Details of Drug Off-Target (DOT)

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

• DOT Name: Ceramide synthase 3 (CERS3)
• Synonyms: CerS3; Dihydroceramide synthase 3; LAG1 longevity assurance homolog 3; Sphingosine N-acyltransferase CERS3; EC 2.3.1.24; Ultra-long-chain ceramide synthase CERS3; EC 2.3.1.298; Very-long-chain ceramide synthase CERS3; EC 2.3.1.297
• Gene Name: CERS3
• Related Disease:
  Atopic dermatitis
  Autosomal recessive congenital ichthyosis 9
  Weill-Marchesani 4 syndrome, recessive
  Exfoliative dermatitis
  Non-syndromic ichthyosis
  Congenital ichthyosiform erythroderma
• UniProt ID: CERS3_HUMAN
• EC Number: 2.3.1.24; 2.3.1.297; 2.3.1.298
• Pfam ID: PF00046 ; PF03798
• Sequence:
  MFWTFKEWFWLERFWLPPTIKWSDLEDHDGLVFVKPSHLYVTIPYAFLLLIIRRVFEKFV
  ASPLAKSFGIKETVRKVTPNTVLENFFKHSTRQPLQTDIYGLAKKCNLTERQVERWFRSR
  RNQERPSRLKKFQEACWRFAFYLMITVAGIAFLYDKPWLYDLWEVWNGYPKQPLLPSQYW
  YYILEMSFYWSLLFRLGFDVKRKDFLAHIIHHLAAISLMSFSWCANYIRSGTLVMIVHDV
  ADIWLESAKMFSYAGWTQTCNTLFFIFSTIFFISRLIVFPFWILYCTLILPMYHLEPFFS
  YIFLNLQLMILQVLHLYWGYYILKMLNRCIFMKSIQDVRSDDEDYEEEEEEEEEEATKGK
  EMDCLKNGLRAERHLIPNGQHGH
• Function: Ceramide synthase that catalyzes the transfer of the acyl chain from acyl-CoA to a sphingoid base, with high selectivity toward very- and ultra-long-chain fatty acyl-CoA (chain length greater than C22). N-acylates sphinganine and sphingosine bases to form dihydroceramides and ceramides in de novo synthesis and salvage pathways, respectively. It is crucial for the synthesis of ultra-long-chain ceramides in the epidermis, to maintain epidermal lipid homeostasis and terminal differentiation.
• Tissue Specificity: Expressed in the epidermis, where it localizes at the interface between the stratum granulosum and the stratum corneum (at protein level).
• 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:ENSG00000154227-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
Atopic dermatitis	DISTCP41	Strong	Altered Expression	[1]
Autosomal recessive congenital ichthyosis 9	DIS5JQTL	Strong	Autosomal recessive	[2]
Weill-Marchesani 4 syndrome, recessive	DISCL3SY	Strong	ChromosomalRearrangement	[3]
Exfoliative dermatitis	DISQEWIW	moderate	Genetic Variation	[4]
Non-syndromic ichthyosis	DISZ9QBQ	moderate	Genetic Variation	[5]
Congenital ichthyosiform erythroderma	DISV8HQX	Supportive	Autosomal recessive	[4]

3 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 Ceramide synthase 3 (CERS3).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Ceramide synthase 3 (CERS3).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Ceramide synthase 3 (CERS3).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Ceramide synthase 3 (CERS3).	[7]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate decreases the expression of Ceramide synthase 3 (CERS3).	[8]

References

• [1] IFN- Reduces Epidermal Barrier Function by Affecting Fatty Acid Composition of Ceramide in a Mouse Atopic Dermatitis Model.J Immunol Res. 2019 Jan 29;2019:3030268. doi: 10.1155/2019/3030268. eCollection 2019.
• [2] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [3] Mutations in CERS3 cause autosomal recessive congenital ichthyosis in humans. PLoS Genet. 2013 Jun;9(6):e1003536. doi: 10.1371/journal.pgen.1003536. Epub 2013 Jun 6.
• [4] Impaired epidermal ceramide synthesis causes autosomal recessive congenital ichthyosis and reveals the importance of ceramide acyl chain length. J Invest Dermatol. 2013 Sep;133(9):2202-11. doi: 10.1038/jid.2013.153. Epub 2013 Apr 2.
• [5] Autosomal recessive congenital ichthyosis: CERS3 mutations identified by a next generation sequencing panel targeting ichthyosis genes.Eur J Hum Genet. 2017 Nov;25(11):1282-1285. doi: 10.1038/ejhg.2017.137. Epub 2017 Sep 6.
• [6] 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.
• [7] 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.
• [8] Nervonoylceramide (C24:1Cer), a lipid biomarker for ocular irritants released from the 3D reconstructed human cornea-like epithelium, MCTT HCE?. Toxicol In Vitro. 2018 Mar;47:94-102. doi: 10.1016/j.tiv.2017.11.008. Epub 2017 Nov 15.
• [9] 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.
• [10] 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.