Development of a Suicide Inhibition-Based Protein Labeling Strategy for Nicotinamide N-Methyltransferase
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Authors
Sen, SudeshnaMondal, Santanu
Zheng, Li
Salinger, Ari J.
Fast, Walter
Weerapana, Eranthie
Thompson, Paul R
UMass Chan Affiliations
Thompson LabProgram in Chemical Biology
Department of Biochemistry and Molecular Pharmacology
Document Type
Accepted ManuscriptPublication Date
2019-04-19Keywords
Nicotinamide N-methytransferaseNNMT
enzymes
suicide substrates
Amino Acids, Peptides, and Proteins
Biochemistry
Cancer Biology
Enzymes and Coenzymes
Medicinal and Pharmaceutical Chemistry
Medicinal-Pharmaceutical Chemistry
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Show full item recordAbstract
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.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
DOI
10.1021/acschembio.9b00211Permanent Link to this Item
http://hdl.handle.net/20.500.14038/46405PubMed ID
30933557Related Resources
Rights
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.ae974a485f413a2113503eed53cd6c53
10.1021/acschembio.9b00211