Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT47TIF3)

• DOT Name: Neutral ceramidase (ASAH2)
• Synonyms: N-CDase; NCDase; EC 3.5.1.-; EC 3.5.1.23; Acylsphingosine deacylase 2; BCDase; LCDase; hCD; N-acylsphingosine amidohydrolase 2; Non-lysosomal ceramidase
• Gene Name: ASAH2
• Related Disease:
  Colorectal neoplasm
  Congenital diaphragmatic hernia
  Cystic fibrosis
  Dementia
  Inflammatory bowel disease
  Lymphoproliferative syndrome
  Obesity
  Glaucoma/ocular hypertension
  Non-insulin dependent diabetes
  Coeliac disease
  Neuroblastoma
  Type-1/2 diabetes
• UniProt ID: ASAH2_HUMAN
• PDB ID: 4WGK
• EC Number: 3.5.1.-; 3.5.1.23
• Pfam ID: PF04734 ; PF17048
• Sequence:
  MAKRTFSNLETFLIFLLVMMSAITVALLSLLFITSGTIENHKDLGGHFFSTTQSPPATQG
  STAAQRSTATQHSTATQSSTATQTSPVPLTPESPLFQNFSGYHIGVGRADCTGQVADINL
  MGYGKSGQNAQGILTRLYSRAFIMAEPDGSNRTVFVSIDIGMVSQRLRLEVLNRLQSKYG
  SLYRRDNVILSGTHTHSGPAGYFQYTVFVIASEGFSNQTFQHMVTGILKSIDIAHTNMKP
  GKIFINKGNVDGVQINRSPYSYLQNPQSERARYSSNTDKEMIVLKMVDLNGDDLGLISWF
  AIHPVSMNNSNHLVNSDNVGYASYLLEQEKNKGYLPGQGPFVAAFASSNLGDVSPNILGP
  RCINTGESCDNANSTCPIGGPSMCIAKGPGQDMFDSTQIIGRAMYQRAKELYASASQEVT
  GPLASAHQWVDMTDVTVWLNSTHASKTCKPALGYSFAAGTIDGVGGLNFTQGKTEGDPFW
  DTIRDQILGKPSEEIKECHKPKPILLHTGELSKPHPWHPDIVDVQIITLGSLAITAIPGE
  FTTMSGRRLREAVQAEFASHGMQNMTVVISGLCNVYTHYITTYEEYQAQRYEAASTIYGP
  HTLSAYIQLFRNLAKAIATDTVANLSRGPEPPFFKQLIVPLIPSIVDRAPKGRTFGDVLQ
  PAKPEYRVGEVAEVIFVGANPKNSVQNQTHQTFLTVEKYEATSTSWQIVCNDASWETRFY
  WHKGLLGLSNATVEWHIPDTAQPGIYRIRYFGHNRKQDILKPAVILSFEGTSPAFEVVTI
• Function: Plasma membrane ceramidase that hydrolyzes sphingolipid ceramides into sphingosine and free fatty acids at neutral pH. Ceramides, sphingosine, and its phosphorylated form sphingosine-1-phosphate are bioactive lipids that mediate cellular signaling pathways regulating several biological processes including cell proliferation, apoptosis and differentiation. Also catalyzes the reverse reaction allowing the synthesis of ceramides from fatty acids and sphingosine. Together with sphingomyelinase, participates in the production of sphingosine and sphingosine-1-phosphate from the degradation of sphingomyelin, a sphingolipid enriched in the plasma membrane of cells. Also participates in the hydrolysis of ceramides from the extracellular milieu allowing the production of sphingosine-1-phosphate inside and outside cells. This is the case for instance with the digestion of dietary sphingolipids in the intestinal tract.
• Tissue Specificity: Primarily expressed in intestine . Ubiquitously expressed with higher levels in kidney, skeletal muscle and heart . The ubiquitous expression observed for ASAH2 might be an experimental artifact due to the paralog ASAH2B .
• KEGG Pathway:
  Sphingolipid metabolism (hsa00600)
  Metabolic pathways (hsa01100)
  Sphingolipid sig.ling pathway (hsa04071)
• Reactome Pathway: Glycosphingolipid catabolism (R-HSA-9840310)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Colorectal neoplasm	DISR1UCN	Strong	Biomarker	[1]
Congenital diaphragmatic hernia	DIS0IPVU	Strong	Biomarker	[2]
Cystic fibrosis	DIS2OK1Q	Strong	Biomarker	[3]
Dementia	DISXL1WY	Strong	Biomarker	[4]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[5]
Lymphoproliferative syndrome	DISMVL8O	Strong	Biomarker	[6]
Obesity	DIS47Y1K	Strong	Genetic Variation	[7]
Glaucoma/ocular hypertension	DISLBXBY	Disputed	Biomarker	[8]
Non-insulin dependent diabetes	DISK1O5Z	Disputed	Biomarker	[9]
Coeliac disease	DISIY60C	Limited	Biomarker	[10]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[11]
Type-1/2 diabetes	DISIUHAP	Limited	Biomarker	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Chlorothiazide	DMLHESP	Approved	Neutral ceramidase (ASAH2) increases the Metabolic disorder ADR of Chlorothiazide.	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Neutral ceramidase (ASAH2).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Neutral ceramidase (ASAH2).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Neutral ceramidase (ASAH2).	[14]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Neutral ceramidase (ASAH2).	[15]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Neutral ceramidase (ASAH2).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Neutral ceramidase (ASAH2).	[18]

