Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKC393S)

• DOT Name: Phosphatidate cytidylyltransferase 2 (CDS2)
• Synonyms: EC 2.7.7.41; CDP-DAG synthase 2; CDP-DG synthase 2; CDP-diacylglycerol synthase 2; CDS 2; CDP-diglyceride pyrophosphorylase 2; CDP-diglyceride synthase 2; CTP:phosphatidate cytidylyltransferase 2
• Gene Name: CDS2
• Related Disease:
  Cardiac failure
  Congestive heart failure
  Disorder of orbital region
  Neoplasm
• UniProt ID: CDS2_HUMAN
• EC Number: 2.7.7.41
• Pfam ID: PF01148
• Sequence:
  MTELRQRVAHEPVAPPEDKESESEAKVDGETASDSESRAESAPLPVSADDTPEVLNRALS
  NLSSRWKNWWVRGILTLAMIAFFFIIIYLGPMVLMIIVMCVQIKCFHEIITIGYNVYHSY
  DLPWFRTLSWYFLLCVNYFFYGETVTDYFFTLVQREEPLRILSKYHRFISFTLYLIGFCM
  FVLSLVKKHYRLQFYMFGWTHVTLLIVVTQSHLVIHNLFEGMIWFIVPISCVICNDIMAY
  MFGFFFGRTPLIKLSPKKTWEGFIGGFFATVVFGLLLSYVMSGYRCFVCPVEYNNDTNSF
  TVDCEPSDLFRLQEYNIPGVIQSVIGWKTVRMYPFQIHSIALSTFASLIGPFGGFFASGF
  KRAFKIKDFANTIPGHGGIMDRFDCQYLMATFVNVYIASFIRGPNPSKLIQQFLTLRPDQ
  QLHIFNTLRSHLIDKGMLTSTTEDE
• Function: Catalyzes the conversion of phosphatidic acid (PA) to CDP-diacylglycerol (CDP-DAG), an essential intermediate in the synthesis of phosphatidylglycerol, cardiolipin and phosphatidylinositol. Exhibits specificity for the nature of the acyl chains at the sn-1 and sn-2 positions in the substrate, PA and the preferred acyl chain composition is 1-stearoyl-2-arachidonoyl-sn-phosphatidic acid. Plays an important role in regulating the growth and maturation of lipid droplets which are storage organelles at the center of lipid and energy homeostasis.
• Tissue Specificity: Widely expressed. Expressed in heart, brain and retina, and to a lesser extent in placenta, lung, liver, skeletal muscle, kidney and pancreas.
• KEGG Pathway:
  Glycerophospholipid metabolism (hsa00564)
  Metabolic pathways (hsa01100)
  Phosphatidylinositol sig.ling system (hsa04070)
• Reactome Pathway: Synthesis of PG (R-HSA-1483148)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cardiac failure	DISDC067	Strong	Altered Expression	[1]
Congestive heart failure	DIS32MEA	Strong	Altered Expression	[1]
Disorder of orbital region	DISH0ECJ	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Phosphatidate cytidylyltransferase 2 (CDS2).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Phosphatidate cytidylyltransferase 2 (CDS2).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Phosphatidate cytidylyltransferase 2 (CDS2).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Phosphatidate cytidylyltransferase 2 (CDS2).	[7]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Phosphatidate cytidylyltransferase 2 (CDS2).	[8]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Phosphatidate cytidylyltransferase 2 (CDS2).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Phosphatidate cytidylyltransferase 2 (CDS2).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Phosphatidate cytidylyltransferase 2 (CDS2).	[12]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Phosphatidate cytidylyltransferase 2 (CDS2).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Phosphatidate cytidylyltransferase 2 (CDS2).	[10]

References

• [1] Cardiolipin biosynthesis and remodeling enzymes are altered during development of heart failure.J Lipid Res. 2009 Aug;50(8):1600-8. doi: 10.1194/jlr.M800561-JLR200. Epub 2008 Nov 10.
• [2] Isolation and chromosomal localization of two human CDP-diacylglycerol synthase (CDS) genes.Genomics. 1998 Nov 15;54(1):140-4. doi: 10.1006/geno.1998.5547.
• [3] Endothelial CDS2 deficiency causes VEGFA-mediated vascular regression and tumor inhibition.Cell Res. 2019 Nov;29(11):895-910. doi: 10.1038/s41422-019-0229-5. Epub 2019 Sep 9.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] 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.
• [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] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [8] 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.
• [9] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [10] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [11] 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.
• [12] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [13] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.