Novel Propargyl-Linked Bisubstrate Analogues as Tight-Binding Inhibitors for Nicotinamide N-Methyltransferase.

ABSTRACT: Nicotinamide N-methyltransferase (NNMT) catalyzes the methyl transfer from the cofactor S-adenosylmethionine to nicotinamide and other pyridine-containing compounds. NNMT is an important regulator for nicotinamide metabolism and methylation potential. Aberrant expression levels of NNMT have been implicated in cancer, metabolic, and neurodegenerative diseases, which makes NNMT a potential therapeutic target. Therefore, potent and selective NNMT inhibitors can serve as valuable tools to investigate the roles of NNMT in its mediated diseases. Here, we applied a rational strategy to design and synthesize the tight-binding bisubstrate inhibitor LL320 through a novel propargyl linker. LL320 demonstrates a K_i value of 1.6 ± 0.3 nM, which is the most potent inhibito

SUBMITTER: Chen D 

PROVIDER: S-EPMC7296983 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature