Inhibitors of nicotinamide N-methyltransferase designed to mimic the methylation reaction transition state

Haren, Matthijs J. van; Taig, Rebecca; Kuppens, Jilles; Toraño, Javier Sastre; Moret, Ed E.; Parsons, Richard B.; Emanuelli, Monica; Martin, Nathaniel I.

doi:10.1039/c7ob01357d

Cited by 45 publications

(62 citation statements)

References 29 publications

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“…An NNMT covalent inhibitor, RS004 ( 2 ), 27 was reported targeting the Cys165 residue within the SAM-binding pocket, and N-methylated quinolinium compounds 3 and 4 28 were disclosed as substrate mimetic inhibitors. During the preparation of this manuscript, a bisubstrate NNMT inhibitor, 5 , 29 was reported targeting both substrate and cofactor binding sites. However, 5 displayed modest potency (IC 50 = 29 μ M) in a biochemical assay and was not characterized in biophysical assays and selectivity assays.…”

Section: Introductionmentioning

confidence: 99%

Discovery of Bisubstrate Inhibitors of Nicotinamide N-Methyltransferase (NNMT)

et al. 2018

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Nicotinamide N-methyltransferase (NNMT) catalyzes the N-methylation of pyridine-containing compounds using the cofactor S-5'-adenosyl-l-methionine (SAM) as the methyl group donor. Through the regulation of the levels of its substrates, cofactor, and products, NNMT plays an important role in physiology and pathophysiology. Overexpression of NNMT has been implicated in various human diseases. Potent and selective small-molecule NNMT inhibitors are valuable chemical tools for testing biological and therapeutic hypotheses. However, very few NNMT inhibitors have been reported. Here, we describe the discovery of a bisubstrate NNMT inhibitor MS2734 (6) and characterization of this inhibitor in biochemical, biophysical, kinetic, and structural studies. Importantly, we obtained the first crystal structure of human NNMT in complex with a small-molecule inhibitor. The structure of the NNMT-6 complex has unambiguously demonstrated that 6 occupied both substrate and cofactor binding sites. The findings paved the way for developing more potent and selective NNMT inhibitors in the future.

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Section: Introductionmentioning

confidence: 99%

Discovery of Bisubstrate Inhibitors of Nicotinamide N-Methyltransferase (NNMT)

et al. 2018

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“…Further, the role of NNMT in the regulation of hepatic glucose, lipid and cholesterol metabolism was demonstrated using cellular and animal models with adenoviral mediated NNMT knockdown 11 . The identification and characterization of small-molecule NNMT inhibitors has recently been reported 12 , 13 . However, till date there are no reports on the feasibility of using small molecule modulators of NNMT in preclinical animal models of metabolic disease to validate NNMT as a pharmacological drug target.…”

Section: Introductionmentioning

confidence: 99%

A small molecule inhibitor of Nicotinamide N-methyltransferase for the treatment of metabolic disorders

Kannt

Rajagopal

Kadnur

et al. 2018

Sci Rep

101

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Nicotinamide N-methyltransferase (NNMT) is a cytosolic enzyme that catalyzes the transfer of a methyl group from the co-factor S-adenosyl-L-methionine (SAM) onto the substrate, nicotinamide (NA) to form 1-methyl-nicotinamide (MNA). Higher NNMT expression and MNA concentrations have been associated with obesity and type-2 diabetes. Here we report a small molecule analog of NA, JBSNF-000088, that inhibits NNMT activity, reduces MNA levels and drives insulin sensitization, glucose modulation and body weight reduction in animal models of metabolic disease. In mice with high fat diet (HFD)-induced obesity, JBSNF-000088 treatment caused a reduction in body weight, improved insulin sensitivity and normalized glucose tolerance to the level of lean control mice. These effects were not seen in NNMT knockout mice on HFD, confirming specificity of JBSNF-000088. The compound also improved glucose handling in ob/ob and db/db mice albeit to a lesser extent and in the absence of weight loss. Co-crystal structure analysis revealed the presence of the N-methylated product of JBSNF-000088 bound to the NNMT protein. The N-methylated product was also detected in the plasma of mice treated with JBSNF-000088. Hence, JBSNF-000088 may act as a slow-turnover substrate analog, driving the observed metabolic benefits.

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“…Beyond that, the mechanism of NNMT has attracted a lot of attention, and inhibitors mimic substrates have been highlighted by researchers in the field of chemical biology. [ 9 ] Ordered binding mechanism of NNMT is observed in product inhibition and dead‐end analogue inhibition studies, where SAM binds first, followed by NA. [ 1d ] The complicated bi‐substrate inhibitor of NNMT imitating the structures of both NA and SAM behaves stronger inhibitory properties compared with the mono‐substrate inhibitor.…”

Section: Introductionmentioning

confidence: 99%

Solvent inhibition profiles and inverse solvent isotope effects for enzymatic methyl transfer catalyzed by nicotinamideN‐methyltransferase

Zhang

Cheng

et al. 2020

J of Physical Organic Chem

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Nicotinamide N‐methyltransferase (NNMT) catalyzes the methyl transfer from universal methyl donor S‐adenosyl methionine (SAM) to nicotinamide (NA) to form the N‐methylnicotinamide. This important process is related to the level of nicotinamide adenine dinucleotide (NAD+) in vivo; thus, NNMT is regarded as an important drug target linked with various diseases. Although NNMT has been extensively studied in the area of biology and medicine, the detailed mechanism of NNMT is still not clear, especially in the aspect of the role of solvents (water) in the enzyme catalysis. Here, we have examined the effects of three common organic solvents (dimethyl sulfoxide [DMSO], methanol, and acetonitrile) and deuterated water to explore the enzymatic methyl transfer activity by NNMT (wild type [WT]) and its mutants. Competitive inhibition was detected for DMSO and acetonitrile as the solvent, and a subtle inhibitory effect was observed with methanol. Molecular docking suggested DMSO and acetonitrile compete with both cofactor and substrate. However, methanol is mainly bound to compete for the substrate. Furthermore, the activity increased when deuterated water was substituted for water with an inverse solvent isotope effect D2Okcat/Km = 0.49 ± 0.17 for WT and D2Okcat/Km = 0.32 ± 0.08 for Y20F. These effects in this enzymatic methyl transfer system without any metal ion or acid/base catalysis were due to the stabilization of protein provided by deuterated water.

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Inhibitors of nicotinamide N-methyltransferase designed to mimic the methylation reaction transition state

Cited by 45 publications

References 29 publications

Discovery of Bisubstrate Inhibitors of Nicotinamide N-Methyltransferase (NNMT)

Discovery of Bisubstrate Inhibitors of Nicotinamide N-Methyltransferase (NNMT)

A small molecule inhibitor of Nicotinamide N-methyltransferase for the treatment of metabolic disorders

Solvent inhibition profiles and inverse solvent isotope effects for enzymatic methyl transfer catalyzed by nicotinamideN‐methyltransferase

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