Substrates for efficient fluorometric screening employing the NAD-dependent sirtuin 5 lysine deacylase (KDAC) enzyme

Journal of Medicinal Chemistry
Andreas S Madsen, Christian A Olsen

Abstract

The class III lysine deacylases (KDACs), also known as the sirtuins, have emerged as interesting drug targets for therapeutic intervention in a variety of diseases. To gain a deeper understanding of the processes affected by sirtuins, the development of selective small molecule modulators of individual isozymes has been a longstanding goal. Essential for the discovery of novel modulators, however, are good screening protocols and mechanistic insights with regard to the targets in question. We therefore evaluated the activities of the seven human sirtuin hydrolases against a panel of fluorogenic substrates. Both commonly used, commercially available substrates and novel chemotypes designed to address recent developments in the field of lysine post-translational modification were evaluated. Our investigations led to the discovery of two new fluorogenic ε-N-succinyllysine-containing substrates that enable highly efficient and enzyme-economical screening employing sirtuin 5 (SIRT5). Furthermore, optimized protocols for facile kinetic investigations were developed, which should be valuable for enzyme kinetic investigations. Finally, these protocols were applied to a kinetic analysis of the inhibition of SIRT5 by suramin, a potent si...Continue Reading

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Citations

Jan 21, 2016·Journal of Medicinal Chemistry·Iacopo GalleanoChristian A Olsen
Jan 3, 2014·Expert Opinion on Drug Discovery·Mike SchutkowskiClemens Steegborn
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Jan 1, 2014·ChemMedChem·Andreas S MadsenChristian A Olsen
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Jul 11, 2013·Organic & Biomolecular Chemistry·Jing HuHening Lin
Feb 11, 2016·The Journal of Biological Chemistry·Andreas S MadsenChristian A Olsen
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Jul 11, 2021·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Haiyang YangGuopeng Wang
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Apr 6, 2017·Cell Metabolism·Kristin A AndersonMatthew D Hirschey

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