064429:Fatty Acid Synthases