Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0LBF1R)

• DOT Name: ORM1-like protein 1 (ORMDL1)
• Synonyms: Adoplin-1
• Gene Name: ORMDL1
• Related Disease: Asthma
• UniProt ID: ORML1_HUMAN
• Pfam ID: PF04061
• Sequence:
  MNVGVAHSEVNPNTRVMNSRGMWLTYALGVGLLHIVLLSIPFFSVPVAWTLTNIIHNLGM
  YVFLHAVKGTPFETPDQGKARLLTHWEQLDYGVQFTSSRKFFTISPIILYFLASFYTKYD
  PTHFILNTASLLSVLIPKMPQLHGVRIFGINKY
• Function: Plays an essential role in the homeostatic regulation of sphingolipid de novo biosynthesis by modulating the activity of the serine palmitoyltransferase (SPT) in response to ceramide levels. When complexed to SPT, the binding of ceramides to its N-terminus stabilizes a conformation that block SPT substrate entry, hence preventing SPT catalytic activity. Through this mechanism, maintains ceramide levels at sufficient concentrations for the production of complex sphingolipids, but which prevents the accumulation of ceramides to levels that trigger apoptosis.
• Tissue Specificity: Widely expressed. Expressed in adult and fetal heart, brain, lung, liver, skeletal muscle and kidney. Expressed in adult pancreas and placenta and in fetal spleen abd thymus. Expressed at intermediate level in pancreas, placenta and brain but low in skeletal muscle and lung.
• Reactome Pathway: Sphingolipid de novo biosynthesis (R-HSA-1660661)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Asthma	DISW9QNS	Limited	Genetic Variation	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of ORM1-like protein 1 (ORMDL1).	[2]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of ORM1-like protein 1 (ORMDL1).	[8]

5 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 ORM1-like protein 1 (ORMDL1).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of ORM1-like protein 1 (ORMDL1).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of ORM1-like protein 1 (ORMDL1).	[5]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of ORM1-like protein 1 (ORMDL1).	[6]
SB-431542	DM0YOXQ	Preclinical	SB-431542 increases the expression of ORM1-like protein 1 (ORMDL1).	[7]

References

• [1] Childhood asthma is associated with mutations and gene expression differences of ORMDL genes that can interact.Allergy. 2015 Oct;70(10):1288-99. doi: 10.1111/all.12652. Epub 2015 Jul 20.
• [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] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [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] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [7] Activin/nodal signaling switches the terminal fate of human embryonic stem cell-derived trophoblasts. J Biol Chem. 2015 Apr 3;290(14):8834-48.
• [8] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.