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Multienzymes in Lipid and Polyketide Biosynthesis

English title Multienzymes in Lipid and Polyketide Biosynthesis
Applicant Maier Timm
Number 159696
Funding scheme Project funding
Research institution Biozentrum der Universität Basel Systembiologie
Institution of higher education University of Basel - BS
Main discipline Molecular Biology
Start/End 01.04.2015 - 31.03.2018
Approved amount 525'000.00
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All Disciplines (2)

Discipline
Molecular Biology
Biophysics

Keywords (8)

molecular machines; multienzyme; structural biology; metabolism; biosystems engineering; electron microscopy; lipid biosynthesis; crystallography

Lay Summary (German)

Lead
Multienzyme sind biologische Fabriken im Nanomassstab. Sie kombinieren funktionale Bereiche einfacher Enzyme zu einer grösseren Einheit, um komplexe Stoffwechselabläufe durchzuführen. Dabei bieten sie vielfältige Möglichkeiten zur genauen Regulation wichtiger Stoffwechselschritte. Dieses Projekt beschäftigt sich mit der Aufklärung der funktionalen Architektur von Multienzymen.
Lay summary

Strukturbiologische Untersuchungen haben die molekularen und mechanistischen Grundlagen einer Vielzahl von Proteinen und Proteinkomplexen aufgeklärt. Einzelne, besonders relevante Klassen von Proteinen, sind jedoch nach wie vor kaum strukturell charakterisiert. Neben den Membranproteinen, die ausserhalb der Membranumgebung oftmals instabil sind, gehören dazu vor allem hochdynamische Proteine, wie die Multienzyme, die aus vielen flexibel verknüpften Einheiten, den Domänen, aufgebaut sind. Dieses Projekt beschäftigt sich mit strukturellen und funktionalen Untersuchungen an Multienzymen, die wichtige Rollen in der mikrobiellen Naturstoffsynthese oder Schlüsselaufgaben im menschlichen Stoffwechsel ausüben.

 In diesem Projekt werden Varianten wichtiger Multienzyme hergestellt und funktio­­­­na­­l charakte­risiert. Anschliessend werden sie mit einer Kombination struktur­biologischer Techniken, wie der Röntgenkristallographie, der Elektronenmikroskopie, der Röntgenstreuung und verschiedener Massenspektrometrie-Anwendungen, bearbeitet. Ziel der Untersuchungen ist die Aufklärung der molekularen Architektur, die als Grundlage für die besonderen Eigenschaften der Multienzyme dient.

 Dieses Projekt befasst sich primär mit einem grundlegenden Verständnis von Schlüsselvorgängen in der Biologie. Die Erkenntnisse und Strukturinformationen, die im Rahmen dieses Projektes gewonnen werden, dienen langfristig auch der Optimierung neuer Methoden zur Medikamentenherstellung durch Multienzyme  und tragen dazu bei, neuartige Angriffspunkte an Proteinen zu finden, deren Fehlregulation eng mit der Entstehung von Krankheiten verknüpft ist. 

 

Direct link to Lay Summary Last update: 31.05.2015

Responsible applicant and co-applicants

Employees

Publications

Publication
Architecture of the human mTORC2 core complex
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.
High-Speed Atomic Force Microscopy Visualization of the Dynamics of the Multienzyme Fatty Acid Synthase
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.
Hybrid Structure of a Dynamic Single-Chain Carboxylase from Deinococcus radiodurans
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.
Mycocerosic acid synthase exemplifies the architecture of reducing polyketide synthases
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.
The dynamic organization of fungal acetyl-CoA carboxylase
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.
Structural basis for regulation of human acetyl-CoA carboxylase
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.

Collaboration

Group / person Country
Types of collaboration
Roderick Lim, Biozentrum, University of Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Henning Stahlberg, Biozentrum, University of Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Craig A. Townsend, Johns Hopkins University, Baltimore United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
7th International Singpaore Lipid Symposium (iSLS7) Talk given at a conference The structural biology of multienzymes in fatty acid and polyketide biosynthesis 06.03.2018 Singapore, Singapore Maier Timm;
XIX. Linz Winterworkshop Poster Watching a Molecular Machine at Work 04.02.2017 Linz, Austria Benning Friederike;
Biozentrum Symposium 2017 Poster Watching a Molecular Machine at Work 18.01.2017 Basel, Switzerland Benning Friederike;
EMBO Conference “Molecular Machines: Integrative Structural and Molecular Biology” Talk given at a conference The Architecture of Reducing Polyketide Synthases 20.11.2016 Heidelberg, Germany, Germany Maier Timm;
Gordon Research Conference - Enzymes Talk given at a conference Structure and Evolution of Fatty Acid and Reducing Polyketide Synthases 24.07.2016 Waterville Valley, New Hampshire, USA, United States of America Maier Timm;


Self-organised

Title Date Place
Biozentrum Lecture by Venki Ramakrishnan 13.10.2015 Biozentrum Basel, Switzerland
29. Rhine-Knee Regiomeeting on Structural Biology 23.09.2015 Engelberg, Switzerland
Session Chair for “Macromolecular Machines” at the ACA Meeting 2015 25.07.2015 Philadelphia, United States of America

Communication with the public

Communication Title Media Place Year
Other activities kids@Science German-speaking Switzerland 2018
Talks/events/exhibitions Fest der Moleküle German-speaking Switzerland 2016
Talks/events/exhibitions Nacht der Wissenschaft German-speaking Switzerland 2015

Associated projects

Number Title Start Funding scheme
177084 Efficient cryo electron microscopy of macromolecular assemblies and membrane proteins 01.09.2018 R'EQUIP
145023 Advanced Imaging System for Biomolecular Crystallization Screening 01.12.2012 R'EQUIP
179323 Macromolecular Assemblies in Metabolic Regulation and Polyketide Biosynthesis 01.04.2018 Project funding
164074 Cryo-Electron Microscopy in the ZMB of the University of Basel 01.06.2016 R'EQUIP
144183 The Bacterial Lectin FimH - High and Low Affinity States 01.10.2012 Project funding
138262 Multienzymes and the Regulation of Eukaryotic Lipid Metabolism 01.01.2012 Project funding

Abstract

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.
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