2. Academic Validation
  3. Citrullination Inactivates Nicotinamide- N-methyltransferase

Citrullination Inactivates Nicotinamide- N-methyltransferase

  • ACS Chem Biol. 2018 Sep 21;13(9):2663-2672. doi: 10.1021/acschembio.8b00578.
Venkatesh V Nemmara 1 2,  Ronak Tilvawala 1 2,  Ari J Salinger 1 2,  Lacey Miller 1,  Son Hong Nguyen 1 2,  Eranthie Weerapana 3,  Paul R Thompson 1 2
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Pharmacology , UMass Medical School , 364 Plantation Street , Worcester , Massachusetts 01605 , United States.
  • 2 Program in Chemical Biology , UMass Medical School , 364 Plantation Street , Worcester , Massachusetts 01605 , United States.
  • 3 Department of Chemistry , Boston College , Chestnut Hill , Massachusetts 02467 , United States.
PMID: 30044909 DOI: 10.1021/acschembio.8b00578
Abstract

Nicotinamide- N-methyltransferase (NNMT) catalyzes the irreversible methylation of nicotinamide (NAM) to form N-methyl nicotinamide using S-adenosyl methionine 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 abolished its methyltransferase activity. Herein, we investigate the mechanism of inactivation. Using tandem mass spectrometry, we identified three sites of citrullination in NNMT. With this information in hand, we used a combination of site-directed mutagenesis, kinetics, and circular dichoism experiments to demonstrate that citrullination of R132 leads to a structural perturbation that ultimately promotes NNMT inactivation.

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