Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKXRUL9)

• DOT Name: Phosphatidylethanolamine N-methyltransferase (PEMT)
• Synonyms: PEAMT; PEMT; EC 2.1.1.17; EC 2.1.1.71; PEMT2; Phospholipid methyltransferase; PLMT
• Gene Name: PEMT
• UniProt ID: PEMT_HUMAN
• EC Number: 2.1.1.17; 2.1.1.71
• Pfam ID: PF04191
• Sequence:
  MTRLLGYVDPLDPSFVAAVITITFNPLYWNVVARWEHKTRKLSRAFGSPYLACYSLSVTI
  LLLNFLRSHCFTQAMLSQPRMESLDTPAAYSLGLALLGLGVVLVLSSFFALGFAGTFLGD
  YFGILKEARVTVFPFNILDNPMYWGSTANYLGWAIMHASPTGLLLTVLVALTYIVALLYE
  EPFTAEIYRQKASGSHKRS
• Function: Catalyzes the three sequential steps of the methylation pathway for the biosynthesis of phosphatidylcholine, a critical and essential component for membrane structure. Uses S-adenosylmethionine (S-adenosyl-L-methionine, SAM or AdoMet) as the methyl group donor for the methylation of phosphatidylethanolamine (1,2-diacyl-sn-glycero-3-phosphoethanolamine, PE) to phosphatidylmonomethylethanolamine (1,2-diacyl-sn-glycero-3-phospho-N-methylethanolamine, PMME), PMME to phosphatidyldimethylethanolamine (1,2-diacyl-sn-glycero-3-phospho-N,N-dimethylethanolamine, PDME), and PDME to phosphatidylcholine (1,2-diacyl-sn-glycero-3-phosphocholine, PC), producing S-adenosyl-L-homocysteine in each step. Responsible for approximately 30% of hepatic PC with the CDP-choline pathway accounting for the other 70% (Probable); [Isoform 1]: Catalyzes the three sequential steps of the methylation of 1,2-diacyl-sn-glycero-3-phospho-N-methylethanolamine (PMME) to 1,2-diacyl-sn-glycero-3-phospho-N,N-dimethylethanolamine (PDME) more efficiently than isoform 2. Induces increase in PC species with longer polyunsaturated chains than isoform 2 ; [Isoform 2]: Produces a higher increase in the level of PC species containing long chains with three double bonds than isoform 1.
• Tissue Specificity: Primarily expressed in liver (at protein level).
• KEGG Pathway:
  Glycerophospholipid metabolism (hsa00564)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Synthesis of PC (R-HSA-1483191)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Phosphatidylethanolamine N-methyltransferase (PEMT) affects the response to substance of Arsenic.	[16]
Choline	DM5D9YK	Investigative	Phosphatidylethanolamine N-methyltransferase (PEMT) affects the response to substance of Choline.	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Phosphatidylethanolamine N-methyltransferase (PEMT).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Phosphatidylethanolamine N-methyltransferase (PEMT).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Phosphatidylethanolamine N-methyltransferase (PEMT).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Phosphatidylethanolamine N-methyltransferase (PEMT).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Phosphatidylethanolamine N-methyltransferase (PEMT).	[5]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Phosphatidylethanolamine N-methyltransferase (PEMT).	[6]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Phosphatidylethanolamine N-methyltransferase (PEMT).	[7]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Phosphatidylethanolamine N-methyltransferase (PEMT).	[8]
Fenofibrate	DMFKXDY	Approved	Fenofibrate increases the expression of Phosphatidylethanolamine N-methyltransferase (PEMT).	[8]
Mifepristone	DMGZQEF	Approved	Mifepristone decreases the expression of Phosphatidylethanolamine N-methyltransferase (PEMT).	[9]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Phosphatidylethanolamine N-methyltransferase (PEMT).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Phosphatidylethanolamine N-methyltransferase (PEMT).	[11]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Phosphatidylethanolamine N-methyltransferase (PEMT).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Phosphatidylethanolamine N-methyltransferase (PEMT).	[13]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Phosphatidylethanolamine N-methyltransferase (PEMT).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Phosphatidylethanolamine N-methyltransferase (PEMT).	[14]

References

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• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [4] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [5] 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.
• [6] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [7] Unique transcriptome, pathways, and networks in the human endometrial fibroblast response to progesterone in endometriosis. Biol Reprod. 2011 Apr;84(4):801-15.
• [8] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [9] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [10] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [11] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [12] BET bromodomain inhibition targets both c-Myc and IL7R in high-risk acute lymphoblastic leukemia. Blood. 2012 Oct 4;120(14):2843-52.
• [13] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [14] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [15] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [16] A distinct and replicable variant of the squamous cell carcinoma gene inositol polyphosphate-5-phosphatase modifies the susceptibility of arsenic-associated skin lesions in Bangladesh. Cancer. 2015 Jul 1;121(13):2222-9. doi: 10.1002/cncr.29291. Epub 2015 Mar 10.
• [17] Lymphocyte gene expression in subjects fed a low-choline diet differs between those who develop organ dysfunction and those who do not. Am J Clin Nutr. 2007 Jul;86(1):230-9. doi: 10.1093/ajcn/86.1.230.