Mechanism-Based Inhibitors of the Human Sirtuin 5 Deacylase: Structure-Activity Relationship, Biostructural, and Kinetic Insight.
Mechanism-Based Inhibitors of the Human Sirtuin 5 Deacylase: Structure-Activity Relationship, Biostructural, and Kinetic Insight.
复制标题
DOI：
10.1002/anie.201709050
复制
发表时间：
2017-11-20
期刊：
影响因子：
--
通讯作者：
Olsen CA
中科院分区：
文献类型：
--
作者：
Rajabi N;Auth M;Troelsen KR;Pannek M;Bhatt DP;Fontenas M;Hirschey MD;Steegborn C;Madsen AS;Olsen CA
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. SAR study of mechanism-based inhibitors, combined with structural insight from X-ray co-crystal structures provide potent inhibitors of the sirtuin 5 hydrolase. Kinetic investigations furthermore reveal unprecedented slow, tight-binding behaviour of several compounds.
登录
查看更多内容
DOI：
10.1006/bbrc.2000.3000
发表时间：
2000-07-05
影响因子：
3.1
作者：
Frye, RA
通讯作者：
Frye, RA
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
29
作者：
Anderson KA;Huynh FK;Fisher-Wellman K;Stuart JD;Peterson BS;Douros JD;Wagner GR;Thompson JW;Madsen AS;Green MF;Sivley RM;Ilkayeva OR;Stevens RD;Backos DS;Capra JA;Olsen CA;Campbell JE;Muoio DM;Grimsrud PA;Hirschey MD
通讯作者：
Hirschey MD
影响因子：
4.8
作者：
Madsen, Andreas S.;Andersen, Christian;Olsen, Christian A.
通讯作者：
Olsen, Christian A.
影响因子：
7.3
作者：
Galleano, Iacopo;Schiedel, Matthias;Olsen, Christian A.
通讯作者：
Olsen, Christian A.