The human fatty acid synthase (FAS) is a key enzyme in the metabolism of fatty acids and a target for anti-neoplastic and anti-obesity 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 malonyl transferase (MAT) domain. Hinge regions are defined that allow for substantial flexibility of the subdomains. The KS domain forms the canonical dimer, and its substrate binding site geometry differs markedly from bacterial homologues but is similar to 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 LD 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.

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