TY - JOUR
T1 - Citrullination Inactivates Nicotinamide-N-methyltransferase
AU - Nemmara, Venkatesh V.
AU - Tilvawala, Ronak
AU - Salinger, Ari J.
AU - Miller, Lacey
AU - Nguyen, Son Hong
AU - Weerapana, Eranthie
AU - Thompson, Paul R.
N1 - Publisher Copyright:
Copyright © 2018 American Chemical Society.
PY - 2018/9/21
Y1 - 2018/9/21
N2 - 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.
AB - 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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U2 - 10.1021/acschembio.8b00578
DO - 10.1021/acschembio.8b00578
M3 - Article
C2 - 30044909
AN - SCOPUS:85050744757
SN - 1554-8929
VL - 13
SP - 2663
EP - 2672
JO - ACS Chemical Biology
JF - ACS Chemical Biology
IS - 9
ER -