Nicotinamide N-Methyltransferase (NNMT) is a cytosolic enzyme that plays a crucial role in the methylation of nicotinamide and other pyridines. This enzyme is involved in various biological processes, including the biotransformation and detoxification of xenobiotic compounds. NNMT is found in human fat cells and the liver, where it catalyzes the N-methylation of nicotinamide to form methylnicotinamide .
NNMT is composed of 264 amino acids and is responsible for the N-methylation of nicotinamide, using S-adenosylmethionine (SAM) as a methyl donor. This reaction converts nicotinamide into methylnicotinamide and S-adenosyl-L-homocysteine (SAH). The enzyme’s activity is essential for maintaining cellular methylation potential, impacting DNA and histone epigenetic modifications .
NNMT overexpression has been observed in various solid cancer tissues and body fluids, including serum, urine, and saliva. This overexpression is associated with increased tumorigenesis and chemoresistance. NNMT knockdown has been shown to significantly decrease tumorigenesis and chemoresistance capacity. Additionally, natural NNMT inhibitors, such as yuanhuadine, have demonstrated the ability to reverse resistance to epidermal growth factor receptor tyrosine kinase inhibitors in lung cancer cells .
NNMT activity increases with age and is closely associated with the onset and progression of age-related diseases. The enzyme’s activity depletes nicotinamide, a precursor of nicotinamide adenine dinucleotide (NAD+), and generates SAH, a precursor of homocysteine (Hcy). The reduction in NAD+ levels and the increase in Hcy levels are considered important factors in the aging process and age-related diseases. RNA interference (RNAi) therapies and small-molecule inhibitors targeting NNMT have shown potential in combating aging and its related pathologies .
Given its role in cancer and aging, NNMT has emerged as a promising therapeutic target. The development of more potent and selective NNMT inhibitors could provide new avenues for cancer treatment and anti-aging therapies. However, further research is needed to elucidate the precise mechanisms by which NNMT influences these processes and to develop targeted pharmaceutical interventions .