Details of Drug Off-Target (DOT)

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

DOT Name	Sphingomyelin phosphodiesterase 3 (SMPD3)
Synonyms	EC 3.1.4.12; Neutral sphingomyelinase 2; nSMase-2; nSMase2; Neutral sphingomyelinase II
Gene Name	SMPD3
Related Disease	Alzheimer disease ( ) Arteriosclerosis ( ) Atherosclerosis ( ) Breast cancer ( ) Breast carcinoma ( ) Breast neoplasm ( ) Chronic kidney disease ( ) Chronic obstructive pulmonary disease ( ) Cognitive impairment ( ) Hepatocellular carcinoma ( ) Hyperphosphatemia ( ) Hypopituitarism ( ) Isolated congenital microcephaly ( ) Leukemia ( ) Mycobacterium infection ( ) Myelodysplastic syndrome ( ) Neoplasm ( ) Osteogenesis imperfecta ( ) Osteogenesis imperfecta type 2 ( ) Osteogenesis imperfecta type 3 ( ) Panhypopituitarism ( ) Parkinson disease ( ) Pulmonary hypertension ( ) Schizophrenia ( ) Zika virus infection ( ) Acute myelogenous leukaemia ( ) Lymphoid leukemia ( ) Nervous system disease ( ) Pachyonychia congenita 3 ( )
UniProt ID	NSMA2_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
PDB ID	5UVG
EC Number	3.1.4.12
Pfam ID	PF03372
Sequence	MVLYTTPFPNSCLSALHCVSWALIFPCYWLVDRLAASFIPTTYEKRQRADDPCCLQLLCT ALFTPIYLALLVASLPFAFLGFLFWSPLQSARRPYIYSRLEDKGLAGGAALLSEWKGTGP GKSFCFATANVCLLPDSLARVNNLFNTQARAKEIGQRIRNGAARPQIKIYIDSPTNTSIS AASFSSLVSPQGGDGVARAVPGSIKRTASVEYKGDGGRHPGDEAANGPASGDPVDSSSPE DACIVRIGGEEGGRPPEADDPVPGGQARNGAGGGPRGQTPNHNQQDGDSGSLGSPSASRE SLVKGRAGPDTSASGEPGANSKLLYKASVVKKAAARRRRHPDEAFDHEVSAFFPANLDFL CLQEVFDKRAATKLKEQLHGYFEYILYDVGVYGCQGCCSFKCLNSGLLFASRYPIMDVAY HCYPNKCNDDALASKGALFLKVQVGSTPQDQRIVGYIACTHLHAPQEDSAIRCGQLDLLQ DWLADFRKSTSSSSAANPEELVAFDVVCGDFNFDNCSSDDKLEQQHSLFTHYRDPCRLGP GEEKPWAIGTLLDTNGLYDEDVCTPDNLQKVLESEEGRREYLAFPTSKSSGQKGRKELLK GNGRRIDYMLHAEEGLCPDWKAEVEEFSFITQLSGLTDHLPVAMRLMVSSGEEEA
Function	Catalyzes the hydrolysis of sphingomyelin to form ceramide and phosphocholine. Ceramide mediates numerous cellular functions, such as apoptosis and growth arrest, and is capable of regulating these 2 cellular events independently. Also hydrolyzes sphingosylphosphocholine. Regulates the cell cycle by acting as a growth suppressor in confluent cells. Probably acts as a regulator of postnatal development and participates in bone and dentin mineralization. Binds to anionic phospholipids (APLs) such as phosphatidylserine (PS) and phosphatidic acid (PA) that modulate enzymatic activity and subcellular location. May be involved in IL-1-beta-induced JNK activation in hepatocytes. May act as a mediator in transcriptional regulation of NOS2/iNOS via the NF-kappa-B activation under inflammatory conditions.
Tissue Specificity	Predominantly expressed in brain.
KEGG Pathway	Sphingolipid metabolism (hsa00600 ) Metabolic pathways (hsa01100 )
Reactome Pathway	Glycosphingolipid catabolism (R-HSA-9840310 ) TNFR1-mediated ceramide production (R-HSA-5626978 )

