Structure of fungal fatty acid synthase and implications for iterative substrate shuttling.
We report crystal structures of the 2.6-megadalton alpha6beta6 heterododecameric fatty acid synthase from Thermomyces lanuginosus at 3.1 angstrom resolution. The alpha and beta polypeptide chains form the six catalytic domains required for fatty acid synthesis and numerous expansion segments responsible for extensive intersubunit connections. Detailed views of all active sites provide insights into substrate specificities and catalytic mechanisms and reveal their unique characteristics, which are due to the integration into the multienzyme. The mode of acyl carrier protein attachment in the reaction chamber, together with the spatial distribution of active sites, suggests that iterative substrate shuttling is achieved by a relatively restricted circular motion of the carrier domain in the multifunctional enzyme.
Jenni
Simon
S
Institute of Molecular Biology and Biophysics, ETH Zurich, 8092 Zurich, Switzerland.
Leibundgut
Marc
M
Boehringer
Daniel
D
Frick
Christian
C
Mikolásek
Bohdan
B
Ban
Nenad
N
D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / Q000378:metabolism; D000123:Acetyltransferases / Q000378:metabolism; D000213:Acyl Carrier Protein / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D000217:Acyltransferases / Q000378:metabolism; D000595:Amino Acid Sequence; D001203:Ascomycota / Q000201:enzymology*; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / Q000378:metabolism; D064429:Fatty Acid Synthases / Q000737:chemistry* / Q000378:metabolism; D005656:Fungal Proteins / Q000737:chemistry* / Q000378:metabolism; D006836:Hydro-Lyases / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009249:NADP / Q000737:chemistry; D011487:Protein Conformation; D021122:Protein Subunits / Q000737:chemistry; D013379:Substrate Specificity
D000213:Acyl Carrier Protein; D005656:Fungal Proteins; D021122:Protein Subunits; D009249:NADP; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH); D000217:Acyltransferases; D000123:Acetyltransferases; D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase; D064429:Fatty Acid Synthases; D006836:Hydro-Lyases