Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5A2DNI)

• DOT Name: Ceramide synthase 5 (CERS5)
• Synonyms: CerS5; LAG1 longevity assurance homolog 5; Sphingoid base N-palmitoyltransferase CERS5; EC 2.3.1.291; Sphingosine N-acyltransferase CERS5; EC 2.3.1.24
• Gene Name: CERS5
• Related Disease:
  Colon cancer
  Congestive heart failure
  High blood pressure
  Rectal carcinoma
  Advanced cancer
  Obesity
• UniProt ID: CERS5_HUMAN
• EC Number: 2.3.1.24; 2.3.1.291
• Pfam ID: PF00046 ; PF03798
• Sequence:
  MATAAQGPLSLLWGWLWSERFWLPENVSWADLEGPADGYGYPRGRHILSVFPLAAGIFFV
  RLLFERFIAKPCALCIGIEDSGPYQAQPNAILEKVFISITKYPDKKRLEGLSKQLDWNVR
  KIQCWFRHRRNQDKPPTLTKFCESMWRFTFYLCIFCYGIRFLWSSPWFWDIRQCWHNYPF
  QPLSSGLYHYYIMELAFYWSLMFSQFTDIKRKDFLIMFVHHLVTIGLISFSYINNMVRVG
  TLIMCLHDVSDFLLEAAKLANYAKYQRLCDTLFVIFSAVFMVTRLGIYPFWILNTTLFES
  WEIIGPYASWWLLNGLLLTLQLLHVIWSYLIARIALKALIRGKVSKDDRSDVESSSEEED
  VTTCTKSPCDSSSSNGANRVNGHMGGSYWAEE
• Function: Ceramide synthase that catalyzes the transfer of the acyl chain from acyl-CoA to a sphingoid base, with high selectivity toward palmitoyl-CoA (hexadecanoyl-CoA; C16:0-CoA). Can use other acyl donors, but with less efficiency. N-acylates sphinganine and sphingosine bases to form dihydroceramides and ceramides in de novo synthesis and salvage pathways, respectively. Plays a role in de novo ceramide synthesis and surfactant homeostasis in pulmonary epithelia.
• 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:ENSG00000139624-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Colon cancer	DISVC52G	Strong	Biomarker	[1]
Congestive heart failure	DIS32MEA	Strong	Altered Expression	[2]
High blood pressure	DISY2OHH	Strong	Genetic Variation	[3]
Rectal carcinoma	DIS8FRR7	Strong	Altered Expression	[4]
Advanced cancer	DISAT1Z9	moderate	Altered Expression	[4]
Obesity	DIS47Y1K	moderate	Biomarker	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Ceramide synthase 5 (CERS5).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Ceramide synthase 5 (CERS5).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Ceramide synthase 5 (CERS5).	[8]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Ceramide synthase 5 (CERS5).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Ceramide synthase 5 (CERS5).	[10]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Ceramide synthase 5 (CERS5).	[11]
Marinol	DM70IK5	Approved	Marinol increases the expression of Ceramide synthase 5 (CERS5).	[12]
Cidofovir	DMA13GD	Approved	Cidofovir increases the expression of Ceramide synthase 5 (CERS5).	[8]
Ifosfamide	DMCT3I8	Approved	Ifosfamide increases the expression of Ceramide synthase 5 (CERS5).	[8]
Clodronate	DM9Y6X7	Approved	Clodronate increases the expression of Ceramide synthase 5 (CERS5).	[8]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Ceramide synthase 5 (CERS5).	[14]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN increases the expression of Ceramide synthase 5 (CERS5).	[15]

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 increases the methylation of Ceramide synthase 5 (CERS5).	[13]

References

• [1] 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.
• [2] A tissue-specific screen of ceramide expression in aged mice identifies ceramide synthase-1 and ceramide synthase-5 as potential regulators of fiber size and strength in skeletal muscle.Aging Cell. 2020 Jan;19(1):e13049. doi: 10.1111/acel.13049. Epub 2019 Nov 6.
• [3] Trans-ancestry meta-analyses identify rare and common variants associated with blood pressure and hypertension.Nat Genet. 2016 Oct;48(10):1151-1161. doi: 10.1038/ng.3654. Epub 2016 Sep 12.
• [4] 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.
• [5] CerS6-Derived Sphingolipids Interact with Mff and Promote Mitochondrial Fragmentation in Obesity.Cell. 2019 May 30;177(6):1536-1552.e23. doi: 10.1016/j.cell.2019.05.008.
• [6] 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.
• [7] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [8] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [9] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [10] 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.
• [11] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [12] Dihydroceramide accumulation mediates cytotoxic autophagy of cancer cells via autolysosome destabilization. Autophagy. 2016 Nov;12(11):2213-2229. doi: 10.1080/15548627.2016.1213927. Epub 2016 Sep 16.
• [13] 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.
• [14] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [15] Molecular mechanisms of quercitrin-induced apoptosis in non-small cell lung cancer. Arch Med Res. 2014 Aug;45(6):445-54.