Department of Biochemistry and Molecular Pharmacology; Program in Chemical Biology; Thompson Lab
Biochemistry | Enzymes and Coenzymes | Medicinal-Pharmaceutical Chemistry | Therapeutics
Nicotinamide-N-methyl transferase (NNMT) catalyzes the irreversible methylation of nicotinamide (NAM) to form N-methyl nicotinamide (MeNAM) using SAM as a methyl donor. NNMT is implicated in several chronic disease conditions, including cancers, kidney disease, cardiovascular disease, and Parkinson's disease. Although phosphorylation of NNMT in gastric tumors is reported, the functional effects of this post-translational modification has not been investigated. We previously reported that citrullination of NNMT by Protein Arginine Deiminases (PADs) abolished its methyltransferase activity. Herein, we investigate the mechanism of inactivation. Using tandem MS, we identified three sites of citrullination in NNMT. With this information in hand, we used a combination of site-directed mutagenesis, kinetics, and CD experiments to demonstrate that citrullination of R132 leads to a structural perturbation that ultimately promotes NNMT inactivation.
Nicotinamide-N-methyl transferase, NNMT, citrullination, Protein Arginine Deiminases (PADs)
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This document is the Accepted Manuscript version of a Published Work that will appear in final form in ACS Chemical Biology, copyright © 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.8b00578.
DOI of Published Version
ACS Chem Biol. 2018 Jul 25. doi: 10.1021/acschembio.8b00578. [Epub ahead of print] Link to article on publisher's site
ACS Chemical Biology
Nemmara, Venkatesh V.; Tilvawala, Ronak; Salinger, Ari J.; Miller, Lacey; Nguyen, Son Hong; Weerapana, Eranthie; and Thompson, Paul R., "Citrullination Inactivates Nicotinamide-N-methyltransferase" (2018). Thompson Lab Publications. 117.