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SIRFUNCT SIGNED

Chemical Tools for Unravelling Sirtuin Function

Total Cost €

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EC-Contrib. €

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Partnership

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Project "SIRFUNCT" data sheet

The following table provides information about the project.

Coordinator
KOBENHAVNS UNIVERSITET 

Organization address
address: NORREGADE 10
city: KOBENHAVN
postcode: 1165
website: www.ku.dk

contact info
title: n.a.
name: n.a.
surname: n.a.
function: n.a.
email: n.a.
telephone: n.a.
fax: n.a.

 Coordinator Country Denmark [DK]
 Total cost 1˙758˙742 €
 EC max contribution 1˙758˙742 € (100%)
 Programme 1. H2020-EU.1.1. (EXCELLENT SCIENCE - European Research Council (ERC))
 Code Call ERC-2016-COG
 Funding Scheme ERC-COG
 Starting year 2017
 Duration (year-month-day) from 2017-04-01   to  2022-03-31

 Partnership

Take a look of project's partnership.

# participants  country  role  EC contrib. [€] 
1    KOBENHAVNS UNIVERSITET DK (KOBENHAVN) coordinator 1˙758˙742.00

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 Project objective

It was recently realized that lysine acetylation affects a wide variety of cellular processes in addition to the initially recognized histone related gene regulation. Together with recent groundbreaking results, revealing the presence of additional acyllysine modifications, the basis for a paradigm shift in this area was formed. Examples of enzymes formerly thought to be lysine deacetylases, have been shown to cleave these new types of lysine modification and members of the sirtuin class of enzymes play a central role. Development of new tools to investigate the importance of these new modifications as well as the sirtuins that cleave them is required. We therefore propose to adopt an interdisciplinary approach by developing selective inhibitors and so-called activity-based probes (ABPs) and applying these to the investigation of proteins recognizing novel post-translational acylations of lysine residues in cells. Such ABPs will be powerful tools for providing insight regarding this rapidly evolving area of biochemistry; however, the current state-of-the-art in ABP design is endowed with severe limitations because the modifications are inherently cleaved by various hydrolases in human cells. Thus, in the present project, I propose that novel designs accommodating non-cleavable modifications are warranted to maintain structural integrity during experiments. Furthermore, I propose to apply similar mechanism-based designs to develop potent and isoform-selective sirtuin inhibitors, which will serve as chemical probes to investigate links between cancer and metabolism, and may ultimately serve as lead compounds for pre-clinical pharmaceutical development.

AIM-I. (a) Development and (b) application of collections of chemical probes for activity-based investigation of enzymes that interact with post-translationally acylated proteins.

AIM-II. Utilization of structural and mechanistic insight to design potent and selective inhibitors of sirtuin enzymes.

 Publications

year authors and title journal last update
List of publications.
2018 Rajabi, Nima; Svensson, Birte; Olsen, Christian; Olesen, Sita; Madsen, Andreas
An NAD + -dependent sirtuin depropionylase and deacetylase (Sir2La) from the probiotic bacterium Lactobacillus acidophilus NCFM
published pages: , ISSN: 1520-4995, DOI: 10.1101/252379
Biochemistry 1 2019-04-18
2017 Nima Rajabi, Marina Auth, Kathrin R. Troelsen, Martin Pannek, Dhaval P. Bhatt, Martin Fontenas, Matthew D. Hirschey, Clemens Steegborn, Andreas S. Madsen, Christian A. Olsen
Mechanism-Based Inhibitors of the Human Sirtuin 5 Deacylase: Structure-Activity Relationship, Biostructural, and Kinetic Insight
published pages: 14836-14841, ISSN: 1433-7851, DOI: 10.1002/anie.201709050
Angewandte Chemie International Edition 56/47 2019-04-18
2018 Madsen, Andreas; Olsen, Christian; Moreno-Yruela, Carlos; Galleano, Iacopo
Histone Deacetylase 11 is an ε-N-Myristoyllysine Hydrolase
published pages: , ISSN: 2451-9448, DOI: 10.1101/211839
Cell Chemical Biology 1 2019-04-18

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The information about "SIRFUNCT" are provided by the European Opendata Portal: CORDIS opendata.

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