Molecular Interaction Atlas (MIA) of This DOT

29 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Alzheimer disease	DISF8S70	Strong	Biomarker	[1]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[2]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[3]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[3]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[4]
Chronic kidney disease	DISW82R7	Strong	Altered Expression	[5]
Chronic obstructive pulmonary disease	DISQCIRF	Strong	Biomarker	[6]
Cognitive impairment	DISH2ERD	Strong	Biomarker	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Genetic Variation	[7]
Hyperphosphatemia	DISHW3R3	Strong	Altered Expression	[5]
Hypopituitarism	DIS1QT3G	Strong	Biomarker	[8]
Isolated congenital microcephaly	DISUXHZ6	Strong	Altered Expression	[9]
Leukemia	DISNAKFL	Strong	Genetic Variation	[10]
Mycobacterium infection	DISNSMUD	Strong	Biomarker	[11]
Myelodysplastic syndrome	DISYHNUI	Strong	Biomarker	[12]
Neoplasm	DISZKGEW	Strong	Biomarker	[7]
Osteogenesis imperfecta	DIS7XQSD	Strong	Biomarker	[13]
Osteogenesis imperfecta type 2	DISMGSS3	Strong	Biomarker	[14]
Osteogenesis imperfecta type 3	DISFJVSJ	Strong	Biomarker	[14]
Panhypopituitarism	DISAKJ4T	Strong	Biomarker	[8]
Parkinson disease	DISQVHKL	Strong	Biomarker	[15]
Pulmonary hypertension	DIS1RSP5	Strong	Therapeutic	[16]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[17]
Zika virus infection	DISQUCTY	Strong	Biomarker	[9]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[10]
Lymphoid leukemia	DIS65TYQ	Limited	Genetic Variation	[10]
Nervous system disease	DISJ7GGT	Limited	Biomarker	[18]
Pachyonychia congenita 3	DISZLC6C	Limited	Altered Expression	[19]
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Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

1 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 3 (SMPD3).	[20]
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15 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Sphingomyelin phosphodiesterase 3 (SMPD3).	[21]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Sphingomyelin phosphodiesterase 3 (SMPD3).	[22]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Sphingomyelin phosphodiesterase 3 (SMPD3).	[23]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Sphingomyelin phosphodiesterase 3 (SMPD3).	[24]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the activity of Sphingomyelin phosphodiesterase 3 (SMPD3).	[25]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Sphingomyelin phosphodiesterase 3 (SMPD3).	[26]
Daunorubicin	DMQUSBT	Approved	Daunorubicin increases the expression of Sphingomyelin phosphodiesterase 3 (SMPD3).	[3]
Plicamycin	DM7C8YV	Approved	Plicamycin decreases the expression of Sphingomyelin phosphodiesterase 3 (SMPD3).	[3]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Sphingomyelin phosphodiesterase 3 (SMPD3).	[28]
Camptothecin	DM6CHNJ	Phase 3	Camptothecin increases the expression of Sphingomyelin phosphodiesterase 3 (SMPD3).	[3]
OTX-015	DMI8RG1	Phase 1/2	OTX-015 increases the expression of Sphingomyelin phosphodiesterase 3 (SMPD3).	[29]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Sphingomyelin phosphodiesterase 3 (SMPD3).	[30]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Sphingomyelin phosphodiesterase 3 (SMPD3).	[31]
Mivebresib	DMCPF90	Phase 1	Mivebresib increases the expression of Sphingomyelin phosphodiesterase 3 (SMPD3).	[29]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Sphingomyelin phosphodiesterase 3 (SMPD3).	[32]
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⏷ Show the Full List of 15 Drug(s)

