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What Are Benefits of 5-Amino-1MQ Inhibiting NNMT reduces adipocyte size and white adipose mass by shifting fat cells from storage mode to mobilization

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This work was supported by the Department of Defense Peer Reviewed Medical Research Program grant PR141776 (S.J.W.), University of Texas Medical Branch Technology Commercialization Award (S.J.W), and NIH grant R01GM112936 (C.C.F)

Additionally, analogues containing the quinolinium scaffold lacked inhibitory activity against enzymes in the NAD + salvage pathway that bind nicotinamide-containing substrate, including NAMPT[27, 32] and the NAD + -dependent SIRT1 enzyme, which deacetylates NAD + to produce NA, a product inhibitor of SIRT1.[33] These results suggest that quinolinium-based NNMT inhibitors achieve selectivity by specifically interacting with the NA-binding pocket of NNMT,[17] unlike several known non-selective methyltransferase inhibitors that interact with the SAM-binding pocket, which is highly conserved among SAM-dependent methyltransferases.[34, 35] Membrane-permeable NNMT inhibitors reduced intracellular 1-MNA levels in a concentration-dependent manner and at pharmacologically relevant concentrations that did not impact cell viability, suggesting these small molecules interact directly with NNMT in cells