Structure of the Human Fatty Acid Synthase KS–MAT Didomain as a Framework for Inhibitor Design

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• 作者：Gü ; nter Pappenberger ; Jö ; rg Benz ; Bernard Gsell ; Michael Hennig ; Armin Ruf ; Martine Stihle ; Ralf Thoma ; Markus G. Rudolph
• 关键词：fatty acid synthesis ; metabolic disease ; synthase ; transferase ; X-ray crystallography
• 刊名：Journal of Molecular Biology
• 出版年：2010
• 出版时间：26 March 2010
• 年：2010
• 卷：397
• 期：2
• 页码：508-519
• 全文大小：2597 K

文摘

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 β-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.