Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTE5BVP9)

• DOT Name: Sphingomyelin phosphodiesterase 2 (SMPD2)
• Synonyms: EC 3.1.4.12; Lyso-platelet-activating factor-phospholipase C; Lyso-PAF-PLC; Neutral sphingomyelinase; N-SMase; nSMase; nSMase1
• Gene Name: SMPD2
• UniProt ID: NSMA_HUMAN
• PDB ID: 8J2F
• EC Number: 3.1.4.12
• Pfam ID: PF03372
• Sequence:
  MKPNFSLRLRIFNLNCWGIPYLSKHRADRMRRLGDFLNQESFDLALLEEVWSEQDFQYLR
  QKLSPTYPAAHHFRSGIIGSGLCVFSKHPIQELTQHIYTLNGYPYMIHHGDWFSGKAVGL
  LVLHLSGMVLNAYVTHLHAEYNRQKDIYLAHRVAQAWELAQFIHHTSKKADVVLLCGDLN
  MHPEDLGCCLLKEWTGLHDAYLETRDFKGSEEGNTMVPKNCYVSQQELKPFPFGVRIDYV
  LYKAVSGFYISCKSFETTTGFDPHRGTPLSDHEALMATLFVRHSPPQQNPSSTHGPAERS
  PLMCVLKEAWTELGLGMAQARWWATFASYVIGLGLLLLALLCVLAAGGGAGEAAILLWTP
  SVGLVLWAGAFYLFHVQEVNGLYRAQAELQHVLGRAREAQDLGPEPQPALLLGQQEGDRT
  KEQ
• Function: Catalyzes, at least in vitro, the hydrolysis of sphingomyelin to form ceramide and phosphocholine. Also hydrolyzes 1-O-alkyl-2-lyso-sn-glycero-3-phosphocholine (lyso-platelet-activating factor) in vivo. Also acts on 1-acyl-2-lyso-sn-glycero-3-phosphocholine (lyso-PC) and sphingosylphosphocholine.
• KEGG Pathway:
  Sphingolipid metabolism (hsa00600)
  Metabolic pathways (hsa01100)
  Sphingolipid sig.ling pathway (hsa04071)
• Reactome Pathway:
  TNFR1-mediated ceramide production (R-HSA-5626978)
  Glycosphingolipid catabolism (R-HSA-9840310)
  Ceramide signalling (R-HSA-193681)

Molecular Interaction Atlas (MIA) of This DOT

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 Sphingomyelin phosphodiesterase 2 (SMPD2).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Sphingomyelin phosphodiesterase 2 (SMPD2).	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Sphingomyelin phosphodiesterase 2 (SMPD2).	[2]
DTI-015	DMXZRW0	Approved	DTI-015 increases the expression of Sphingomyelin phosphodiesterase 2 (SMPD2).	[3]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Sphingomyelin phosphodiesterase 2 (SMPD2).	[4]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Sphingomyelin phosphodiesterase 2 (SMPD2).	[6]
27-hydroxycholesterol	DM2L6OZ	Investigative	27-hydroxycholesterol decreases the activity of Sphingomyelin phosphodiesterase 2 (SMPD2).	[7]
Nicotinamide-Adenine-Dinucleotide	DM9LRKB	Investigative	Nicotinamide-Adenine-Dinucleotide affects the activity of Sphingomyelin phosphodiesterase 2 (SMPD2).	[8]

References

• [1] 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.
• [2] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [3] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [4] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [5] 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.
• [6] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [7] 27-Hydroxycholesterol inhibits neutral sphingomyelinase in cultured human endothelial cells. Life Sci. 2004 Aug 13;75(13):1567-77. doi: 10.1016/j.lfs.2004.05.004.
• [8] Reciprocal relationship between cytosolic NADH and ENOX2 inhibition triggers sphingolipid-induced apoptosis in HeLa cells. J Cell Biochem. 2010 Aug 15;110(6):1504-11. doi: 10.1002/jcb.22724.