Abstract
Nicotinamide-N-methyltransferase (NNMT) is a cytosolic enzyme catalyzing the transfer of a methyl group from S-adenosyl-methionine (SAM) to nicotinamide (Nam). It is expressed in many tissues including the liver, adipose tissue, and skeletal muscle. Its expression in several cancer cell lines has been widely discussed in the literature, and recent work established a link between NNMT expression and metabolic diseases. Here we describe our approach to identify potent small molecule inhibitors of NNMT featuring different binding modes as elucidated by X-ray crystallographic studies.
Highlights
Nicotinamide-N-methyltransferase (NNMT) is a cytosolic enzyme that catalyzes the transfer of a methyl group from S-adenosyl-methionine (SAM) to nicotinamide (Nam), yielding S-adenosyl-homocysteine (SAH) and 1-methylnicotinamide (MNam) [1,2]
The binding mode of these inhibitors has been elucidated by X-ray crystallography and we used this information for the design of the novel inhibitors (33)
Our bisubstrate inhibitors posed a significant challenge for optimization towards acceptable metabolic stabilities while maintaining sufficient in vitro inhibitory potency
Summary
Nicotinamide-N-methyltransferase (NNMT) is a cytosolic enzyme that catalyzes the transfer of a methyl group from S-adenosyl-methionine (SAM) to nicotinamide (Nam), yielding S-adenosyl-homocysteine (SAH) and 1-methylnicotinamide (MNam) [1,2]. It is expressed in most tissues including the liver, adipose tissue, and skeletal muscle [3], and in several human cancers [4]. Interventions to improve metabolic health such as exercise and bariatric surgery were shown to decrease adipose NNMT expression and plasma MNam levels in obese individuals with insulin resistance or T2D [10]
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