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

Fig 1.tif (4309 kB)
Fig 1

Fig 2.tif (2587 kB)
Fig 2

Fig 3.tif (3122 kB)
Fig 3

Fig 4.tif (3825 kB)
Fig 4

Supporting Information ver 7.pdf (688 kB)
Supporting Info

Share

COinS
 
 

To view the content in your browser, please download Adobe Reader or, alternately,
you may Download the file to your hard drive.

NOTE: The latest versions of Adobe Reader do not support viewing PDF files within Firefox on Mac OS and if you are using a modern (Intel) Mac, there is no official plugin for viewing PDF files within the browser window.