Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTT8TAEA)

• DOT Name: Ethanolamine-phosphate cytidylyltransferase (PCYT2)
• Synonyms: EC 2.7.7.14; CTP:phosphoethanolamine cytidylyltransferase; Phosphorylethanolamine transferase
• Gene Name: PCYT2
• Related Disease:
  Hereditary spastic paraplegia 54
  Spastic paraplegia 82, autosomal recessive
• UniProt ID: PCY2_HUMAN
• PDB ID: 3ELB; 4XSV
• EC Number: 2.7.7.14
• Pfam ID: PF01467
• Sequence:
  MIRNGRGAAGGAEQPGPGGRRAVRVWCDGCYDMVHYGHSNQLRQARAMGDYLIVGVHTDE
  EIAKHKGPPVFTQEERYKMVQAIKWVDEVVPAAPYVTTLETLDKYNCDFCVHGNDITLTV
  DGRDTYEEVKQAGRYRECKRTQGVSTTDLVGRMLLVTKAHHSSQEMSSEYREYADSFGKC
  PGGRNPWTGVSQFLQTSQKIIQFASGKEPQPGETVIYVAGAFDLFHIGHVDFLEKVHRLA
  ERPYIIAGLHFDQEVNHYKGKNYPIMNLHERTLSVLACRYVSEVVIGAPYAVTAELLSHF
  KVDLVCHGKTEIIPDRDGSDPYQEPKRRGIFRQIDSGSNLTTDLIVQRIITNRLEYEARN
  QKKEAKELAFLEAARQQAAQPLGERDGDF
• Function: Ethanolamine-phosphate cytidylyltransferase that catalyzes the second step in the synthesis of phosphatidylethanolamine (PE) from ethanolamine via the CDP-ethanolamine pathway. Phosphatidylethanolamine is a dominant inner-leaflet phospholipid in cell membranes, where it plays a role in membrane function by structurally stabilizing membrane-anchored proteins, and participates in important cellular processes such as cell division, cell fusion, blood coagulation, and apoptosis.
• Tissue Specificity: Strongest expression in liver, heart, and skeletal muscle.
• KEGG Pathway:
  Phospho.te and phosphi.te metabolism (hsa00440)
  Glycerophospholipid metabolism (hsa00564)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Synthesis of PE (R-HSA-1483213)
• BioCyc Pathway: MetaCyc:HS06840-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hereditary spastic paraplegia 54	DIS2AY6F	Definitive	Autosomal recessive	[1]
Spastic paraplegia 82, autosomal recessive	DIS3203M	Strong	Autosomal recessive	[2]

4 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 Ethanolamine-phosphate cytidylyltransferase (PCYT2).	[3]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Ethanolamine-phosphate cytidylyltransferase (PCYT2).	[8]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Ethanolamine-phosphate cytidylyltransferase (PCYT2).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Ethanolamine-phosphate cytidylyltransferase (PCYT2).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Ethanolamine-phosphate cytidylyltransferase (PCYT2).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Ethanolamine-phosphate cytidylyltransferase (PCYT2).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Ethanolamine-phosphate cytidylyltransferase (PCYT2).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Ethanolamine-phosphate cytidylyltransferase (PCYT2).	[7]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Ethanolamine-phosphate cytidylyltransferase (PCYT2).	[9]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Ethanolamine-phosphate cytidylyltransferase (PCYT2).	[10]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Ethanolamine-phosphate cytidylyltransferase (PCYT2).	[11]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Ethanolamine-phosphate cytidylyltransferase (PCYT2).	[12]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Ethanolamine-phosphate cytidylyltransferase (PCYT2).	[13]
Fluoxetine	DM3PD2C	Approved	Fluoxetine increases the expression of Ethanolamine-phosphate cytidylyltransferase (PCYT2).	[14]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of Ethanolamine-phosphate cytidylyltransferase (PCYT2).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Ethanolamine-phosphate cytidylyltransferase (PCYT2).	[4]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Ethanolamine-phosphate cytidylyltransferase (PCYT2).	[18]

References

• [1] Expanding the clinical and genetic spectrum of PCYT2-related disorders. Brain. 2020 Sep 1;143(9):e76. doi: 10.1093/brain/awaa229.
• [2] Mutations in PCYT2 disrupt etherlipid biosynthesis and cause a complex hereditary spastic paraplegia. Brain. 2019 Nov 1;142(11):3382-3397. doi: 10.1093/brain/awz291.
• [3] 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.
• [4] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [5] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] 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.
• [9] Gene expression profile induced by arsenic trioxide in chronic lymphocytic leukemia cells reveals a central role for heme oxygenase-1 in apoptosis and regulation of matrix metalloproteinase-9. Oncotarget. 2016 Dec 13;7(50):83359-83377.
• [10] 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.
• [11] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [12] Gene induction and apoptosis in human hepatocellular carci-noma cells SMMC-7721 exposed to 5-aza-2'-deoxycytidine. Chin Med J (Engl). 2007 Sep 20;120(18):1626-31.
• [13] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [14] 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.
• [15] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [16] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [17] 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.
• [18] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.