Structure of the human fatty acid synthase KS-MAT didomain as a framework for inhibitor design.
The human fatty acid synthase (FAS) is a key enzyme in the metabolism of fatty acids and a target for antineoplastic and antiobesity drug development. Due to its size and flexibility, structural studies of mammalian FAS have been limited to individual domains or intermediate-resolution studies of the complete porcine FAS. We describe the high-resolution crystal structure of a large part of human FAS that encompasses the tandem domain of beta-ketoacyl synthase (KS) connected by a linker domain to the malonyltransferase (MAT) domain. Hinge regions that allow for substantial flexibility of the subdomains are defined. The KS domain forms the canonical dimer, and its substrate-binding site geometry differs markedly from that of bacterial homologues but is similar to that of the porcine orthologue. The didomain structure reveals a possible way to generate a small and compact KS domain by omitting a large part of the linker and MAT domains, which could greatly aid in rapid screening of KS inhibitors. In the crystal, the MAT domain exhibits two closed conformations that differ significantly by rigid-body plasticity. This flexibility may be important for catalysis and extends the conformational space previously known for type I FAS and 6-deoxyerythronolide B synthase.
Pappenberger
Günter
G
F. Hoffmann La-Roche, Basel, CH-4070 Basel, Switzerland.
Benz
Jörg
J
Gsell
Bernard
B
Hennig
Michael
M
Ruf
Armin
A
Stihle
Martine
M
Thoma
Ralf
R
Rudolph
Markus G
MG
D001665:Binding Sites; D018360:Crystallography, X-Ray; D054890:Fatty Acid Synthase, Type I / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D017434:Protein Structure, Tertiary
C518729:FASN protein, human; D054890:Fatty Acid Synthase, Type I