The crystal structure of a mammalian fatty acid synthase.
Mammalian fatty acid synthase is a large multienzyme that catalyzes all steps of fatty acid synthesis. We have determined its crystal structure at 3.2 angstrom resolution covering five catalytic domains, whereas the flexibly tethered terminal acyl carrier protein and thioesterase domains remain unresolved. The structure reveals a complex architecture of alternating linkers and enzymatic domains. Substrate shuttling is facilitated by flexible tethering of the acyl carrier protein domain and by the limited contact between the condensing and modifying portions of the multienzyme, which are mainly connected by linkers rather than direct interaction. The structure identifies two additional nonenzymatic domains: (i) a pseudo-ketoreductase and (ii) a peripheral pseudo-methyltransferase that is probably a remnant of an ancestral methyltransferase domain maintained in some related polyketide synthases. The structural comparison of mammalian fatty acid synthase with modular polyketide synthases shows how their segmental construction allows the variation of domain composition to achieve diverse product synthesis.
Maier
Timm
T
Institute of Molecular Biology and Biophysics, ETH Zurich, 8092 Zurich, Switzerland.
Leibundgut
Marc
M
Ban
Nenad
N
D000213:Acyl Carrier Protein / Q000737:chemistry / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D019281:Dimerization; D019143:Evolution, Molecular; D054890:Fatty Acid Synthase, Type I / Q000737:chemistry*; D005227:Fatty Acids / Q000096:biosynthesis; D008780:Methyltransferases / Q000737:chemistry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009249:NADP / Q000737:chemistry / Q000378:metabolism; D048630:Polyketide Synthases / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D013552:Swine / Q000378:metabolism*
D000213:Acyl Carrier Protein; D005227:Fatty Acids; D009249:NADP; D048630:Polyketide Synthases; D008780:Methyltransferases; D054890:Fatty Acid Synthase, Type I