molecular machines; multienzyme; structural biology; metabolism; biosystems engineering; electron microscopy; lipid biosynthesis; crystallography
Stuttfeld Edward, Aylett Christopher HS, Imseng Stefan, Boehringer Daniel, Scaiola Alain, Sauer Evelyn, Hall Michael N, Maier Timm, Ban Nenad (2018), Architecture of the human mTORC2 core complex, in eLife
, 7, e33101.
Benning Friederike M. C., Sakiyama Yusuke, Mazur Adam, Bukhari Habib S. T., Lim Roderick Y. H., Maier Timm (2017), High-Speed Atomic Force Microscopy Visualization of the Dynamics of the Multienzyme Fatty Acid Synthase, in ACS Nano
, 11, 10852-10859.
Hagmann Anna, Hunkeler Moritz, Stuttfeld Edward, Maier Timm (2016), Hybrid Structure of a Dynamic Single-Chain Carboxylase from Deinococcus radiodurans, in Structure
, 24(8), 1227-1236.
Herbst Dominik A., Jakob Roman P., Zähringer Franziska, Maier Timm (2016), Mycocerosic acid synthase exemplifies the architecture of reducing polyketide synthases, in Nature
, 531(7595), 533-537.
Hunkeler Moritz, Stuttfeld Edward, Hagmann Anna, Imseng Stefan, Maier Timm (2016), The dynamic organization of fungal acetyl-CoA carboxylase, in Nature Communications
, 7, 11196-11196.
Hunkeler Moritz, Hagmann Anna, Stuttfeld Edward, Chami Mohamed, Guri Yakir, Stahlberg Henning, Maier Timm, Structural basis for regulation of human acetyl-CoA carboxylase, in Nature
The current project focuses on the structural and functional characterization of multienzymes in lipid and polyketide metabolism, in particular fatty acid (FAS) & polyketide synthases (PKS) and biotin-dependent Coenzyme A-carboxylases (CAC). Animal FAS and CACs are key players in fatty acid and lipid metabolism and use their complex multienzymes architecture not only to catalyze multiple reaction steps, but also to integrate regulatory signals for the control of lipid metabolism. Together, they have emerged as relevant drug targets in cancer therapy. Microbial polyketide synthase are related to animal FAS and are responsible for the production of a wide range of polyketide natural products with remarkable biological and pharmaceutical activities. Despite their outstanding relevance, key aspects of the complex multienzyme and multidomain architectures underlying the function of PKS systems are still unknown. Combining X-ray crystallographic structure determination, with electron microscopy, functional characterization and targeted re-engineering, we aim to uncover the diversity of ß-carbon modifying regions in FAS/PKS and to reveal the functional architecture of key multienzyme CACs. The expected results provide the structural basis for fundamental understanding of emergent properties of multienzymes. They contribute to rational re-engineering of complex multistep enzymatic systems and help to uncover key regulatory mechanisms in lipid metabolism.