Mechanism-Based Inhibitors of the Human Sirtuin 5 Deacylase: Structure-Activity Relationship, Biostructural, and Kinetic Insight.
Angew Chem Int Ed Engl
; 56(47): 14836-14841, 2017 11 20.
Article
en En
| MEDLINE
| ID: mdl-29044784
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Sirtuinas
/
Inhibidores de Histona Desacetilasas
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Angew Chem Int Ed Engl
Año:
2017
Tipo del documento:
Article
País de afiliación:
Dinamarca