Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTM6EPUS)

• DOT Name: Ceramide synthase (TLCD3B)
• Synonyms: EC 2.3.1.-; Protein FAM57B; TLC domain-containing protein 3B
• Gene Name: TLCD3B
• Related Disease:
  Adult glioblastoma
  Advanced cancer
  Atopic dermatitis
  Breast cancer
  Breast carcinoma
  Fatty liver disease
  Gastric cancer
  Glioblastoma multiforme
  Psoriasis
  Stomach cancer
  Head-neck squamous cell carcinoma
  Cone-rod dystrophy
  Parkinson disease
  Prostate cancer
  Prostate carcinoma
• UniProt ID: TLC3B_HUMAN
• EC Number: 2.3.1.-
• Pfam ID: PF03798
• Sequence:
  MLTPMVAGGVVFPGLFLLSKNTLQRLPQLRWEEADAVIVSARLVSSVQAIMASTAGYIVS
  TSCKHIIDDQHWLSSAYTQFAVPYFIYDIYAMFLCHWHKHQVKGHGGDDGAARAPGSTWA
  IARGYLHKEFLMVLHHAAMVLVCFPLSVVWRQGKGDFFLGCMLMAEVSTPFVCLGKILIQ
  YKQQHTLLHKVNGALMLLSFLCCRVLLFPYLYWAYGRHAGLPLLAVPLAIPAHVNLGAAL
  LLAPQLYWFFLICRGACRLFWPRSRPPPACQAQD
• Function: Involved in ceramide synthesis.
• Tissue Specificity: Expressed in testis . Expressed in the retina with higher expression levels in the macular than in the peripheral region .

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Atopic dermatitis	DISTCP41	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[4]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[4]
Fatty liver disease	DIS485QZ	Strong	Altered Expression	[5]
Gastric cancer	DISXGOUK	Strong	Biomarker	[6]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[1]
Psoriasis	DIS59VMN	Strong	Altered Expression	[3]
Stomach cancer	DISKIJSX	Strong	Biomarker	[6]
Head-neck squamous cell carcinoma	DISF7P24	moderate	Biomarker	[7]
Cone-rod dystrophy	DISY9RWN	Supportive	Autosomal dominant	[8]
Parkinson disease	DISQVHKL	Limited	Altered Expression	[9]
Prostate cancer	DISF190Y	Limited	Altered Expression	[10]
Prostate carcinoma	DISMJPLE	Limited	Altered Expression	[10]

2 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 (TLCD3B).	[11]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of Ceramide synthase (TLCD3B).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Ceramide synthase (TLCD3B).	[13]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Ceramide synthase (TLCD3B).	[14]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Ceramide synthase (TLCD3B).	[15]

References

• [1] Bcl2L13 is a ceramide synthase inhibitor in glioblastoma.Proc Natl Acad Sci U S A. 2014 Apr 15;111(15):5682-7. doi: 10.1073/pnas.1316700111. Epub 2014 Mar 31.
• [2] Dihydroceramide desaturase knockdown impacts sphingolipids and apoptosis after photodamage in human head and neck squamous carcinoma cells.Anticancer Res. 2013 Jan;33(1):77-84.
• [3] Interferon- decreases ceramides with long-chain fatty acids: possible involvement in atopic dermatitis and psoriasis.J Invest Dermatol. 2014 Mar;134(3):712-718. doi: 10.1038/jid.2013.364. Epub 2013 Sep 5.
• [4] Increased ceramide synthase 2 and 6 mRNA levels in breast cancer tissues and correlation with sphingosine kinase expression.Biochem Biophys Res Commun. 2010 Jan 1;391(1):219-23. doi: 10.1016/j.bbrc.2009.11.035. Epub 2009 Nov 11.
• [5] A novel role for ceramide synthase 6 in mouse and human alcoholic steatosis.FASEB J. 2018 Jan;32(1):130-142. doi: 10.1096/fj.201601142R. Epub 2017 Sep 1.
• [6] Jaspine B induces nonapoptotic cell death in gastric cancer cells independently of its inhibition of ceramide synthase.J Lipid Res. 2017 Aug;58(8):1500-1513. doi: 10.1194/jlr.M072611. Epub 2017 Jun 1.
• [7] Fumonisin B1 Inhibits Endoplasmic Reticulum Stress Associated-apoptosis After FoscanPDT Combined with C6-Pyridinium Ceramide or Fenretinide.Anticancer Res. 2017 Feb;37(2):455-463. doi: 10.21873/anticanres.11337.
• [8] Ceramide synthase TLCD3B is a novel gene associated with human recessive retinal dystrophy. Genet Med. 2021 Mar;23(3):488-497. doi: 10.1038/s41436-020-01003-x. Epub 2020 Oct 20.
• [9] Altered ceramide acyl chain length and ceramide synthase gene expression in Parkinsons disease.Mov Disord. 2014 Apr;29(4):518-26. doi: 10.1002/mds.25729.
• [10] PKCalpha activation downregulates ATM and radio-sensitizes androgen-sensitive human prostate cancer cells in vitro and in vivo.Cancer Biol Ther. 2009 Jan;8(1):54-63. doi: 10.4161/cbt.8.1.7119. Epub 2009 Jan 4.
• [11] 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.
• [12] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [13] 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.
• [14] 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.
• [15] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.