Details of Drug Off-Target (DOT)

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

• DOT Name: Sphingomyelin synthase-related protein 1 (SAMD8)
• Synonyms: SMSr; EC 2.7.8.-; Ceramide phosphoethanolamine synthase; CPE synthase; Sterile alpha motif domain-containing protein 8; SAM domain-containing protein 8
• Gene Name: SAMD8
• UniProt ID: SAMD8_HUMAN
• EC Number: 2.7.8.-
• Pfam ID: PF14360 ; PF00536
• Sequence:
  MAGPNQLCIRRWTTKHVAVWLKDEGFFEYVDILCNKHRLDGITLLTLTEYDLRSPPLEIK
  VLGDIKRLMLSVRKLQKIHIDVLEEMGYNSDSPMGSMTPFISALQSTDWLCNGELSHDCD
  GPITDLNSDQYQYMNGKNKHSVRRLDPEYWKTILSCIYVFIVFGFTSFIMVIVHERVPDM
  QTYPPLPDIFLDSVPRIPWAFAMTEVCGMILCYIWLLVLLLHKHRSILLRRLCSLMGTVF
  LLRCFTMFVTSLSVPGQHLQCTGKIYGSVWEKLHRAFAIWSGFGMTLTGVHTCGDYMFSG
  HTVVLTMLNFFVTEYTPRSWNFLHTLSWVLNLFGIFFILAAHEHYSIDVFIAFYITTRLF
  LYYHTLANTRAYQQSRRARIWFPMFSFFECNVNGTVPNEYCWPFSKPAIMKRLIG
• Function: Sphingomyelin synthases synthesize sphingolipids through transfer of a phosphatidyl head group on to the primary hydroxyl of ceramide. SAMD8 is an endoplasmic reticulum (ER) transferase that has no sphingomyelin synthase activity but can convert phosphatidylethanolamine (PE) and ceramide to ceramide phosphoethanolamine (CPE) albeit with low product yield. Appears to operate as a ceramide sensor to control ceramide homeostasis in the endoplasmic reticulum rather than a converter of ceramides. Seems to be critical for the integrity of the early secretory pathway.
• Reactome Pathway: Sphingolipid de novo biosynthesis (R-HSA-1660661)

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 synthase-related protein 1 (SAMD8).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Sphingomyelin synthase-related protein 1 (SAMD8).	[8]

8 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 Sphingomyelin synthase-related protein 1 (SAMD8).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Sphingomyelin synthase-related protein 1 (SAMD8).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Sphingomyelin synthase-related protein 1 (SAMD8).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Sphingomyelin synthase-related protein 1 (SAMD8).	[5]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Sphingomyelin synthase-related protein 1 (SAMD8).	[6]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Sphingomyelin synthase-related protein 1 (SAMD8).	[7]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Sphingomyelin synthase-related protein 1 (SAMD8).	[9]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Sphingomyelin synthase-related protein 1 (SAMD8).	[10]

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] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] 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.
• [4] 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.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] 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.
• [7] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [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] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [10] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.