Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWOBMQ9)

• DOT Name: Ectonucleotide pyrophosphatase/phosphodiesterase family member 7 (ENPP7)
• Synonyms: E-NPP 7; NPP-7; EC 3.1.4.12; Alkaline sphingomyelin phosphodiesterase; Intestinal alkaline sphingomyelinase; Alk-SMase
• Gene Name: ENPP7
• Related Disease:
  Adenoma
  Arteriosclerosis
  Atherosclerosis
  Colon cancer
  Colon carcinoma
  Cystic fibrosis
  Familial adenomatous polyposis
  Neoplasm
  Colonic neoplasm
• UniProt ID: ENPP7_HUMAN
• PDB ID: 5TCD; 5UDY
• EC Number: 3.1.4.12
• Pfam ID: PF01663
• Sequence:
  MRGPAVLLTVALATLLAPGAGAPVQSQGSQNKLLLVSFDGFRWNYDQDVDTPNLDAMARD
  GVKARYMTPAFVTMTSPCHFTLVTGKYIENHGVVHNMYYNTTSKVKLPYHATLGIQRWWD
  NGSVPIWITAQRQGLRAGSFFYPGGNVTYQGVAVTRSRKEGIAHNYKNETEWRANIDTVM
  AWFTEEDLDLVTLYFGEPDSTGHRYGPESPERREMVRQVDRTVGYLRESIARNHLTDRLN
  LIITSDHGMTTVDKRAGDLVEFHKFPNFTFRDIEFELLDYGPNGMLLPKEGRLEKVYDAL
  KDAHPKLHVYKKEAFPEAFHYANNPRVTPLLMYSDLGYVIHGRINVQFNNGEHGFDNKDM
  DMKTIFRAVGPSFRAGLEVEPFESVHVYELMCRLLGIVPEANDGHLATLLPMLHTESALP
  PDGRPTLLPKGRSALPPSSRPLLVMGLLGTVILLSEVA
• Function: Choline-specific phosphodiesterase that hydrolyzes sphingomyelin releasing the ceramide and phosphocholine and therefore is involved in sphingomyelin digestion, ceramide formation, and fatty acid (FA) absorption in the gastrointestinal tract. Has also phospholipase C activity and can also cleave phosphocholine from palmitoyl lyso-phosphatidylcholine and platelet-activating factor (PAF) leading to its inactivation. Does not have nucleotide pyrophosphatase activity. May promote cholesterol absorption by affecting the levels of sphingomyelin derived from either diet or endogenous sources, in the intestinal lumen.
• Tissue Specificity: Detected in the colon (at protein level). Expressed in the duodenum, jejunum and liver and at low levels in the ileum. Expression was very low in the esophagus, stomach and colon.
• KEGG Pathway:
  Sphingolipid metabolism (hsa00600)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Glycosphingolipid catabolism (R-HSA-9840310)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenoma	DIS78ZEV	Strong	Biomarker	[1]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[2]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[2]
Colon cancer	DISVC52G	Strong	Biomarker	[2]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[2]
Cystic fibrosis	DIS2OK1Q	Strong	Biomarker	[3]
Familial adenomatous polyposis	DISW53RE	Strong	Genetic Variation	[1]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[1]
Colonic neoplasm	DISSZ04P	Disputed	Altered Expression	[4]

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Lysophosphatidylcholine	DMOGFVH	Investigative	Ectonucleotide pyrophosphatase/phosphodiesterase family member 7 (ENPP7) increases the hydrolysis of Lysophosphatidylcholine.	[8]

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 Ectonucleotide pyrophosphatase/phosphodiesterase family member 7 (ENPP7).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Ectonucleotide pyrophosphatase/phosphodiesterase family member 7 (ENPP7).	[11]

5 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 Ectonucleotide pyrophosphatase/phosphodiesterase family member 7 (ENPP7).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Ectonucleotide pyrophosphatase/phosphodiesterase family member 7 (ENPP7).	[7]
Adenosine triphosphate	DM79F6G	Approved	Adenosine triphosphate decreases the activity of Ectonucleotide pyrophosphatase/phosphodiesterase family member 7 (ENPP7).	[8]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Ectonucleotide pyrophosphatase/phosphodiesterase family member 7 (ENPP7).	[9]
OTX-015	DMI8RG1	Phase 1/2	OTX-015 decreases the expression of Ectonucleotide pyrophosphatase/phosphodiesterase family member 7 (ENPP7).	[10]

References

• [1] Reduction in alkaline sphingomyelinase in colorectal tumorigenesis is not related to the APC gene mutation.Int J Colorectal Dis. 2003 Jul;18(4):309-13. doi: 10.1007/s00384-002-0471-y. Epub 2003 Mar 4.
• [2] Alkaline sphingomyelinase: an old enzyme with novel implications.Biochim Biophys Acta. 2006 Mar;1761(3):281-91. doi: 10.1016/j.bbalip.2006.03.007. Epub 2006 Mar 30.
• [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] Intestinal alkaline sphingomyelinase hydrolyses and inactivates platelet-activating factor by a phospholipase C activity.Biochem J. 2006 Feb 15;394(Pt 1):299-308. doi: 10.1042/BJ20051121.
• [5] 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.
• [6] 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.
• [7] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [8] Identification of human intestinal alkaline sphingomyelinase as a novel ecto-enzyme related to the nucleotide phosphodiesterase family. J Biol Chem. 2003 Oct 3;278(40):38528-36. doi: 10.1074/jbc.M305437200. Epub 2003 Jul 28.
• [9] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [10] Comprehensive transcriptome profiling of BET inhibitor-treated HepG2 cells. PLoS One. 2022 Apr 29;17(4):e0266966. doi: 10.1371/journal.pone.0266966. eCollection 2022.
• [11] 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.
• [12] Identification of human intestinal alkaline sphingomyelinase as a novel ecto-enzyme related to the nucleotide phosphodiesterase family. J Biol Chem. 2003 Oct 3;278(40):38528-36. doi: 10.1074/jbc.M305437200. Epub 2003 Jul 28.