Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGLCPE8)

• DOT Name: Phenylethanolamine N-methyltransferase (PNMT)
• Synonyms: PNMTase; EC 2.1.1.28; Noradrenaline N-methyltransferase
• Gene Name: PNMT
• UniProt ID: PNMT_HUMAN
• PDB ID: 1HNN ; 1N7I ; 1N7J ; 1YZ3 ; 2AN3 ; 2AN4 ; 2AN5 ; 2G70 ; 2G71 ; 2G72 ; 2G8N ; 2OBF ; 2ONY ; 2ONZ ; 2OPB ; 3HCA ; 3HCB ; 3HCC ; 3HCD ; 3HCE ; 3HCF ; 3KPJ ; 3KPU ; 3KPV ; 3KPW ; 3KPY ; 3KQM ; 3KQO ; 3KQP ; 3KQQ ; 3KQS ; 3KQT ; 3KQV ; 3KQW ; 3KQY ; 3KR0 ; 3KR1 ; 3KR2 ; 4DM3 ; 4MIK ; 4MQ4 ; 6WS1 ; 7TWU ; 7TX2
• EC Number: 2.1.1.28
• Pfam ID: PF01234
• Sequence:
  MSGADRSPNAGAAPDSAPGQAAVASAYQRFEPRAYLRNNYAPPRGDLCNPNGVGPWKLRC
  LAQTFATGEVSGRTLIDIGSGPTVYQLLSACSHFEDITMTDFLEVNRQELGRWLQEEPGA
  FNWSMYSQHACLIEGKGECWQDKERQLRARVKRVLPIDVHQPQPLGAGSPAPLPADALVS
  AFCLEAVSPDLASFQRALDHITTLLRPGGHLLLIGALEESWYLAGEARLTVVPVSEEEVR
  EALVRSGYKVRDLRTYIMPAHLQTGVDDVKGVFFAWAQKVGL
• Function: Catalyzes the transmethylation of nonepinephrine (noradrenaline) to form epinephrine (adrenaline), using S-adenosyl-L-methionine as the methyl donor. Other substrates include phenylethanolamine and octopamine. Also methylates normetanephrine.
• KEGG Pathway:
  Tyrosine metabolism (hsa00350)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Catecholamine biosynthesis (R-HSA-209905)
• BioCyc Pathway: MetaCyc:HS06868-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Phenylethanolamine N-methyltransferase (PNMT).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Phenylethanolamine N-methyltransferase (PNMT).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Phenylethanolamine N-methyltransferase (PNMT).	[2]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Phenylethanolamine N-methyltransferase (PNMT).	[3]
Phenobarbital	DMXZOCG	Approved	Phenobarbital decreases the expression of Phenylethanolamine N-methyltransferase (PNMT).	[4]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Phenylethanolamine N-methyltransferase (PNMT).	[5]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Phenylethanolamine N-methyltransferase (PNMT).	[6]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Phenylethanolamine N-methyltransferase (PNMT).	[7]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Phenylethanolamine N-methyltransferase (PNMT).	[9]

References

• [1] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [2] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [3] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [4] Dose- and time-dependent effects of phenobarbital on gene expression profiling in human hepatoma HepaRG cells. Toxicol Appl Pharmacol. 2009 Feb 1;234(3):345-60.
• [5] Genistein disrupts glucocorticoid receptor signaling in human uterine endometrial Ishikawa cells. Environ Health Perspect. 2015 Jan;123(1):80-7. doi: 10.1289/ehp.1408437. Epub 2014 Aug 19.
• [6] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [7] Nicotine promotes cell proliferation via alpha7-nicotinic acetylcholine receptor and catecholamine-synthesizing enzymes-mediated pathway in human colon adenocarcinoma HT-29 cells. Toxicol Appl Pharmacol. 2007 Jun 15;221(3):261-7. doi: 10.1016/j.taap.2007.04.002. Epub 2007 Apr 12.
• [8] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [9] Cellular reactions to long-term volatile organic compound (VOC) exposures. Sci Rep. 2016 Dec 1;6:37842. doi: 10.1038/srep37842.