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5-Amino-1-methylquinolinium (5-amino-1MQ) is a small-molecule inhibitor of nicotinamide N-methyltransferase (NNMT), an enzyme that catalyzes the methylation of nicotinamide using S-adenosyl-L-methionine (SAM) as a methyl donor. NNMT activity intersects two critical metabolic pathways: the NAD⁺ salvage pathway and one-carbon methyl-group metabolism. Elevated NNMT expression has been documented in adipose tissue, liver, and stromal compartments during obesity, insulin resistance, and certain cancers. [netnewsledger.com], [frontiersin.org], [link.springer.com]
By competitively inhibiting NNMT, 5-amino-1MQ reduces the formation of 1-methylnicotinamide (1-MNA), thereby preserving nicotinamide for NAD⁺ biosynthesis and conserving methyl donors for epigenetic processes. This biochemical shift increases intracellular NAD⁺ availability, which supports mitochondrial oxidative metabolism and enhances the activity of NAD⁺-dependent enzymes such as sirtuins (e.g., SIRT1), key regulators of energy homeostasis and chromatin remodeling. [fluxlabsusa.com], [nature.com]
In diet-induced obese (DIO) mouse models, NNMT inhibition via 5-amino-1MQ has been associated with:
Mechanistically, these effects are linked to enhanced mitochondrial respiration, increased fatty acid oxidation, and improved metabolic flexibility. Importantly, NNMT inhibition does not act as a central nervous system stimulant; rather, it exerts its influence at the enzymatic level, making it a valuable research tool for studying metabolic regulation. [fluxlabsusa.com]
Current investigations focus on NNMT inhibition as a strategy to explore: