Details of Drug Off-Target (DOT)

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

• DOT Name: Transmembrane O-methyltransferase (LRTOMT)
• Synonyms: EC 2.1.1.6; Catechol O-methyltransferase 2; Protein LRTOMT2
• Gene Name: LRTOMT
• Related Disease:
  Autosomal recessive nonsyndromic hearing loss 63
  Breast cancer
  Breast carcinoma
  Deafness
  Sensorineural hearing loss disorder
  Hearing loss, autosomal recessive
• UniProt ID: TOMT_HUMAN
• EC Number: 2.1.1.6
• Pfam ID: PF01596
• Sequence:
  MGTPWRKRKGIAGPGLPDLSCALVLQPRAQVGTMSPAIALAFLPLVVTLLVRYRHYFRLL
  VRTVLLRSLRDCLSGLRIEERAFSYVLTHALPGDPGHILTTLDHWSSRCEYLSHMGPVKG
  QILMRLVEEKAPACVLELGTYCGYSTLLIARALPPGGRLLTVERDPRTAAVAEKLIRLAG
  FDEHMVELIVGSSEDVIPCLRTQYQLSRADLVLLAHRPRCYLRDLQLLEAHALLPAGATV
  LADHVLFPGAPRFLQYAKSCGRYRCRLHHTGLPDFPAIKDGIAQLTYAGPG
• Function: Catalyzes the O-methylation, and thereby the inactivation, of catecholamine neurotransmitters and catechol hormones. Required for auditory function. Component of the cochlear hair cell's mechanotransduction (MET) machinery. Involved in the assembly of the asymmetric tip-link MET complex. Required for transportation of TMC1 and TMC2 proteins into the mechanically sensitive stereocilia of the hair cells. The function in MET is independent of the enzymatic activity.
• KEGG Pathway:
  Steroid hormone biosynthesis (hsa00140)
  Tyrosine metabolism (hsa00350)
  Metabolic pathways (hsa01100)
  Dopaminergic sy.pse (hsa04728)
• Reactome Pathway: Enzymatic degradation of dopamine by COMT (R-HSA-379397)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal recessive nonsyndromic hearing loss 63	DISQF924	Definitive	Autosomal recessive	[1]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[2]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[2]
Deafness	DISKCLH4	Strong	Genetic Variation	[3]
Sensorineural hearing loss disorder	DISJV45Z	Strong	Biomarker	[4]
Hearing loss, autosomal recessive	DIS8G9R9	Supportive	Autosomal recessive	[5]

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 Transmembrane O-methyltransferase (LRTOMT).	[6]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Transmembrane O-methyltransferase (LRTOMT).	[7]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Transmembrane O-methyltransferase (LRTOMT).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Transmembrane O-methyltransferase (LRTOMT).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Transmembrane O-methyltransferase (LRTOMT).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Transmembrane O-methyltransferase (LRTOMT).	[9]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Val158Met Polymorphism in catechol-O-methyltransferase gene associated with risk factors for breast cancer.Cancer Epidemiol Biomarkers Prev. 2003 Sep;12(9):838-47.
• [3] The c.242G>A mutation in LRTOMT gene is responsible for a high prevalence of deafness in the Moroccan population.Mol Biol Rep. 2012 Dec;39(12):11011-6. doi: 10.1007/s11033-012-2003-3. Epub 2012 Oct 8.
• [4] A catechol-O-methyltransferase that is essential for auditory function in mice and humans.Proc Natl Acad Sci U S A. 2008 Sep 23;105(38):14609-14. doi: 10.1073/pnas.0807219105. Epub 2008 Sep 15.
• [5] Genetic Hearing Loss Overview. 1999 Feb 14 [updated 2023 Sep 28]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [6] 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.
• [7] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [8] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [9] 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.
• [10] 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.
• [11] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.