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. 2018 Jun 5;8:8637. doi: 10.1038/s41598-018-26882-8

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© The Author(s) 2018

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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NNMT links NAD⁺ and methionine metabolism. NA is metabolized to NAM via the amidation pathway. NA and NAM are the common forms of Vitamin B₃, and are converted to NAD⁺ through the Preiss-Handler and salvage pathways, respectively. NAD⁺ is metabolized to NAM by the enzymatic activities of NAD⁺-consuming enzymes (Sirtuins, PARPs, cADPR synthases). NNMT methylates NAM, using SAM as a methyl donor, yielding MNA and SAH. MNA and its oxidation products, 2PY and 4PY are major metabolites of NAM. GNMT, GAMT and PEMT are the main methyltransferases mediating SAM catabolism in the liver. BHMT1 is the enzyme for the re-methylation of homocysteine to generate methionine. Abbreviations: NA, nicotinic acid; NAM, nicotinamide; NAD, nicotinamide adenine dinucleotide; NMN, nicotinamide mononucleotide; PARP, poly adenosine diphosphate ribose polymerase; cADPR, cyclic adenosine diphosphate-ribose; NAMPT, nicotinamide phosphoribosyltransferase; NNMT, nicotinamide N-methyltransferase; MNA, 1-methylnicotinamide; 2PY, N-methyl-2-pyridone-5-carboxamide; 4PY, N-methyl-4-pyridone-5-carboxamide; SAM, S-adenosylmethionine; SAH, S-adenosylhomocysteine; GNMT, glycine N-methyltransferase; GAMT, guanidinoacetate N-methyltransferase; PEMT, phosphatidylethanolamine N-methyltransferase; BHMT, betaine homocysteine methyltransferase.