Thompson Lab's Venkatesh Nemmara Publishes Paper in ACS Chemical Biology

Date Posted: Monday, August 27, 2018

Citrullination Inactivates Nicotinamide‑N‑methyltransferase

NNMTNicotinamide-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. We investigated for the first time, the functional effects of post-translational modification on NNMT. We discovered that citrullination of NNMT by Protein Arginine Deiminases (PADs) abolished its methyltransferase activity. 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 dichroism experiments to demonstrate that citrullination of R132 leads to a structural perturbation that ultimately promotes NNMT inactivation.

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