References

• [1] Functions of neutral ceramidase in the Golgi apparatus.J Lipid Res. 2018 Nov;59(11):2116-2125. doi: 10.1194/jlr.M088187. Epub 2018 Aug 28.
• [2] AAV2/8-humanFOXP3 gene therapy shows robust anti-atherosclerosis efficacy in LDLR-KO mice on high cholesterol diet.J Transl Med. 2015 Jul 18;13:235. doi: 10.1186/s12967-015-0597-7.
• [3] Expression of intestinal and lung alkaline sphingomyelinase and neutral ceramidase in cystic fibrosis f508del transgenic mice.J Pediatr Gastroenterol Nutr. 2008 Nov;47(5):547-54. doi: 10.1097/MPG.0b013e3181826daf.
• [4] Comparative benefits of simvastatin and exercise in a mouse model of vascular cognitive impairment and dementia.FASEB J. 2019 Dec;33(12):13280-13293. doi: 10.1096/fj.201901002R. Epub 2019 Sep 26.
• [5] Loss of neutral ceramidase increases inflammation in a mouse model of inflammatory bowel disease.Prostaglandins Other Lipid Mediat. 2012 Dec;99(3-4):124-30. doi: 10.1016/j.prostaglandins.2012.08.003. Epub 2012 Aug 31.
• [6] Heavy-chain diseases.Hematol Oncol Clin North Am. 1999 Dec;13(6):1281-94. doi: 10.1016/s0889-8588(05)70127-1.
• [7] Effects of Providing High-Fat versus High-Carbohydrate Meals on Daily and Postprandial Physical Activity and Glucose Patterns: a Randomised Controlled Trial.Nutrients. 2018 Apr 30;10(5):557. doi: 10.3390/nu10050557.
• [8] Optic Nerve Lipidomics Reveal Impaired Glucosylsphingosine Lipids Pathway in Glaucoma.Invest Ophthalmol Vis Sci. 2019 Apr 1;60(5):1789-1798. doi: 10.1167/iovs.18-25802.
• [9] Neutral Ceramidase Secreted Via Exosome Protects Against Palmitate-Induced Apoptosis in INS-1 Cells.Exp Clin Endocrinol Diabetes. 2017 Feb;125(2):130-135. doi: 10.1055/s-0042-116314. Epub 2016 Dec 22.
• [10] Celiac disease biomarkers identified by transcriptome analysis of small intestinal biopsies.Cell Mol Life Sci. 2018 Dec;75(23):4385-4401. doi: 10.1007/s00018-018-2898-5. Epub 2018 Aug 10.
• [11] Role of down-regulated neutral ceramidase during all-trans retinoic acid-induced neuronal differentiation in SH-SY5Y neuroblastoma cells.J Biochem. 2012 Jun;151(6):611-20. doi: 10.1093/jb/mvs033. Epub 2012 Mar 26.
• [12] Hypoglycemic Efficacy of Docking Selected Natural Compounds against -Glucosidase and -Amylase.Molecules. 2018 Sep 5;23(9):2260. doi: 10.3390/molecules23092260.
• [13] 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.
• [14] 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.
• [15] Endoplasmic reticulum stress contributes to arsenic trioxide-induced intrinsic apoptosis in human umbilical and bone marrow mesenchymal stem cells. Environ Toxicol. 2016 Mar;31(3):314-28.
• [16] 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.
• [17] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [18] Comparison of transcriptome expression alterations by chronic exposure to low-dose bisphenol A in different subtypes of breast cancer cells. Toxicol Appl Pharmacol. 2019 Dec 15;385:114814. doi: 10.1016/j.taap.2019.114814. Epub 2019 Nov 9.
• [19] Genome-wide association analyses suggest NELL1 influences adverse metabolic response to HCTZ in African Americans. Pharmacogenomics J. 2014 Feb;14(1):35-40. doi: 10.1038/tpj.2013.3. Epub 2013 Feb 12.