Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQ681DT)

• DOT Name: Sphingomyelin phosphodiesterase 4 (SMPD4)
• Synonyms: EC 3.1.4.12; Neutral sphingomyelinase 3; nSMase-3; nSMase3; Neutral sphingomyelinase III
• Gene Name: SMPD4
• Related Disease: Neurodevelopmental disorder with microcephaly, arthrogryposis, and structural brain anomalies
• UniProt ID: NSMA3_HUMAN
• EC Number: 3.1.4.12
• Pfam ID: PF14724
• Sequence:
  MTTFGAVAEWRLPSLRRATLWIPQWFAKKAIFNSPLEAAMAFPHLQQPSFLLASLKADSI
  NKPFAQQCQDLVKVIEDFPAKELHTIFPWLVESIFGSLDGVLVGWNLRCLQGRVNPVEYS
  IVMEFLDPGGPMMKLVYKLQAEDYKFDFPVSYLPGPVKASIQECILPDSPLYHNKVQFTP
  TGGLGLNLALNPFEYYIFFFALSLITQKPLPVSLHVRTSDCAYFILVDRYLSWFLPTEGS
  VPPPLSSSPGGTSPSPPPRTPAIPFASYGLHHTSLLKRHISHQTSVNADPASHEIWRSET
  LLQVFVEMWLHHYSLEMYQKMQSPHAKLEVLHYRLSVSSALYSPAQPSLQALHAYQESFT
  PTEEHVLVVRLLLKHLHAFANSLKPEQASPSAHSHATSPLEEFKRAAVPRFVQQKLYLFL
  QHCFGHWPLDASFRAVLEMWLSYLQPWRYAPDKQAPGSDSQPRCVSEKWAPFVQENLLMY
  TKLFVGFLNRALRTDLVSPKHALMVFRVAKVFAQPNLAEMIQKGEQLFLEPELVIPHRQH
  RLFTAPTFTGSFLSPWPPAVTDASFKVKSHVYSLEGQDCKYTPMFGPEARTLVLRLAQLI
  TQAKHTAKSISDQCAESPAGHSFLSWLGFSSMDTNGSYTANDLDEMGQDSVRKTDEYLEK
  ALEYLRQIFRLSEAQLRQFTLALGTTQDENGKKQLPDCIVGEDGLILTPLGRYQIINGLR
  RFEIEYQGDPELQPIRSYEIASLVRTLFRLSSAINHRFAGQMAALCSRDDFLGSFCRYHL
  TEPGLASRHLLSPVGRRQVAGHTRGPRLSLRFLGSYRTLVSLLLAFFVASLFCVGPLPCT
  LLLTLGYVLYASAMTLLTERGKLHQP
• Function: Catalyzes the hydrolysis of membrane sphingomyelin to form phosphorylcholine and ceramide. It has a relevant role in the homeostasis of membrane sphingolipids, thereby influencing membrane integrity, and endoplasmic reticulum organization and function. May sensitize cells to DNA damage-induced apoptosis. In skeletal muscle, mediates TNF-stimulated oxidant production.
• Tissue Specificity: Widely expressed, with highest levels in heart and skeletal muscle.; [Isoform 1]: Expressed in skeletal muscle (at protein level).; [Isoform 2]: Expressed in skeletal muscle but a lower levels than isoform 1 (at protein level).
• KEGG Pathway:
  Sphingolipid metabolism (hsa00600)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Glycosphingolipid catabolism (R-HSA-9840310)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neurodevelopmental disorder with microcephaly, arthrogryposis, and structural brain anomalies	DISM5BRZ	Strong	Autosomal recessive	[1]

4 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 4 (SMPD4).	[2]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Sphingomyelin phosphodiesterase 4 (SMPD4).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Sphingomyelin phosphodiesterase 4 (SMPD4).	[8]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Sphingomyelin phosphodiesterase 4 (SMPD4).	[9]

6 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 Sphingomyelin phosphodiesterase 4 (SMPD4).	[3]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Sphingomyelin phosphodiesterase 4 (SMPD4).	[4]
Marinol	DM70IK5	Approved	Marinol increases the expression of Sphingomyelin phosphodiesterase 4 (SMPD4).	[6]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Sphingomyelin phosphodiesterase 4 (SMPD4).	[7]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Sphingomyelin phosphodiesterase 4 (SMPD4).	[10]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Sphingomyelin phosphodiesterase 4 (SMPD4).	[11]

References

• [1] Loss of SMPD4 Causes a Developmental Disorder Characterized by Microcephaly and Congenital Arthrogryposis. Am J Hum Genet. 2019 Oct 3;105(4):689-705. doi: 10.1016/j.ajhg.2019.08.006. Epub 2019 Sep 5.
• [2] 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.
• [3] 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.
• [4] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [5] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [6] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [7] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [8] 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.
• [9] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [10] Isobaric tags for relative and absolute quantitation-based proteomics analysis of the effect of ginger oil on bisphenol A-induced breast cancer cell proliferation. Oncol Lett. 2021 Feb;21(2):101. doi: 10.3892/ol.2020.12362. Epub 2020 Dec 8.
• [11] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.