Mechanism-based Inhibitors of the Human Sirtuin 5 Deacylase: Structure-Activity Relationship, Biostructural, and Kinetic Insight

Nima Rajabi; Marina Auth; Kathrin Rentzius Troelsen; Martin Pannek; Dhaval Bhatt; Martin Fontenas; Matthew Hirschey; Clemens Steegborn; Andreas Stahl Madsen; Christian Adam Olsen

doi:10.1002/anie.201709050

Mechanism-based Inhibitors of the Human Sirtuin 5 Deacylase: Structure-Activity Relationship, Biostructural, and Kinetic Insight

Nima Rajabi, Marina Auth, Kathrin Rentzius Troelsen, Martin Pannek, Dhaval Bhatt, Martin Fontenas, Matthew Hirschey, Clemens Steegborn, Andreas Stahl Madsen, Christian Adam Olsen

22 Citationer (Scopus)

Abstract

The sirtuin enzymes are important regulatory deacylases in a variety of biochemical contexts and may therefore be potential therapeutic targets through either activation or inhibition by small molecules. Here, we describe the discovery of the most potent inhibitor of sirtuin 5 (SIRT5) reported to date. We provide rationalization of the mode of binding by solving co-crystal structures of selected inhibitors in complex with both human and zebrafish SIRT5, which provide insight for future optimization of inhibitors with more “drug-like” properties. Importantly, enzyme kinetic evaluation revealed a slow, tight-binding mechanism of inhibition, which is unprecedented for SIRT5. This is important information when applying inhibitors to probe mechanisms in biology.

Originalsprog	Engelsk
Tidsskrift	Angewandte Chemie, Int. Ed.
Vol/bind	56
Udgave nummer	47
Sider (fra-til)	14836-14841
ISSN	1433-7851
DOI	https://doi.org/10.1002/anie.201709050
Status	Udgivet - 20 nov. 2017

Adgang til dokumentet

10.1002/anie.201709050

http://europepmc.org/articles/pmc5814306?pdf=renderLicens: Ikke-specificeret

Citationsformater

@article{c667fa0410b64eff9bc691e422113537,

title = "Mechanism-based Inhibitors of the Human Sirtuin 5 Deacylase: Structure-Activity Relationship, Biostructural, and Kinetic Insight",

abstract = "The sirtuin enzymes are important regulatory deacylases in a variety of biochemical contexts and may therefore be potential therapeutic targets through either activation or inhibition by small molecules. Here, we describe the discovery of the most potent inhibitor of sirtuin 5 (SIRT5) reported to date. We provide rationalization of the mode of binding by solving co-crystal structures of selected inhibitors in complex with both human and zebrafish SIRT5, which provide insight for future optimization of inhibitors with more “drug-like” properties. Importantly, enzyme kinetic evaluation revealed a slow, tight-binding mechanism of inhibition, which is unprecedented for SIRT5. This is important information when applying inhibitors to probe mechanisms in biology.",

author = "Nima Rajabi and Marina Auth and Troelsen, {Kathrin Rentzius} and Martin Pannek and Dhaval Bhatt and Martin Fontenas and Matthew Hirschey and Clemens Steegborn and Madsen, {Andreas Stahl} and Olsen, {Christian Adam}",

year = "2017",

month = nov,

day = "20",

doi = "10.1002/anie.201709050",

language = "English",

volume = "56",

pages = "14836--14841",

journal = "Angewandte Chemie, Int. Ed.",

issn = "1433-7851",

publisher = "Wiley-VCH Verlag GmbH & Co. KGaA",

number = "47",

}

TY - JOUR

T1 - Mechanism-based Inhibitors of the Human Sirtuin 5 Deacylase: Structure-Activity Relationship, Biostructural, and Kinetic Insight

AU - Rajabi, Nima

AU - Auth, Marina

AU - Troelsen, Kathrin Rentzius

AU - Pannek, Martin

AU - Bhatt, Dhaval

AU - Fontenas, Martin

AU - Hirschey, Matthew

AU - Steegborn, Clemens

AU - Madsen, Andreas Stahl

AU - Olsen, Christian Adam

PY - 2017/11/20

Y1 - 2017/11/20

N2 - The sirtuin enzymes are important regulatory deacylases in a variety of biochemical contexts and may therefore be potential therapeutic targets through either activation or inhibition by small molecules. Here, we describe the discovery of the most potent inhibitor of sirtuin 5 (SIRT5) reported to date. We provide rationalization of the mode of binding by solving co-crystal structures of selected inhibitors in complex with both human and zebrafish SIRT5, which provide insight for future optimization of inhibitors with more “drug-like” properties. Importantly, enzyme kinetic evaluation revealed a slow, tight-binding mechanism of inhibition, which is unprecedented for SIRT5. This is important information when applying inhibitors to probe mechanisms in biology.

AB - The sirtuin enzymes are important regulatory deacylases in a variety of biochemical contexts and may therefore be potential therapeutic targets through either activation or inhibition by small molecules. Here, we describe the discovery of the most potent inhibitor of sirtuin 5 (SIRT5) reported to date. We provide rationalization of the mode of binding by solving co-crystal structures of selected inhibitors in complex with both human and zebrafish SIRT5, which provide insight for future optimization of inhibitors with more “drug-like” properties. Importantly, enzyme kinetic evaluation revealed a slow, tight-binding mechanism of inhibition, which is unprecedented for SIRT5. This is important information when applying inhibitors to probe mechanisms in biology.

U2 - 10.1002/anie.201709050

DO - 10.1002/anie.201709050

M3 - Journal article

C2 - 29044784

SN - 1433-7851

VL - 56

SP - 14836

EP - 14841

JO - Angewandte Chemie, Int. Ed.

JF - Angewandte Chemie, Int. Ed.

IS - 47

ER -

Mechanism-based Inhibitors of the Human Sirtuin 5 Deacylase: Structure-Activity Relationship, Biostructural, and Kinetic Insight

Abstract

Adgang til dokumentet

Fingeraftryk

Citationsformater