UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology; Program in Chemical Biology; Thompson Lab

Publication Date


Document Type

Article Postprint


Amino Acids, Peptides, and Proteins | Biochemistry | Cancer Biology | Enzymes and Coenzymes | Medicinal and Pharmaceutical Chemistry | Medicinal-Pharmaceutical Chemistry


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.


Nicotinamide N-methytransferase, NNMT, enzymes, suicide substrates

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This document is the Accepted Manuscript version of a Published Work that appeared in final form in ACS Chemical Biology, copyright © 2019 American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see Accepted manuscript posted after 12 months as allowed by publisher's Journal Publishing Agreement User’s Guide at

DOI of Published Version



Sen S, Mondal S, Zheng L, Salinger AJ, Fast W, Weerapana E, Thompson PR. 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. Epub 2019 Apr 5. PubMed PMID: 30933557. Link to article on publisher's site

Journal/Book/Conference Title

ACS Chemical Biology

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Link to article in PubMed

PubMed ID


Available for download on Sunday, April 19, 2020