Details of Drug Off-Target (DOT)

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

• DOT Name: Protein O-mannosyl-transferase TMTC3 (TMTC3)
• Synonyms: EC 2.4.1.109; Protein SMILE; Transmembrane O-mannosyltransferase targeting cadherins 3; Transmembrane and tetratricopeptide repeat-containing 3
• Gene Name: TMTC3
• Related Disease:
  Epilepsy
  Acute myocardial infarction
  Adult lymphoma
  Breast cancer
  Breast carcinoma
  Cardiac failure
  Congestive heart failure
  Extranodal NK/T-cell Lymphoma
  Leukopenia
  Lissencephaly 8
  Lymphoma
  Myocardial infarction
  Myopia
  Non-small-cell lung cancer
  Pediatric lymphoma
  Cobblestone lissencephaly
  Intellectual disability
  Periventricular nodular heterotopia
  Dental caries
  Keratoconjunctivitis sicca
• UniProt ID: TMTC3_HUMAN
• EC Number: 2.4.1.109
• Pfam ID: PF08409 ; PF13431 ; PF13174 ; PF13181
• Sequence:
  MANINLKEITLIVGVVTACYWNSLFCGFVFDDVSAILDNKDLHPSTPLKTLFQNDFWGTP
  MSEERSHKSYRPLTVLTFRLNYLLSELKPMSYHLLNMIFHAVVSVIFLKVCKLFLDNKSS
  VIASLLFAVHPIHTEAVTGVVGRAELLSSIFFLAAFLSYTRSKGPDNSIIWTPIALTVFL
  VAVATLCKEQGITVVGICCVYEVFIAQGYTLPLLCTTAGQFLRGKGSIPFSMLQTLVKLI
  VLMFSTLLLVVIRVQVIQSQLPVFTRFDNPAAVSPTPTRQLTFNYLLPVNAWLLLNPSEL
  CCDWTMGTIPLIESLLDIRNLATFTFFCFLGMLGVFSIRYSGDSSKTVLMALCLMALPFI
  PASNLFFPVGFVVAERVLYVPSMGFCILVAHGWQKISTKSVFKKLSWICLSMVILTHSLK
  TFHRNWDWESEYTLFMSALKVNKNNAKLWNNVGHALENEKNFERALKYFLQATHVQPDDI
  GAHMNVGRTYKNLNRTKEAEESYMMAKSLMPQIIPGKKYAARIAPNHLNVYINLANLIRA
  NESRLEEADQLYRQAISMRPDFKQAYISRGELLLKMNKPLKAKEAYLKALELDRNNADLW
  YNLAIVHIELKEPNEALKKNFNRALELNPKHKLALFNSAIVMQESGEVKLRPEARKRLLS
  YINEEPLDANGYFNLGMLAMDDKKDNEAEIWMKKAIKLQADFRSALFNLALLYSQTAKEL
  KALPILEELLRYYPDHIKGLILKGDILMNQKKDILGAKKCFERILEMDPSNVQGKHNLCV
  VYFEEKDLLKAERCLLETLALAPHEEYIQRHLNIVRDKISSSSFIEPIFPTSKISSVEGK
  KIPTESVKEIRGESRQTQIVKTSDNKSQSKSNKQLGKNGDEETPHKTTKDIKEIEKKRVA
  ALKRLEEIERILNGE
• 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. Involved in the positive regulation of proteasomal protein degradation in the endoplasmic reticulum (ER), and the control of ER stress response.

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Epilepsy	DISBB28L	Definitive	Biomarker	[1]
Acute myocardial infarction	DISE3HTG	Strong	Biomarker	[2]
Adult lymphoma	DISK8IZR	Strong	Genetic Variation	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[4]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[4]
Cardiac failure	DISDC067	Strong	Biomarker	[5]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[5]
Extranodal NK/T-cell Lymphoma	DIS72GCL	Strong	Genetic Variation	[6]
Leukopenia	DISJMBMM	Strong	Biomarker	[3]
Lissencephaly 8	DISKUZRU	Strong	Autosomal recessive	[7]
Lymphoma	DISN6V4S	Strong	Biomarker	[8]
Myocardial infarction	DIS655KI	Strong	Genetic Variation	[9]
Myopia	DISK5S60	Strong	Biomarker	[10]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Genetic Variation	[11]
Pediatric lymphoma	DIS51BK2	Strong	Genetic Variation	[3]
Cobblestone lissencephaly	DIS56826	moderate	Biomarker	[12]
Intellectual disability	DISMBNXP	moderate	Genetic Variation	[13]
Periventricular nodular heterotopia	DISU3ZRI	Supportive	Autosomal dominant	[13]
Dental caries	DISRBCMD	Limited	Biomarker	[14]
Keratoconjunctivitis sicca	DISNOENH	Limited	Biomarker	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Protein O-mannosyl-transferase TMTC3 (TMTC3).	[16]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Protein O-mannosyl-transferase TMTC3 (TMTC3).	[17]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Protein O-mannosyl-transferase TMTC3 (TMTC3).	[18]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Protein O-mannosyl-transferase TMTC3 (TMTC3).	[19]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Protein O-mannosyl-transferase TMTC3 (TMTC3).	[20]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Protein O-mannosyl-transferase TMTC3 (TMTC3).	[21]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Protein O-mannosyl-transferase TMTC3 (TMTC3).	[22]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Protein O-mannosyl-transferase TMTC3 (TMTC3).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Protein O-mannosyl-transferase TMTC3 (TMTC3).	[24]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Protein O-mannosyl-transferase TMTC3 (TMTC3).	[25]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Protein O-mannosyl-transferase TMTC3 (TMTC3).	[26]

