Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFM38GU)

• DOT Name: Nicotinamide N-methyltransferase (NNMT)
• Synonyms: EC 2.1.1.1
• Gene Name: NNMT
• UniProt ID: NNMT_HUMAN
• PDB ID: 2IIP; 3ROD; 5YJF; 6CHH; 6ORR; 6PVE; 6PVS; 7BKG; 7BLE; 7EGU; 7EHZ; 7EI2; 7ET7; 7EU5; 7NBJ; 7NBM; 7NBQ; 7RKK; 7RKL; 7SOK; 7WMC; 7WMT
• EC Number: 2.1.1.1
• Pfam ID: PF01234
• Sequence:
  MESGFTSKDTYLSHFNPRDYLEKYYKFGSRHSAESQILKHLLKNLFKIFCLDGVKGDLLI
  DIGSGPTIYQLLSACESFKEIVVTDYSDQNLQELEKWLKKEPEAFDWSPVVTYVCDLEGN
  RVKGPEKEEKLRQAVKQVLKCDVTQSQPLGAVPLPPADCVLSTLCLDAACPDLPTYCRAL
  RNLGSLLKPGGFLVIMDALKSSYYMIGEQKFSSLPLGREAVEAAVKEAGYTIEWFEVISQ
  SYSSTMANNEGLFSLVARKLSRPL
• Function: Catalyzes the N-methylation of nicotinamide using the universal methyl donor S-adenosyl-L-methionine to form N1-methylnicotinamide and S-adenosyl-L-homocysteine, a predominant nicotinamide/vitamin B3 clearance pathway. Plays a central role in regulating cellular methylation potential, by consuming S-adenosyl-L-methionine and limiting its availability for other methyltransferases. Actively mediates genome-wide epigenetic and transcriptional changes through hypomethylation of repressive chromatin marks, such as H3K27me3. In a developmental context, contributes to low levels of the repressive histone marks that characterize pluripotent embryonic stem cell pre-implantation state. Acts as a metabolic regulator primarily on white adipose tissue energy expenditure as well as hepatic gluconeogenesis and cholesterol biosynthesis. In white adipocytes, regulates polyamine flux by consuming S-adenosyl-L-methionine which provides for propylamine group in polyamine biosynthesis, whereas by consuming nicotinamide controls NAD(+) levels through the salvage pathway. Via its product N1-methylnicotinamide regulates protein acetylation in hepatocytes, by repressing the ubiquitination and increasing the stability of SIRT1 deacetylase. Can also N-methylate other pyridines structurally related to nicotinamide and play a role in xenobiotic detoxification.
• Tissue Specificity: Predominantly expressed in the liver. A lower expression is seen in the kidney, lung, skeletal muscle, placenta and heart. Not detected in the brain or pancreas.
• KEGG Pathway:
  Nicoti.te and nicoti.mide metabolism (hsa00760)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Nicotinamide salvaging (R-HSA-197264)
  Metabolism of ingested SeMet, Sec, MeSec into H2Se (R-HSA-2408508)
  Methylation (R-HSA-156581)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Regulation of Drug Effects of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Glutathione	DMAHMT9	Approved	Nicotinamide N-methyltransferase (NNMT) increases the abundance of Glutathione.	[21]
Oxidized glutathione	DM9EQC0	Approved	Nicotinamide N-methyltransferase (NNMT) increases the abundance of Oxidized glutathione.	[21]

21 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Nicotinamide N-methyltransferase (NNMT).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Nicotinamide N-methyltransferase (NNMT).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Nicotinamide N-methyltransferase (NNMT).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Nicotinamide N-methyltransferase (NNMT).	[4]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Nicotinamide N-methyltransferase (NNMT).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Nicotinamide N-methyltransferase (NNMT).	[6]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Nicotinamide N-methyltransferase (NNMT).	[7]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Nicotinamide N-methyltransferase (NNMT).	[8]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Nicotinamide N-methyltransferase (NNMT).	[9]
Dasatinib	DMJV2EK	Approved	Dasatinib increases the expression of Nicotinamide N-methyltransferase (NNMT).	[10]
Clozapine	DMFC71L	Approved	Clozapine increases the expression of Nicotinamide N-methyltransferase (NNMT).	[11]
Gemcitabine	DMSE3I7	Approved	Gemcitabine increases the expression of Nicotinamide N-methyltransferase (NNMT).	[12]
Benzatropine	DMF7EXL	Approved	Benzatropine increases the expression of Nicotinamide N-methyltransferase (NNMT).	[11]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Nicotinamide N-methyltransferase (NNMT).	[13]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Nicotinamide N-methyltransferase (NNMT).	[14]
Seocalcitol	DMKL9QO	Phase 3	Seocalcitol decreases the expression of Nicotinamide N-methyltransferase (NNMT).	[15]
Atorvastatin	DMF28YC	Phase 3 Trial	Atorvastatin increases the expression of Nicotinamide N-methyltransferase (NNMT).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Nicotinamide N-methyltransferase (NNMT).	[17]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Nicotinamide N-methyltransferase (NNMT).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Nicotinamide N-methyltransferase (NNMT).	[19]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of Nicotinamide N-methyltransferase (NNMT).	[20]

References

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• [2] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [3] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [4] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [5] Gene expression profiling of human peri-implantation endometria between natural and stimulated cycles. Fertil Steril. 2008 Dec;90(6):2152-64.
• [6] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [7] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [8] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [9] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [10] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [11] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [12] Gene expression profiling of breast cancer cells in response to gemcitabine: NF-kappaB pathway activation as a potential mechanism of resistance. Breast Cancer Res Treat. 2007 Apr;102(2):157-72.
• [13] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [14] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [15] Expression profiling in squamous carcinoma cells reveals pleiotropic effects of vitamin D3 analog EB1089 signaling on cell proliferation, differentiation, and immune system regulation. Mol Endocrinol. 2002 Jun;16(6):1243-56.
• [16] Atorvastatin and pravastatin stimulate nitric oxide and reactive oxygen species generation, affect mitochondrial network architecture and elevate nicotinamide N-methyltransferase level in endothelial cells. J Appl Toxicol. 2021 Jul;41(7):1076-1088. doi: 10.1002/jat.4094. Epub 2020 Oct 19.
• [17] Effect of benzo[a]pyrene on proliferation and metastasis of oral squamous cell carcinoma cells: A transcriptome analysis based on RNA-seq. Environ Toxicol. 2022 Nov;37(11):2589-2604. doi: 10.1002/tox.23621. Epub 2022 Jul 23.
• [18] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [19] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [20] Gene expression signature-based chemical genomic prediction identifies a novel class of HSP90 pathway modulators. Cancer Cell. 2006 Oct;10(4):321-30.
• [21] Nicotinamide N-methyltransferase expression in SH-SY5Y human neuroblastoma cells decreases oxidative stress. J Biochem Mol Toxicol. 2020 Mar;34(3):e22439. doi: 10.1002/jbt.22439. Epub 2020 Jan 7.