Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAB7MZF)

• DOT Name: ORM1-like protein 3 (ORMDL3)
• Gene Name: ORMDL3
• Related Disease:
  Allergic rhinitis
  Ankylosing spondylitis
  Arteriosclerosis
  Atherosclerosis
  Autoimmune disease
  Chronic obstructive pulmonary disease
  Colitis
  Glioma
  Inflammatory bowel disease
  Lupus
  Primary biliary cholangitis
  Rhinitis
  Systemic lupus erythematosus
  Breast cancer
  Breast carcinoma
  Crohn disease
  Immune system disorder
  Neoplasm
  Rheumatoid arthritis
  Ulcerative colitis
• UniProt ID: ORML3_HUMAN
• PDB ID: 6M4N; 6M4O; 7CQI; 7CQK; 7K0M; 7K0N; 7K0O; 7K0P; 7K0Q; 7YIU; 7YIY; 7YJ1; 7YJ2
• Pfam ID: PF04061
• Sequence:
  MNVGTAHSEVNPNTRVMNSRGIWLSYVLAIGLLHIVLLSIPFVSVPVVWTLTNLIHNMGM
  YIFLHTVKGTPFETPDQGKARLLTHWEQMDYGVQFTASRKFLTITPIVLYFLTSFYTKYD
  QIHFVLNTVSLMSVLIPKLPQLHGVRIFGINKY
• 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 and thymus.
• Reactome Pathway:
  Neutrophil degranulation (R-HSA-6798695)
  Sphingolipid de novo biosynthesis (R-HSA-1660661)

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Allergic rhinitis	DIS3U9HN	Strong	Genetic Variation	[1]
Ankylosing spondylitis	DISRC6IR	Strong	Genetic Variation	[2]
Arteriosclerosis	DISK5QGC	Strong	Genetic Variation	[3]
Atherosclerosis	DISMN9J3	Strong	Genetic Variation	[3]
Autoimmune disease	DISORMTM	Strong	Genetic Variation	[4]
Chronic obstructive pulmonary disease	DISQCIRF	Strong	Genetic Variation	[5]
Colitis	DISAF7DD	Strong	Biomarker	[6]
Glioma	DIS5RPEH	Strong	Genetic Variation	[7]
Inflammatory bowel disease	DISGN23E	Strong	Genetic Variation	[8]
Lupus	DISOKJWA	Strong	Altered Expression	[9]
Primary biliary cholangitis	DIS43E0O	Strong	Genetic Variation	[10]
Rhinitis	DISKLMN7	Strong	Genetic Variation	[5]
Systemic lupus erythematosus	DISI1SZ7	Strong	Altered Expression	[9]
Breast cancer	DIS7DPX1	moderate	Genetic Variation	[11]
Breast carcinoma	DIS2UE88	moderate	Genetic Variation	[11]
Crohn disease	DIS2C5Q8	moderate	Biomarker	[12]
Immune system disorder	DISAEGPH	moderate	Biomarker	[13]
Neoplasm	DISZKGEW	moderate	Genetic Variation	[11]
Rheumatoid arthritis	DISTSB4J	Limited	Genetic Variation	[14]
Ulcerative colitis	DIS8K27O	Limited	Genetic Variation	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of ORM1-like protein 3 (ORMDL3).	[16]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of ORM1-like protein 3 (ORMDL3).	[17]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of ORM1-like protein 3 (ORMDL3).	[18]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of ORM1-like protein 3 (ORMDL3).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of ORM1-like protein 3 (ORMDL3).	[22]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of ORM1-like protein 3 (ORMDL3).	[23]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of ORM1-like protein 3 (ORMDL3).	[25]

3 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 ORM1-like protein 3 (ORMDL3).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of ORM1-like protein 3 (ORMDL3).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of ORM1-like protein 3 (ORMDL3).	[24]

References

• [1] Variants in the 17q21 asthma susceptibility locus are associated with allergic rhinitis in the Japanese population.Allergy. 2013 Jan;68(1):92-100. doi: 10.1111/all.12066. Epub 2012 Nov 12.
• [2] Genetic variants on 17q21 are associated with ankylosing spondylitis susceptibility and severity in a Chinese Han population.Scand J Rheumatol. 2013;42(6):469-72. doi: 10.3109/03009742.2013.786755.
• [3] ORMDL3 and its implication in inflammatory disorders.Int J Rheum Dis. 2018 Jun;21(6):1154-1162. doi: 10.1111/1756-185X.13324.
• [4] 17q21 asthma-risk variants switch CTCF binding and regulate IL-2 production by T cells.Nat Commun. 2016 Nov 16;7:13426. doi: 10.1038/ncomms13426.
• [5] A polymorphism in ORMDL3 is associated not only with asthma without rhinitis but also with chronic obstructive pulmonary disease.J Investig Allergol Clin Immunol. 2013;23(4):256-61.
• [6] Upregulation of miR-665 promotes apoptosis and colitis in inflammatory bowel disease by repressing the endoplasmic reticulum stress components XBP1 and ORMDL3.Cell Death Dis. 2017 Mar 23;8(3):e2699. doi: 10.1038/cddis.2017.76.
• [7] Allergy and glioma risk: test of association by genotype.Int J Cancer. 2011 Apr 1;128(7):1736-40. doi: 10.1002/ijc.25483. Epub 2010 May 25.
• [8] Ceramide Imbalance and Impaired TLR4-Mediated Autophagy in BMDM of an ORMDL3-Overexpressing Mouse Model.Int J Mol Sci. 2019 Mar 20;20(6):1391. doi: 10.3390/ijms20061391.
• [9] ORMDL3 Facilitates the Survival of Splenic B Cells via an ATF6-Endoplasmic Reticulum Stress-Beclin1 Autophagy Regulatory Pathway.J Immunol. 2017 Sep 1;199(5):1647-1659. doi: 10.4049/jimmunol.1602124. Epub 2017 Jul 26.
• [10] Identification of the functional variant driving ORMDL3 and GSDMB expression in human chromosome 17q12-21 in primary biliary cholangitis.Sci Rep. 2017 Jun 6;7(1):2904. doi: 10.1038/s41598-017-03067-3.
• [11] Identifying genes with tri-modal association with survival and tumor grade in cancer patients.BMC Bioinformatics. 2019 Jan 8;20(1):13. doi: 10.1186/s12859-018-2582-7.
• [12] Influence of Crohn's disease related polymorphisms in innate immune function on ileal microbiome.PLoS One. 2019 Feb 28;14(2):e0213108. doi: 10.1371/journal.pone.0213108. eCollection 2019.
• [13] Chromosome 17q21 Genes ORMDL3 and GSDMB in Asthma and Immune Diseases.Adv Immunol. 2017;135:1-52. doi: 10.1016/bs.ai.2017.06.001. Epub 2017 Jul 19.
• [14] Use of a multiethnic approach to identify rheumatoid- arthritis-susceptibility loci, 1p36 and 17q12.Am J Hum Genet. 2012 Mar 9;90(3):524-32. doi: 10.1016/j.ajhg.2012.01.010. Epub 2012 Feb 23.
• [15] Deep Resequencing of Ulcerative Colitis-Associated Genes Identifies Novel Variants in Candidate Genes in the Korean Population.Inflamm Bowel Dis. 2018 Jul 12;24(8):1706-1717. doi: 10.1093/ibd/izy122.
• [16] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [17] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [18] 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.
• [19] 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.
• [20] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [21] 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.
• [22] 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.
• [23] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [24] 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.
• [25] 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.