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

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Mechanism-based Inhibitors of the Human Sirtuin 5 Deacylase: Structure-Activity Relationship, Biostructural, and Kinetic Insight. / Rajabi, Nima; Auth, Marina; Troelsen, Kathrin Rentzius; Pannek, Martin; Bhatt, Dhaval; Fontenas, Martin; Hirschey, Matthew; Steegborn, Clemens; Madsen, Andreas Stahl; Olsen, Christian Adam.

In: Angewandte Chemie, Int. Ed., Vol. 56, No. 47, 20.11.2017, p. 14836-14841.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Rajabi, N, Auth, M, Troelsen, KR, Pannek, M, Bhatt, D, Fontenas, M, Hirschey, M, Steegborn, C, Madsen, AS & Olsen, CA 2017, 'Mechanism-based Inhibitors of the Human Sirtuin 5 Deacylase: Structure-Activity Relationship, Biostructural, and Kinetic Insight', Angewandte Chemie, Int. Ed., vol. 56, no. 47, pp. 14836-14841. https://doi.org/10.1002/anie.201709050

APA

Rajabi, N., Auth, M., Troelsen, K. R., Pannek, M., Bhatt, D., Fontenas, M., Hirschey, M., Steegborn, C., Madsen, A. S., & Olsen, C. A. (2017). Mechanism-based Inhibitors of the Human Sirtuin 5 Deacylase: Structure-Activity Relationship, Biostructural, and Kinetic Insight. Angewandte Chemie, Int. Ed., 56(47), 14836-14841. https://doi.org/10.1002/anie.201709050

Vancouver

Rajabi N, Auth M, Troelsen KR, Pannek M, Bhatt D, Fontenas M et al. Mechanism-based Inhibitors of the Human Sirtuin 5 Deacylase: Structure-Activity Relationship, Biostructural, and Kinetic Insight. Angewandte Chemie, Int. Ed. 2017 Nov 20;56(47):14836-14841. https://doi.org/10.1002/anie.201709050

Author

Rajabi, Nima ; Auth, Marina ; Troelsen, Kathrin Rentzius ; Pannek, Martin ; Bhatt, Dhaval ; Fontenas, Martin ; Hirschey, Matthew ; Steegborn, Clemens ; Madsen, Andreas Stahl ; Olsen, Christian Adam. / Mechanism-based Inhibitors of the Human Sirtuin 5 Deacylase: Structure-Activity Relationship, Biostructural, and Kinetic Insight. In: Angewandte Chemie, Int. Ed. 2017 ; Vol. 56, No. 47. pp. 14836-14841.

Bibtex

@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 sirtuins. 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 International Edition",
issn = "1433-7851",
publisher = "Wiley-VCH Verlag GmbH & Co. KGaA",
number = "47",

}

RIS

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 sirtuins. 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 sirtuins. 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

VL - 56

SP - 14836

EP - 14841

JO - Angewandte Chemie International Edition

JF - Angewandte Chemie International Edition

SN - 1433-7851

IS - 47

ER -

ID: 184635999