Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZ3KNFJ)

• DOT Name: Acid sphingomyelinase-like phosphodiesterase 3b (SMPDL3B)
• Synonyms: ASM-like phosphodiesterase 3b; EC 3.1.4.-
• Gene Name: SMPDL3B
• Related Disease:
  Nephropathy
  Diabetic kidney disease
  Focal segmental glomerulosclerosis
  Moyamoya disease
• UniProt ID: ASM3B_HUMAN
• EC Number: 3.1.4.-
• Pfam ID: PF19272 ; PF00149
• Sequence:
  MRLLAWLIFLANWGGARAEPGKFWHIADLHLDPDYKVSKDPFQVCPSAGSQPVPDAGPWG
  DYLCDSPWALINSSIYAMKEIEPEPDFILWTGDDTPHVPDEKLGEAAVLEIVERLTKLIR
  EVFPDTKVYAALGNHDFHPKNQFPAGSNNIYNQIAELWKPWLSNESIALFKKGAFYCEKL
  PGPSGAGRIVVLNTNLYYTSNALTADMADPGQQFQWLEDVLTDASKAGDMVYIVGHVPPG
  FFEKTQNKAWFREGFNEKYLKVVRKHHRVIAGQFFGHHHTDSFRMLYDDAGVPISAMFIT
  PGVTPWKTTLPGVVNGANNPAIRVFEYDRATLSLKDMVTYFMNLSQANAQGTPRWELEYQ
  LTEAYGVPDASAHSMHTVLDRIAGDQSTLQRYYVYNSVSYSAGVCDEACSMQHVCAMRQV
  DIDAYTTCLYASGTTPVPQLPLLLMALLGLCTLVL
• Function: Lipid-modulating phosphodiesterase. Active on the surface of macrophages and dendritic cells and strongly influences macrophage lipid composition and membrane fluidity. Acts as a negative regulator of Toll-like receptor signaling. Has in vitro phosphodiesterase activity, but the physiological substrate is unknown. Lacks activity with phosphocholine-containing lipids, but can cleave CDP-choline, and can release phosphate from ATP and ADP (in vitro).

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Nephropathy	DISXWP4P	Definitive	Altered Expression	[1]
Diabetic kidney disease	DISJMWEY	Strong	Biomarker	[2]
Focal segmental glomerulosclerosis	DISJNHH0	Strong	Altered Expression	[3]
Moyamoya disease	DISO62CA	moderate	Genetic Variation	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Acid sphingomyelinase-like phosphodiesterase 3b (SMPDL3B).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Acid sphingomyelinase-like phosphodiesterase 3b (SMPDL3B).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Acid sphingomyelinase-like phosphodiesterase 3b (SMPDL3B).	[7]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Acid sphingomyelinase-like phosphodiesterase 3b (SMPDL3B).	[9]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Acid sphingomyelinase-like phosphodiesterase 3b (SMPDL3B).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Acid sphingomyelinase-like phosphodiesterase 3b (SMPDL3B).	[12]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Acid sphingomyelinase-like phosphodiesterase 3b (SMPDL3B).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Acid sphingomyelinase-like phosphodiesterase 3b (SMPDL3B).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Acid sphingomyelinase-like phosphodiesterase 3b (SMPDL3B).	[11]

References

• [1] Rituximab protects podocytes and exerts anti-proteinuric effects in rat adriamycin-induced nephropathy independent of B-lymphocytes.Nephrology (Carlton). 2017 Jan;22(1):49-57. doi: 10.1111/nep.12737.
• [2] SMPDL3b modulates insulin receptor signaling in diabetic kidney disease.Nat Commun. 2019 Jun 19;10(1):2692. doi: 10.1038/s41467-019-10584-4.
• [3] Lipid biology of the podocyte--new perspectives offer new opportunities.Nat Rev Nephrol. 2014 Jul;10(7):379-88. doi: 10.1038/nrneph.2014.87. Epub 2014 May 27.
• [4] Novel Susceptibility Loci for Moyamoya Disease Revealed by a Genome-Wide Association Study.Stroke. 2018 Jan;49(1):11-18. doi: 10.1161/STROKEAHA.117.017430.
• [5] 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.
• [6] 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.
• [7] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [8] 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.
• [9] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [10] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [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] 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.
• [13] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.