Development of a Suicide Inhibition-Based Protein Labeling Strategy for Nicotinamide N-Methyltransferase.
ACS Chem Biol
; 14(4): 613-618, 2019 04 19.
Article
en En
| MEDLINE
| ID: mdl-30933557
ABSTRACT
Nicotinamide N-methyltransferase (NNMT) catalyzes the S-adenosyl-l-methionine-dependent methylation of nicotinamide to form N-methylnicotinamide. This enzyme detoxifies xenobiotics and regulates NAD+ biosynthesis. Additionally, NNMT is overexpressed in various cancers. Herein, we describe the first NNMT-targeted suicide substrates. These compounds, which include 4-chloropyridine and 4-chloronicotinamide, exploit the broad substrate scope of NNMT; methylation of the pyridine nitrogen enhances the electrophilicity of the C4 position, thereby promoting an aromatic nucleophilic substitution by C159, a noncatalytic cysteine. On the basis of this activity, we developed a suicide inhibition-based protein labeling strategy using an alkyne-substituted 4-chloropyridine that selectively labels NNMT in vitro and in cells. In total, this study describes the first NNMT-directed activity-based probes.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Proteínas
/
Nicotinamida N-Metiltransferasa
Límite:
Humans
Idioma:
En
Revista:
ACS Chem Biol
Año:
2019
Tipo del documento:
Article
País de afiliación:
Estados Unidos