Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTY1QWYU)

• DOT Name: Protein O-mannosyl-transferase TMTC2 (TMTC2)
• Synonyms: EC 2.4.1.109; Transmembrane O-mannosyltransferase targeting cadherins 2; Transmembrane and tetratricopeptide repeat-containing 2
• Gene Name: TMTC2
• Related Disease:
  Glaucoma/ocular hypertension
  Asthma
  OPTN-related open angle glaucoma
  Sensorineural hearing loss disorder
  Nonsyndromic genetic hearing loss
• UniProt ID: TMTC2_HUMAN
• EC Number: 2.4.1.109
• Pfam ID: PF08409 ; PF00515 ; PF13424 ; PF13432 ; PF13181
• Sequence:
  MIAELVSSALGLALYLNTLSADFCYDDSRAIKTNQDLLPETPWTHIFYNDFWGTLLTHSG
  SHKSYRPLCTLSFRLNHAIGGLNPWSYHLVNVLLHAAVTGLFTSFSKILLGDGYWTFMAG
  LMFASHPIHTEAVAGIVGRADVGASLFFLLSLLCYIKHCSTRGYSARTWGWFLGSGLCAG
  CSMLWKEQGVTVLAVSAVYDVFVFHRLKIKQILPTIYKRKNLSLFLSISLLIFWGSSLLG
  ARLYWMGNKPPSFSNSDNPAADSDSLLTRTLTFFYLPTKNLWLLLCPDTLSFDWSMDAVP
  LLKTVCDWRNLHTVAFYTGLLLLAYYGLKSPSVDRECNGKTVTNGKQNANGHSCLSDVEY
  QNSETKSSFASKVENGIKNDVSQRTQLPSTENIVVLSLSLLIIPFVPATNLFFYVGFVIA
  ERVLYIPSMGFCLLITVGARALYVKVQKRFLKSLIFYATATLIVFYGLKTAIRNGDWQNE
  EMLYRSGIKVNPAKAWGNLGNVLKSQSKISEAESAYRNALYYRSNMADMLYNLGLLLQEN
  SRFAEALHYYKLAIGSRPTLASAYLNTGIILMNQGRTEEARRTFLKCSEIPDENLKDPHA
  HKSSVTSCLYNLGKLYHEQGHYEEALSVYKEAIQKMPRQFAPQSLYNMMGEAYMRLSKLP
  EAEHWYMESLRSKTDHIPAHLTYGKLLALTGRKSEAEKLFLKAIELDPTKGNCYMHYGQF
  LLEEARLIEAAEMAKKAAELDSTEFDVVFNAAHMLRQASLNEAAEKYYDLAARLRPNYPA
  ALMNLGAILHLNGRLQKAEANYLRALQLKPDDVITQSNLRKLWNIMEKQGLKTSKT
• Function: Transfers mannosyl residues to the hydroxyl group of serine or threonine residues. The 4 members of the TMTC family are O-mannosyl-transferases dedicated primarily to the cadherin superfamily, each member seems to have a distinct role in decorating the cadherin domains with O-linked mannose glycans at specific regions. Also acts as O-mannosyl-transferase on other proteins such as PDIA3.

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Glaucoma/ocular hypertension	DISLBXBY	Definitive	Genetic Variation	[1]
Asthma	DISW9QNS	Strong	Genetic Variation	[2]
OPTN-related open angle glaucoma	DISDR98A	Strong	Genetic Variation	[1]
Sensorineural hearing loss disorder	DISJV45Z	moderate	Genetic Variation	[3]
Nonsyndromic genetic hearing loss	DISZX61P	Disputed	Autosomal dominant	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Protein O-mannosyl-transferase TMTC2 (TMTC2).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Protein O-mannosyl-transferase TMTC2 (TMTC2).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Protein O-mannosyl-transferase TMTC2 (TMTC2).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protein O-mannosyl-transferase TMTC2 (TMTC2).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Protein O-mannosyl-transferase TMTC2 (TMTC2).	[9]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Protein O-mannosyl-transferase TMTC2 (TMTC2).	[10]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Protein O-mannosyl-transferase TMTC2 (TMTC2).	[11]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Protein O-mannosyl-transferase TMTC2 (TMTC2).	[12]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Protein O-mannosyl-transferase TMTC2 (TMTC2).	[13]
Cidofovir	DMA13GD	Approved	Cidofovir decreases the expression of Protein O-mannosyl-transferase TMTC2 (TMTC2).	[6]
Ifosfamide	DMCT3I8	Approved	Ifosfamide decreases the expression of Protein O-mannosyl-transferase TMTC2 (TMTC2).	[6]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Protein O-mannosyl-transferase TMTC2 (TMTC2).	[14]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Protein O-mannosyl-transferase TMTC2 (TMTC2).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Protein O-mannosyl-transferase TMTC2 (TMTC2).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Protein O-mannosyl-transferase TMTC2 (TMTC2).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Protein O-mannosyl-transferase TMTC2 (TMTC2).	[5]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Protein O-mannosyl-transferase TMTC2 (TMTC2).	[19]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Protein O-mannosyl-transferase TMTC2 (TMTC2).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Protein O-mannosyl-transferase TMTC2 (TMTC2).	[18]

References

• [1] Genetic Variant Near PLXDC2 Influences the Risk of Primary Open-angle Glaucoma by Increasing Intraocular Pressure in the Japanese Population.J Glaucoma. 2017 Nov;26(11):963-966. doi: 10.1097/IJG.0000000000000790.
• [2] Meta-analysis identifies seven susceptibility loci involved in the atopic march.Nat Commun. 2015 Nov 6;6:8804. doi: 10.1038/ncomms9804.
• [3] TMTC2 variant associated with sensorineural hearing loss and auditory neuropathy spectrum disorder in a family dyad.Mol Genet Genomic Med. 2018 Apr 19;6(4):653-9. doi: 10.1002/mgg3.397. Online ahead of print.
• [4] 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.
• [5] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [6] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [7] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [8] 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.
• [9] Real-time monitoring of cisplatin-induced cell death. PLoS One. 2011;6(5):e19714. doi: 10.1371/journal.pone.0019714. Epub 2011 May 16.
• [10] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [11] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [12] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [13] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [14] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [15] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [20] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.