UMMS Affiliation

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

Publication Date

2019-04-19

Document Type

Article Postprint

Disciplines

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

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.

Keywords

Nicotinamide N-methytransferase, NNMT, enzymes, suicide substrates

Rights and Permissions

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 https://doi.org/10.1021/acschembio.9b00211. Accepted manuscript posted after 12 months as allowed by publisher's Journal Publishing Agreement User’s Guide at https://pubs.acs.org/userimages/ContentEditor/1285231362937/jpa_user_guide.pdf.

DOI of Published Version

10.1021/acschembio.9b00211

Source

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

Related Resources

Link to article in PubMed

PubMed ID

30933557

Available for download on Sunday, April 19, 2020

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