Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2N1MW0)

• DOT Name: ORM1-like protein 2 (ORMDL2)
• Synonyms: Adoplin-2
• Gene Name: ORMDL2
• Related Disease: Asthma
• UniProt ID: ORML2_HUMAN
• Pfam ID: PF04061
• Sequence:
  MNVGVAHSEVNPNTRVMNSRGIWLAYIILVGLLHMVLLSIPFFSIPVVWTLTNVIHNLAT
  YVFLHTVKGTPFETPDQGKARLLTHWEQMDYGLQFTSSRKFLSISPIVLYLLASFYTKYD
  AAHFLINTASLLSVLLPKLPQFHGVRVFGINKY
• 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.
• 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]

1 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 2 (ORMDL2).	[2]

16 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 2 (ORMDL2).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of ORM1-like protein 2 (ORMDL2).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of ORM1-like protein 2 (ORMDL2).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate affects the expression of ORM1-like protein 2 (ORMDL2).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of ORM1-like protein 2 (ORMDL2).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin increases the expression of ORM1-like protein 2 (ORMDL2).	[8]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of ORM1-like protein 2 (ORMDL2).	[9]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of ORM1-like protein 2 (ORMDL2).	[10]
Menadione	DMSJDTY	Approved	Menadione affects the expression of ORM1-like protein 2 (ORMDL2).	[11]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of ORM1-like protein 2 (ORMDL2).	[12]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of ORM1-like protein 2 (ORMDL2).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of ORM1-like protein 2 (ORMDL2).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of ORM1-like protein 2 (ORMDL2).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of ORM1-like protein 2 (ORMDL2).	[16]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of ORM1-like protein 2 (ORMDL2).	[17]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of ORM1-like protein 2 (ORMDL2).	[18]

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] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] 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.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [8] 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.
• [9] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [10] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [11] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [12] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [18] Ochratoxin a lowers mRNA levels of genes encoding for key proteins of liver cell metabolism. Cancer Genomics Proteomics. 2008 Nov-Dec;5(6):319-32.