References

• [1] Self-Management education for adults with poorly controlled epILEpsy [SMILE (UK)]: a randomised controlled trial.Health Technol Assess. 2018 Apr;22(21):1-142. doi: 10.3310/hta22210.
• [2] Cardioprotective role of zofenopril in hypertensive patients with acute myocardial infarction: a pooled individual data analysis of the SMILE studies.Blood Press. 2017 Aug;26(4):211-219. doi: 10.1080/08037051.2017.1281712. Epub 2017 Feb 3.
• [3] Pretreatment EBV-DNA copy number is predictive of response and toxicities to SMILE chemotherapy for extranodal NK/T-cell lymphoma, nasal type.Clin Cancer Res. 2012 Aug 1;18(15):4183-90. doi: 10.1158/1078-0432.CCR-12-1064. Epub 2012 Jun 6.
• [4] Smartphone problem-solving and behavioural activation therapy to reduce fear of recurrence among patients with breast cancer (SMartphone Intervention to LEssen fear of cancer recurrence: SMILE project): protocol for a randomised controlled trial.BMJ Open. 2018 Nov 8;8(11):e024794. doi: 10.1136/bmjopen-2018-024794.
• [5] A Prospective, Multicenter, Post-Marketing Surveillance Study to Evaluate the Safety and Effectiveness of Tolvaptan in Patients with Reduced, Preserved, and Mid-Range Ejection Fraction Heart Failure.Int Heart J. 2019 Sep 27;60(5):1123-1130. doi: 10.1536/ihj.18-671. Epub 2019 Sep 4.
• [6] Defining the toxicity of current regimens for extranodal NK/T cell lymphoma: a systematic review and metaproportion.Expert Rev Anticancer Ther. 2019 Jan;19(1):93-104. doi: 10.1080/14737140.2019.1549992. Epub 2018 Nov 23.
• [7] mSmile is necessary for bronchial smooth muscle and alveolar myofibroblast development. Anat Rec (Hoboken). 2012 Jan;295(1):167-76. doi: 10.1002/ar.21475. Epub 2011 Sep 28.
• [8] Epstein-Barr virus-associated natural killer/T-cell lymphomas.Best Pract Res Clin Haematol. 2013 Mar;26(1):15-21. doi: 10.1016/j.beha.2013.04.002. Epub 2013 May 25.
• [9] Efficacy and Safety of Zofenopril Versus Ramipril in the Treatment of Myocardial Infarction and Heart Failure: A Review of the Published and Unpublished Data of the Randomized Double-Blind SMILE-4 Study.Adv Ther. 2018 May;35(5):604-618. doi: 10.1007/s12325-018-0697-x. Epub 2018 Apr 17.
• [10] Surgical treatment of corneal dermoid by using intrastromal lenticule obtained from small-incision lenticule extraction.Int Ophthalmol. 2020 Jan;40(1):43-49. doi: 10.1007/s10792-019-01201-w. Epub 2019 Nov 17.
• [11] Factors associated with improvement in symptoms and quality of life for first-line EGFR-tyrosine kinase inhibitor treatment in patients with EGFR-mutated non-small-cell lung cancer - A multicenter prospective SMILE study.J Cancer. 2019 Jul 10;10(17):4151-4158. doi: 10.7150/jca.30507. eCollection 2019.
• [12] Endoplasmic reticulum transmembrane protein TMTC3 contributes to O-mannosylation of E-cadherin, cellular adherence, and embryonic gastrulation.Mol Biol Cell. 2020 Feb 1;31(3):167-183. doi: 10.1091/mbc.E19-07-0408. Epub 2019 Dec 18.
• [13] Identification of a novel synaptic protein, TMTC3, involved in periventricular nodular heterotopia with intellectual disability and epilepsy. Hum Mol Genet. 2017 Nov 1;26(21):4278-4289. doi: 10.1093/hmg/ddx316.
• [14] Development and Relative Validity of a Food Frequency Questionnaire to Assess Intakes of Total and Free Sugars in Australian Toddlers.Int J Environ Res Public Health. 2017 Nov 8;14(11):1361. doi: 10.3390/ijerph14111361.
• [15] Dry Eye After LASIK.Invest Ophthalmol Vis Sci. 2018 Nov 1;59(14):DES109-DES115. doi: 10.1167/iovs.17-23538.
• [16] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [17] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [18] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [19] 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.
• [20] 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.
• [21] 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.
• [22] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [23] 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.
• [24] 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.
• [25] 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.
• [26] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.