NNMT

NNMT (nicotinamide N-methyltransferase) is a cytosolic methyltransferase that transfers a methyl group from S-adenosylmethionine (SAM) to nicotinamide (NAM), generating 1-methylnicotinamide (1-MNA) and S-adenosylhomocysteine (SAH), thereby connecting NAD⁺ metabolism with cellular methyl-donor utilization^[1][2]. Mechanistically, NNMT regulates metabolic homeostasis by influencing intracellular SAM availability, NAD⁺ salvage, and methylation potential, which positions the enzyme at the intersection of energy metabolism and epigenetic control^[1][3][4]. NNMT-driven consumption of methyl donors can create a metabolic methylation sink that remodels histone methylation patterns and alters gene-expression programs in cancer cells^[3]. In disease models, elevated NNMT expression has been associated with obesity, metabolic dysfunction, fibrosis, and multiple malignancies, whereas genetic or pharmacological suppression of NNMT improves metabolic phenotypes and modifies disease progression pathways^[4][5][6]. Compared with related methyltransferases such as GNMT (glycine N-methyltransferase), which primarily regulates systemic SAM/SAH balance through glycine methylation, NNMT directly links NAM turnover to NAD⁺ and one-carbon metabolism, giving it a distinct role in metabolic reprogramming^[2][7]. For experimental applications, selective small-molecule NNMT inhibitors and bisubstrate analogs have been developed as chemical probes to evaluate target engagement, metabolic remodeling, and therapeutic responses in cancer and metabolic disease models^[6][8].