References

1	Neutral Sphingomyelinase-2 Deficiency Ameliorates Alzheimer's Disease Pathology and Improves Cognition in the 5XFAD Mouse.J Neurosci. 2016 Aug 17;36(33):8653-67. doi: 10.1523/JNEUROSCI.1429-16.2016.
2	nSMase2 (Type 2-Neutral Sphingomyelinase) Deficiency or Inhibition by GW4869 Reduces Inflammation and Atherosclerosis in Apoe(-/-) Mice.Arterioscler Thromb Vasc Biol. 2018 Jul;38(7):1479-1492. doi: 10.1161/ATVBAHA.118.311208. Epub 2018 May 24.
3	Transcriptional regulation of neutral sphingomyelinase 2 gene expression of a human breast cancer cell line, MCF-7, induced by the anti-cancer drug, daunorubicin. Biochim Biophys Acta. 2009 Nov-Dec;1789(11-12):681-90. doi: 10.1016/j.bbagrm.2009.08.006. Epub 2009 Aug 19.
4	Comparative epigenomics of human and mouse mammary tumors.Genes Chromosomes Cancer. 2009 Jan;48(1):83-97. doi: 10.1002/gcc.20620.
5	Barley--glucans reduce systemic inflammation, renal injury and aortic calcification through ADAM17 and neutral-sphingomyelinase2 inhibition.Sci Rep. 2019 Nov 28;9(1):17810. doi: 10.1038/s41598-019-54306-8.
6	Neutral sphingomyelinase 2: a novel target in cigarette smoke-induced apoptosis and lung injury.Am J Respir Cell Mol Biol. 2011 Mar;44(3):350-60. doi: 10.1165/rcmb.2009-0422OC. Epub 2010 May 6.
7	Increased liver tumor formation in neutral sphingomyelinase-2-deficient mice.J Lipid Res. 2018 May;59(5):795-804. doi: 10.1194/jlr.M080879. Epub 2018 Mar 22.
8	Neutral sphingomyelinase 2 (smpd3) in the control of postnatal growth and development.Proc Natl Acad Sci U S A. 2005 Mar 22;102(12):4554-9. doi: 10.1073/pnas.0406380102. Epub 2005 Mar 11.
9	Exosomes mediate Zika virus transmission through SMPD3 neutral Sphingomyelinase in cortical neurons.Emerg Microbes Infect. 2019;8(1):307-326. doi: 10.1080/22221751.2019.1578188.
10	Mutations in the neutral sphingomyelinase gene SMPD3 implicate the ceramide pathway in human leukemias.Blood. 2008 May 1;111(9):4716-22. doi: 10.1182/blood-2007-10-113068. Epub 2008 Feb 25.
11	Mycobacterial Infection is Promoted by Neutral Sphingomyelinase 2 Regulating a Signaling Cascade Leading to Activation of 1-Integrin.Cell Physiol Biochem. 2018;51(4):1815-1829. doi: 10.1159/000495683. Epub 2018 Nov 30.
12	Implications of sphingosine kinase 1 expression level for the cellular sphingolipid rheostat: relevance as a marker for daunorubicin sensitivity of leukemia cells.Int J Hematol. 2008 Apr;87(3):266-75. doi: 10.1007/s12185-008-0052-0. Epub 2008 Feb 20.
13	Neutral Sphingomyelinase 2 (SMPD3) Deficiency in Mice Causes Chondrodysplasia with Unimpaired Skeletal Mineralization.Am J Pathol. 2019 Sep;189(9):1831-1845. doi: 10.1016/j.ajpath.2019.05.008. Epub 2019 Jun 12.
14	A deletion in the gene encoding sphingomyelin phosphodiesterase 3 (Smpd3) results in osteogenesis and dentinogenesis imperfecta in the mouse.Nat Genet. 2005 Aug;37(8):803-5. doi: 10.1038/ng1603. Epub 2005 Jul 17.
15	Inhibition of nSMase2 Reduces the Transfer of Oligomeric -Synuclein Irrespective of Hypoxia.Front Mol Neurosci. 2019 Aug 28;12:200. doi: 10.3389/fnmol.2019.00200. eCollection 2019.
16	Activation of neutral sphingomyelinase is involved in acute hypoxic pulmonary vasoconstriction.Cardiovasc Res. 2009 May 1;82(2):296-302. doi: 10.1093/cvr/cvn349. Epub 2008 Dec 16.
17	Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways.Am J Hum Genet. 2019 Aug 1;105(2):334-350. doi: 10.1016/j.ajhg.2019.06.012.
18	Neutral sphingomyelinase 2 inhibitors based on the 4-(1H-imidazol-2-yl)-2,6-dialkoxyphenol scaffold.Eur J Med Chem. 2019 May 15;170:276-289. doi: 10.1016/j.ejmech.2019.03.015. Epub 2019 Mar 9.
19	Osteolytic prostate cancer cells induce the expression of specific cytokines in bone-forming osteoblasts through a Stat3/5-dependent mechanism.Bone. 2010 Feb;46(2):524-33. doi: 10.1016/j.bone.2009.09.024. Epub 2009 Sep 29.
20	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.
21	Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
22	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.
23	Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
24	Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
25	Reactive nitrogen and oxygen species activate different sphingomyelinases to induce apoptosis in airway epithelial cells. Exp Cell Res. 2007 Jul 15;313(12):2680-6. doi: 10.1016/j.yexcr.2007.04.002. Epub 2007 Apr 6.
26	Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
27	Transcriptional regulation of neutral sphingomyelinase 2 gene expression of a human breast cancer cell line, MCF-7, induced by the anti-cancer drug, daunorubicin. Biochim Biophys Acta. 2009 Nov-Dec;1789(11-12):681-90. doi: 10.1016/j.bbagrm.2009.08.006. Epub 2009 Aug 19.
28	Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
29	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.
30	Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
31	CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
32	Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.