Neuroprotective Effects of Nicotinamide<i>N</i>‐Methyltransferase and its Metabolite 1‐Methylnicotinamide

Milani, Zeinab H.; Ramsden, D.; Parsons, Richard B.

doi:10.1002/jbt.21508

Cited by 27 publications

(34 citation statements)

References 34 publications

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“…As to how NNMT-V5 induced SirT expression is unclear. It is possible that MeN, the metabolic product of NNMT N-methylation of nicotinamide, may be responsible, which is supported by our previous studies that demonstrated that MeN increased CxI activity and cellular ATP content in SH-SY5Y cells [10,11]. In accord with this, Xie et al [33] reported that increased MeN production was responsible for the NNMTmediated increase in cellular ATP content in human colorectal cancer cells.…”

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 53%

“…This increase in CxI activity resulted in a subsequent increase in ATP synthesis [10] and protection against a range of mitotoxins [10,11]. The increase in CxI activity observed was mediated via a reduction in the degradation of the NDUFS3 30kDa subunit of CxI [10].…”

Section: Introductionmentioning

confidence: 83%

“…Recent studies which provide compelling evidence of a role for NNMT in the regulation of energy metabolism and cell survival in vitro [10,11,14], in particular NNMT's ability to induce CxI activity, ATP synthesis and synapse formation [10,20], have transformed NNMT from merely a Phase II enzyme into a key mediator of many fundamental processes essential for the maintenance of cellular health and function. This effect upon CxI is of particular interest, as reduced CxI activity is a cardinal feature of PD [9].…”

Section: Page 10 Of 20mentioning

confidence: 99%

“…The S.NNMT.LP cell-line does not closely mimic the dopaminergic neuronal phenotype of the neurons which degenerate in PD, indeed it was our sole original intention to model NNMT expression using a cell-line which has no endogenous expression of NNMT, to provide the ability to investigate the biochemical effects of NNMT upon the cell in isolation [10,11,20]. However, this originated from our research into the expression of NNMT in human PD brain tissue [2,3], thus our studies provide evidence for what may be occurring biochemically within the dopaminergic neuron in the PD brain.…”

Section: Induction Of Nnmt Expression In the Parkinsonian Brain May Bmentioning

confidence: 99%

“…SH-SY5Y human neuroblastoma, which do not endogenously express NNMT, and S.NNMT.LP human neuroblastoma, comprising SH-SY5Y stably expressing NNMT Cterminally tagged to the V5 epitope (NNMT-V5) and produced as part of our ongoing studies [10,11,20], were cultured as previously described. Although SH-SY5Y do not represent a differentiated neurone-like model, they do exhibit pan-neuronal characteristics, express many neuronal markers such as synaptophysin and are readily amenable to genetic manipulation [10,20].…”

Section: Cell Culturementioning

confidence: 99%

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Nicotinamide N-methyltransferase increases complex I activity in SH-SY5Y cells via sirtuin 3

Liu

Mistry

Aguirre

et al. 2015

Biochemical and Biophysical Research Communications

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Nicotinamide N-methyltransferase (NNMT, E.C. 2.1.1.1) N-methylates nicotinamide to 1-methylnicotinamide. We have previously shown that NNMT is significantly overexpressed in the brains of patients who have died of Parkinson's disease, and others have shown that NNMT is significantly overexpressed in a variety of diseases ranging from cancer to hepatic cirrhosis. In vitro overexpression has revealed many cytoprotective effects of NNMT, in particular increased complex I activity and ATP synthesis. Although this appears to be mediated by an increase in 1-methylnicotinamide production, the molecular mechanisms involved remain unclear. In the present study, we have investigated the role that sirtuins 1, 2 and 3, class III DNA deacetylase enzymes known to regulate mitochondrial energy production and cell cycle, have in mediating the effects of NNMT upon complex I activity. Expression of NNMT in SH-SY5Y human neuroblastoma cells, which have no endogenous expression of NNMT, significantly increased the expression of all three sirtuins. siRNA-mediated silencing of sirtuin 3 expression decreased complex I activity in NNMT-expressing SH-SY5Y cells to that observed in wild-type SH-SY5Y, and significantly reduced cellular ATP content also. These results demonstrate that sirtuin 3 is a key mediator of NNMT-induced complex I activity and ATP synthesis. These results further reinforce a central role for NNMT in the regulation of energy homeostasis and provide further mechanistic insight into the consequences of enhanced NNMT expression.

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Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 53%

Section: Introductionmentioning

confidence: 83%

Section: Page 10 Of 20mentioning

confidence: 99%

Section: Induction Of Nnmt Expression In the Parkinsonian Brain May Bmentioning

confidence: 99%

Section: Cell Culturementioning

confidence: 99%

See 3 more Smart Citations

Nicotinamide N-methyltransferase increases complex I activity in SH-SY5Y cells via sirtuin 3

Liu

Mistry

Aguirre

et al. 2015

Biochemical and Biophysical Research Communications

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Nicotinamide N‐methyltransferase expression in SH‐SY5Y human neuroblastoma cells decreases oxidative stress

Mistry

Klamt

Ramsden

et al. 2020

J Biochem & Molecular Tox

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Nicotinamide N‐methyltransferase (NNMT) plays a central role in cellular metabolism, regulating pathways including epigenetic regulation, cell signalling, and energy production. Our previous studies have shown that the expression of NNMT in the human neuroblastoma cell line SH‐SY5Y increased complex I activity and subsequent ATP synthesis. This increase in ATP synthesis was lower than the increase in complex I activity, suggesting uncoupling of the mitochondrial respiratory chain. We, therefore, hypothesised that pathways that reduce oxidative stress are also increased in NNMT‐expressing SH‐Y5Y cells. The expression of uncoupling protein‐2 messenger RNA and protein were significantly increased in NNMT‐expressing cells (57% ± 5.2% and 20.1% ± 1.5%, respectively; P = .001 for both). Total GSH (22 ± 0.3 vs 35.6 ± 1.1 nmol/mg protein), free GSH (21.9 ± 0.2 vs 33.5 ± 1 nmol/mg protein), and GSSG (0.6 ± 0.02 vs 1 ± 0.05 nmol/mg protein; P = .001 for all) concentrations were significantly increased in NNMT‐expressing cells, whereas the GSH:GSSG ratio was decreased (39.4 ± 1.8 vs 32.3 ± 2.5; P = .02). Finally, reactive oxygen species (ROS) content was decreased in NNMT‐expressing cells (0.3 ± 0.08 vs 0.12 ± 0.03; P = .039), as was the concentration of 8‐isoprostane F2α (200 ± 11.5 vs 45 ± 2.6 pg/mg protein; P = .0012). Taken together, these results suggest that NNMT expression reduced ROS generation and subsequent lipid peroxidation by uncoupling the mitochondrial membrane potential and increasing GSH buffering capacity, most likely to compensate for increased complex I activity and ATP production.

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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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Neuroprotective Effects of NicotinamideN‐Methyltransferase and its Metabolite 1‐Methylnicotinamide

Cited by 27 publications

References 34 publications

Nicotinamide N-methyltransferase increases complex I activity in SH-SY5Y cells via sirtuin 3

Nicotinamide N-methyltransferase increases complex I activity in SH-SY5Y cells via sirtuin 3

Nicotinamide N‐methyltransferase expression in SH‐SY5Y human neuroblastoma cells decreases oxidative stress

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

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