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

  • ACS Chem Biol. 2019 Apr 19;14(4):613-618. doi: 10.1021/acschembio.9b00211.
Sudeshna Sen  1  2 ,  Santanu Mondal  1  2 ,  Li Zheng  1  2 ,  Ari J Salinger  1  2 ,  Walter Fast  3 ,  Eranthie Weerapana  4 ,  Paul R Thompson  1  2
Affiliations
  • 1. Department of Biochemistry and Molecular Pharmacology , University of Massachusetts Medical School , 364 Plantation Street , Worcester , Massachusetts 01605 , United States.
  • 2. Program in Chemical Biology , University of Massachusetts Medical School , 364 Plantation Street , Worcester , Massachusetts 01605 , United States.
  • 3. Division of Chemical Biology and Medicinal Chemistry, College of Pharmacy , The University of Texas , Austin , Texas 78712 , United States.
  • 4. Department of Chemistry , Boston College , Chestnut Hill , Massachusetts 02467 , United States.
PMID: 30933557 DOI: 10.1021/acschembio.9b00211
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.

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