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Development of a Suicide Inhibition-Based Protein Labeling Strategy for Nicotinamide N-Methyltransferase.


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.

SUBMITTER: Sen S 

PROVIDER: S-EPMC6644700 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Development of a Suicide Inhibition-Based Protein Labeling Strategy for Nicotinamide N-Methyltransferase.

Sen Sudeshna S   Mondal Santanu S   Zheng Li L   Salinger Ari J AJ   Fast Walter W   Weerapana Eranthie E   Thompson Paul R PR  

ACS chemical biology 20190405 4


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<sup>+</sup> 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 e  ...[more]

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