Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTV5ENAX)

• DOT Name: Ceramide synthase 4 (CERS4)
• Synonyms: CerS4; EC 2.3.1.-; LAG1 longevity assurance homolog 4; Sphingosine N-acyltransferase CERS4; EC 2.3.1.24
• Gene Name: CERS4
• Related Disease:
  Chronic kidney disease
  Chronic renal failure
  Advanced cancer
  Atopic dermatitis
  Breast cancer
  Breast carcinoma
  Colon cancer
  Colorectal carcinoma
  Rectal carcinoma
  Carcinoma of liver and intrahepatic biliary tract
  Liver cancer
• UniProt ID: CERS4_HUMAN
• EC Number: 2.3.1.-; 2.3.1.24
• Pfam ID: PF00046 ; PF03798
• Sequence:
  MLSSFNEWFWQDRFWLPPNVTWTELEDRDGRVYPHPQDLLAALPLALVLLAMRLAFERFI
  GLPLSRWLGVRDQTRRQVKPNATLEKHFLTEGHRPKEPQLSLLAAQCGLTLQQTQRWFRR
  RRNQDRPQLTKKFCEASWRFLFYLSSFVGGLSVLYHESWLWAPVMCWDRYPNQTLKPSLY
  WWYLLELGFYLSLLIRLPFDVKRKDFKEQVIHHFVAVILMTFSYSANLLRIGSLVLLLHD
  SSDYLLEACKMVNYMQYQQVCDALFLIFSFVFFYTRLVLFPTQILYTTYYESISNRGPFF
  GYYFFNGLLMLLQLLHVFWSCLILRMLYSFMKKGQMEKDIRSDVEESDSSEEAAAAQEPL
  QLKNGAAGGPRPAPTDGPRSRVAGRLTNRHTTAT
• Function: Ceramide synthase that catalyzes formation of ceramide from sphinganine and acyl-CoA substrates, with high selectivity toward long and very-long chains (C18:0-C22:0) as acyl donor.
• KEGG Pathway:
  Sphingolipid metabolism (hsa00600)
  Metabolic pathways (hsa01100)
  Sphingolipid sig.ling pathway (hsa04071)
• Reactome Pathway: Sphingolipid de novo biosynthesis (R-HSA-1660661)
• BioCyc Pathway: MetaCyc:ENSG00000090661-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Chronic kidney disease	DISW82R7	Definitive	Genetic Variation	[1]
Chronic renal failure	DISGG7K6	Definitive	Genetic Variation	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Atopic dermatitis	DISTCP41	Strong	Altered Expression	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[4]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[4]
Colon cancer	DISVC52G	Strong	Biomarker	[5]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[2]
Rectal carcinoma	DIS8FRR7	Strong	Altered Expression	[2]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Limited	Biomarker	[6]
Liver cancer	DISDE4BI	Limited	Biomarker	[6]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Ceramide synthase 4 (CERS4) affects the response to substance of Cisplatin.	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Ceramide synthase 4 (CERS4).	[7]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Ceramide synthase 4 (CERS4).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Ceramide synthase 4 (CERS4).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Ceramide synthase 4 (CERS4).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Ceramide synthase 4 (CERS4).	[11]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Ceramide synthase 4 (CERS4).	[12]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Ceramide synthase 4 (CERS4).	[14]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Ceramide synthase 4 (CERS4).	[15]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Ceramide synthase 4 (CERS4).	[16]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Ceramide synthase 4 (CERS4).	[18]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Ceramide synthase 4 (CERS4).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Ceramide synthase 4 (CERS4).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Ceramide synthase 4 (CERS4).	[17]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Ceramide synthase 4 (CERS4).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Ceramide synthase 4 (CERS4).	[20]

References

• [1] Genome-Wide Association Studies of Metabolites in Patients with CKD Identify Multiple Loci and Illuminate Tubular Transport Mechanisms.J Am Soc Nephrol. 2018 May;29(5):1513-1524. doi: 10.1681/ASN.2017101099. Epub 2018 Mar 15.
• [2] Altered mRNA expression levels of the major components of sphingolipid metabolism, ceramide synthases and their clinical implication in colorectal cancer.Oncol Rep. 2018 Dec;40(6):3489-3500. doi: 10.3892/or.2018.6712. Epub 2018 Sep 18.
• [3] Ceramide synthase 4 is highly expressed in involved skin of patients with atopic dermatitis.J Eur Acad Dermatol Venereol. 2017 Jan;31(1):135-141. doi: 10.1111/jdv.13777. Epub 2016 Jun 29.
• [4] Acid ceramidase 1 expression correlates with a better prognosis in ER-positive breast cancer.Climacteric. 2009 Dec;12(6):502-13. doi: 10.3109/13697130902939913.
• [5] Linking the ceramide synthases (CerSs) 4 and 5 with apoptosis, endometrial and colon cancers.Exp Mol Pathol. 2015 Jun;98(3):585-92. doi: 10.1016/j.yexmp.2015.03.019. Epub 2015 Mar 13.
• [6] Ceramide synthase-4 orchestrates the cell proliferation and tumor growth of liver cancer in vitro and in vivo through the nuclear factor-B signaling pathway.Oncol Lett. 2017 Aug;14(2):1477-1483. doi: 10.3892/ol.2017.6365. Epub 2017 Jun 9.
• [7] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] 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.
• [13] 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.
• [14] Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells. Toxicol Appl Pharmacol. 2012 Jun 1;261(2):204-16.
• [15] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [16] The roles of bioactive sphingolipids in resveratrol-induced apoptosis in HL60: acute myeloid leukemia cells. J Cancer Res Clin Oncol. 2011 Feb;137(2):279-86. doi: 10.1007/s00432-010-0884-x. Epub 2010 Apr 18.
• [17] 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.
• [18] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [19] 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.
• [20] 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.
• [21] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [22] Establishment and gene analysis of a cisplatin-resistant cell line, Sa-3R, derived from oral squamous cell carcinoma. Oncol Rep. 2005 Apr;13(4):709-14.