Type I fatty acid synthase (FAS) trapped in the octanoyl-bound state

  • De novo fatty acid biosynthesis in humans is accomplished by a multidomain protein, the type I fatty acid synthase (FAS). Although ubiquitously expressed in all tissues, fatty acid synthesis is not essential in normal healthy cells due to sufficient supply with fatty acids by the diet. However, FAS is overexpressed in cancer cells and correlates with tumor malignancy, which makes FAS an attractive selective therapeutic target in tumorigenesis. Herein, we present a crystal structure of the condensing part of murine FAS, highly homologous to human FAS, with octanoyl moieties covalently bound to the transferase (MAT) and the condensation (KS) domain. The MAT domain binds the octanoyl moiety in a novel (unique) conformation, which reflects the pronounced conformational dynamics of the substrate binding site responsible for the MAT substrate promiscuity. In contrast, the KS binding pocket just subtly adapts to the octanoyl moiety upon substrate binding. Besides the rigid domain structure, we found a positive cooperative effect in the substrate binding of the KS domain by a comprehensive enzyme kinetic study. These structural and mechanistic findings contribute significantly to our understanding of the mode of action of FAS and may guide future rational inhibitor designs.

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Metadaten
Author:Alexander RittnerORCiDGND, Karthik Shivaji PaithankarORCiDGND, Aaron Himmler, Martin GriningerORCiDGND
URN:urn:nbn:de:hebis:30:3-726003
DOI:https://doi.org/10.1101/747683
Parent Title (English):bioRxiv
Document Type:Preprint
Language:English
Date of Publication (online):2019/08/28
Date of first Publication:2019/08/28
Publishing Institution:Universit├Ątsbibliothek Johann Christian Senckenberg
Release Date:2023/03/25
Issue:747683
Page Number:51
HeBIS-PPN:509912273
Institutes:Biochemie, Chemie und Pharmazie
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
Sammlungen:Universit├Ątspublikationen
Licence (German):License LogoCreative Commons - CC BY-NC - Namensnennung - Nicht kommerziell 4.0 International