Small Changes Make the Difference for SIRT2: Two Different Binding Modes for 3-Arylmercapto-Acylated Lysine Derivatives.
Biochemistry
; 61(17): 1705-1722, 2022 09 06.
Article
en En
| MEDLINE
| ID: mdl-35972884
ABSTRACT
Sirtuins are protein deacylases regulating metabolism and stress responses and implicated in aging-related diseases. Modulators of the human sirtuins 1-7 are sought as chemical tools and potential therapeutics, for example, for treatment of cancer. We were able to show that 3-aryl-mercapto-succinylated- and 3-benzyl-mercapto-succinylated peptide derivatives yield selective Sirt5 inhibitors with low nM Ki values. Here, we synthesized and characterized 3-aryl-mercapto-butyrylated peptide derivatives as effective and selective sirtuin 2 inhibitors with KD values in the low nanomolar range. According to kinetic measurements and microscale thermophoresis/surface plasmon resonance experiments, the respective inhibitors bind with the 3-aryl-mercapto moiety in the selectivity pocket of Sirtuin 2, inducing a rearrangement of the active site. In contrast, 3-aryl-mercapto-nonalyl or palmitoyl derivatives are characterized by a switch in the binding mode blocking both the hydrophobic channel by the fatty acyl chain and the nicotinamide pocket by the 3-aryl-mercapto moiety.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Sirtuinas
/
Sirtuina 2
Límite:
Humans
Idioma:
En
Revista:
Biochemistry
Año:
2022
Tipo del documento:
Article
País de afiliación:
Alemania