Nicotinamide N-methyltransferase (NNMT) is a cytosolic small molecule methyltransferase enzyme responsible for the conversion of nicotinamide (NA, vitamin B3) to 1-methylnicotinamide (MNA). NNMT utilizes the cofactor S-adenosyl-l-methionine (SAM) as a methyl donor, which is converted to S-adenosyl-l-homocysteine (SAH) upon methylation of nicotinamide (figure 1.)

Under normal physiological conditions, NNMT is primarily expressed in the liver where it plays a key role in the detoxification of xenobiotics. Recently, however, NNMT overexpression has also been found in other tissues, such as adipocytes and a number of human cancers. Elevated NNMT activity is correlated with obesity, insulin resistance and blood glucose levels as well as tumor aggressiveness and is proposed to promote cancer migration, invasion, and proliferation through epigenetic changes.

NNMT acts on both the NAD+ cycle and the methionine cycle as illustrated in figure 2. After methylation of nicotinamide, the MNA formed is excreted, reducing available nicotinamide to participate in the NAD+ cycle. At the same time, the available SAM is converted to SAH leading to a decrease in the SAM/SAH balance also known as the methylation potential of cells. The change in the SAM/SAH balance directly affects other SAM-dependent methyltransferase enzymes involved in gene regulation and transcription.