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
PubMed ID
30933557
Repository Citation
Sen S, Mondal S, Zheng L, Salinger AJ, Fast W, Weerapana E, Thompson PR. (2019). Development of a Suicide Inhibition-Based Protein Labeling Strategy for Nicotinamide N-Methyltransferase. University of Massachusetts Medical School Publications. https://doi.org/10.1021/acschembio.9b00211. Retrieved from https://escholarship.umassmed.edu/publications/15
Included in
Amino Acids, Peptides, and Proteins Commons, Biochemistry Commons, Cancer Biology Commons, Enzymes and Coenzymes Commons, Medicinal and Pharmaceutical Chemistry Commons, Medicinal-Pharmaceutical Chemistry Commons