Bisubstrate Inhibitors of Nicotinamide <i>N</i>-Methyltransferase (NNMT) with Enhanced Activity

Gao, Yongzhi; Haren, Matthijs J. van; Moret, Ed E.; Rood, Johannes J.M.; Sartini, Davide; Salvucci, Alessia; Emanuelli, Monica; Craveur, Pierrick; Babault, Nicolas; Jin, Jian; Martin, Nathaniel I.

doi:10.1021/acs.jmedchem.9b00413

Cited by 54 publications

(68 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…If elevated NNMT expression contributes to disease pathogenesis, inhibitors of NNMT may be effective in mitigating this. NNMT is currently the focus of intense drug discovery studies for developing NNMT inhibitors as anti-cancer therapeutics [30,[70][71][72]. Conversely, if elevated NNMT expression is a stress response of the neurone to disease pathogenesis, therapies which induce, or mimic, elevated NNMT expression may be of benefit.…”

Section: Discussionmentioning

confidence: 99%

High Expression of Nicotinamide N-Methyltransferase in Patients with Sporadic Alzheimer’s Disease

et al. 2021

View full text Add to dashboard Cite

We have previously shown that the expression of nicotinamide N-methyltransferase (NNMT) is significantly increased in the brains of patients who have died of Parkinson’s disease (PD). In this study, we have compared the expression of NNMT in post-mortem medial temporal lobe, hippocampus and cerebellum of 10 Alzheimer’s disease (AD) and 9 non-disease control subjects using a combination of quantitative Western blotting, immunohistochemistry and dual-label confocal microscopy coupled with quantitative analysis of colocalisation. NNMT was detected as a single protein of 29 kDa in both AD and non-disease control brains, which was significantly increased in AD medial temporal lobe compared to non-disease controls (7.5-fold, P < 0.026). There was no significant difference in expression in the cerebellum (P = 0.91). NNMT expression in AD medial temporal lobe and hippocampus was present in cholinergic neurones with no glial localisation. Cell-type expression was identical in both non-disease control and AD tissues. These results are the first to show, in a proof-of-concept study using a small patient cohort, that NNMT protein expression is increased in the AD brain and is present in neurones which degenerate in AD. These results suggest that the elevation of NNMT may be a common feature of many neurodegenerative diseases. Confirmation of this overexpression using a larger AD patient cohort will drive the future development of NNMT-targetting therapeutics which may slow or stop the disease pathogenesis, in contrast to current therapies which solely address AD symptoms.

show abstract

Section: Discussionmentioning

confidence: 99%

High Expression of Nicotinamide N-Methyltransferase in Patients with Sporadic Alzheimer’s Disease

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Our X-ray crystallographic data and docking studies guided us to keep the key nitrogen interactions with Val143 intact, while exploring different heteroaryl ring systems. Interestingly, quinolinone (21) showed reasonable potency, whereas the corresponding isoquinolinone derivative (22) was not active. However, the metabolic stability of compounds (21) and (23) did not improve.…”

Section: Optimization Of a Bisubstrate-like Inhibitor Series Based Onmentioning

confidence: 99%

Novel Inhibitors of Nicotinamide-N-Methyltransferase for the Treatment of Metabolic Disorders

et al. 2021

View full text Add to dashboard Cite

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.

show abstract

“…[ 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. [ 10 ] A compelling and unusual feature of NNMT catalysis is that, in the kinetic analysis of N ‐methylation of 4‐phenylpyridine, dimethyl sulfoxide (DMSO) displays competitive inhibitory abilities. [ 11 ] Competitive inhibition of enzymes by substrate analogues is normal and common, [ 12 ] but the fact that solvents act as competitive inhibitors is not fully understood.…”

Section: Introductionmentioning

confidence: 99%

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

Zhang

Cheng

et al. 2020

J of Physical Organic Chem

View full text Add to dashboard Cite

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.

show abstract

Bisubstrate Inhibitors of Nicotinamide N-Methyltransferase (NNMT) with Enhanced Activity

Cited by 54 publications

References 59 publications

High Expression of Nicotinamide N-Methyltransferase in Patients with Sporadic Alzheimer’s Disease

High Expression of Nicotinamide N-Methyltransferase in Patients with Sporadic Alzheimer’s Disease

Novel Inhibitors of Nicotinamide-N-Methyltransferase for the Treatment of Metabolic Disorders

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

Contact Info

Product

Resources

About