Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTX2A47A)

• DOT Name: Ethanolaminephosphotransferase 1 (SELENOI)
• Synonyms: hEPT1; EC 2.7.8.1; Selenoprotein I; SelI
• Gene Name: SELENOI
• Related Disease:
  Hepatocellular carcinoma
  Hereditary spastic paraplegia
  Coronary heart disease
  Neoplasm
• UniProt ID: EPT1_HUMAN
• EC Number: 2.7.8.1
• Pfam ID: PF01066
• Sequence:
  MAGYEYVSPEQLAGFDKYKYSAVDTNPLSLYVMHPFWNTIVKVFPTWLAPNLITFSGFLL
  VVFNFLLMAYFDPDFYASAPGHKHVPDWVWIVVGILNFVAYTLDGVDGKQARRTNSSTPL
  GELFDHGLDSWSCVYFVVTVYSIFGRGSTGVSVFVLYLLLWVVLFSFILSHWEKYNTGIL
  FLPWGYDISQVTISFVYIVTAVVGVEAWYEPFLFNFLYRDLFTAMIIGCALCVTLPMSLL
  NFFRSYKNNTLKLNSVYEAMVPLFSPCLLFILSTAWILWSPSDILELHPRVFYFMVGTAF
  ANSTCQLIVCQMSSTRCPTLNWLLVPLFLVVLVVNLGVASYVESILLYTLTTAFTLAHIH
  YGVRVVKQLSSHFQIYPFSLRKPNSDULGMEEKNIGL
• Function: Ethanolaminephosphotransferase that catalyzes the transfer of phosphoethanolamine/PE from CDP-ethanolamine to lipid acceptors, the final step in the synthesis of PE via the 'Kennedy' pathway. PE is the second most abundant phospholipid of membranes in mammals and is involved in various membrane-related cellular processes. The enzyme is critical for the synthesis of several PE species and could also catalyze the synthesis of ether-linked phospholipids like plasmanyl- and plasmenyl-PE which could explain it is required for proper myelination and neurodevelopment.
• Tissue Specificity: Widely expressed. Abundant in brain, placenta, liver and pancreas, followed by heart, skeletal muscle, lung and kidney. In brain it is strongly expressed in cerebellum, followed by the occipital pole and the frontal lobe.
• KEGG Pathway:
  Phospho.te and phosphi.te metabolism (hsa00440)
  Glycerophospholipid metabolism (hsa00564)
  Ether lipid metabolism (hsa00565)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Synthesis of PE (R-HSA-1483213)
• BioCyc Pathway: MetaCyc:HS06434-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[1]
Hereditary spastic paraplegia	DISGZQV1	Strong	Genetic Variation	[2]
Coronary heart disease	DIS5OIP1	moderate	Genetic Variation	[3]
Neoplasm	DISZKGEW	Limited	Genetic Variation	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Ethanolaminephosphotransferase 1 (SELENOI).	[5]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Ethanolaminephosphotransferase 1 (SELENOI).	[9]

8 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 Ethanolaminephosphotransferase 1 (SELENOI).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Ethanolaminephosphotransferase 1 (SELENOI).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Ethanolaminephosphotransferase 1 (SELENOI).	[8]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Ethanolaminephosphotransferase 1 (SELENOI).	[10]
Fluoxetine	DM3PD2C	Approved	Fluoxetine increases the expression of Ethanolaminephosphotransferase 1 (SELENOI).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Ethanolaminephosphotransferase 1 (SELENOI).	[12]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Ethanolaminephosphotransferase 1 (SELENOI).	[13]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Ethanolaminephosphotransferase 1 (SELENOI).	[14]

References

• [1] Bcl-2 gene silencing in pediatric epithelial liver tumors.J Surg Res. 2008 Jan;144(1):43-8. doi: 10.1016/j.jss.2007.03.054. Epub 2007 Jun 14.
• [2] A mutation of EPT1 (SELENOI) underlies a new disorder of Kennedy pathway phospholipid biosynthesis.Brain. 2017 Mar 1;140(3):547-554. doi: 10.1093/brain/aww318.
• [3] Identification of 64 Novel Genetic Loci Provides an Expanded View on the Genetic Architecture of Coronary Artery Disease.Circ Res. 2018 Feb 2;122(3):433-443. doi: 10.1161/CIRCRESAHA.117.312086. Epub 2017 Dec 6.
• [4] Characterization of the continuous cell line HepT1 derived from a human hepatoblastoma.Lab Invest. 1996 Apr;74(4):809-18.
• [5] 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.
• [6] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [9] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [10] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [11] Screening autism-associated environmental factors in differentiating human neural progenitors with fractional factorial design-based transcriptomics. Sci Rep. 2023 Jun 29;13(1):10519. doi: 10.1038/s41598-023-37488-0.
• [12] 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.
• [13] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [14] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.