Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYW1KP2)

• DOT Name: Transmembrane and coiled-coil domain-containing protein 3 (TMCO3)
• Synonyms: Putative LAG1-interacting protein
• Gene Name: TMCO3
• Related Disease:
  Early-onset anterior polar cataract
  Fuchs' endothelial dystrophy
• UniProt ID: TMCO3_HUMAN
• Pfam ID: PF00999
• Sequence:
  MKVLGRSFFWVLFPVLPWAVQAVEHEEVAQRVIKLHRGRGVAAMQSRQWVRDSCRKLSGL
  LRQKNAVLNKLKTAIGAVEKDVGLSDEEKLFQVHTFEIFQKELNESENSVFQAVYGLQRA
  LQGDYKDVVNMKESSRQRLEALREAAIKEETEYMELLAAEKHQVEALKNMQHQNQSLSML
  DEILEDVRKAADRLEEEIEEHAFDDNKSVKGVNFEAVLRVEEEEANSKQNITKREVEDDL
  GLSMLIDSQNNQYILTKPRDSTIPRADHHFIKDIVTIGMLSLPCGWLCTAIGLPTMFGYI
  ICGVLLGPSGLNSIKSIVQVETLGEFGVFFTLFLVGLEFSPEKLRKVWKISLQGPCYMTL
  LMIAFGLLWGHLLRIKPTQSVFISTCLSLSSTPLVSRFLMGSARGDKEGDIDYSTVLLGM
  LVTQDVQLGLFMAVMPTLIQAGASASSSIVVEVLRILVLIGQILFSLAAVFLLCLVIKKY
  LIGPYYRKLHMESKGNKEILILGISAFIFLMLTVTELLDVSMELGCFLAGALVSSQGPVV
  TEEIATSIEPIRDFLAIVFFASIGLHVFPTFVAYELTVLVFLTLSVVVMKFLLAALVLSL
  ILPRSSQYIKWIVSAGLAQVSEFSFVLGSRARRAGVISREVYLLILSVTTLSLLLAPVLW
  RAAITRCVPRPERRSSL
• Function: Probable Na(+)/H(+) antiporter.
• Tissue Specificity: Expressed in the cornea, lens capsule and choroid-retinal pigment epithelium (at protein level).

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Early-onset anterior polar cataract	DISTOPIY	Strong	Genetic Variation	[1]
Fuchs' endothelial dystrophy	DISL7TXC	Limited	Autosomal dominant	[2]

11 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 Transmembrane and coiled-coil domain-containing protein 3 (TMCO3).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Transmembrane and coiled-coil domain-containing protein 3 (TMCO3).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Transmembrane and coiled-coil domain-containing protein 3 (TMCO3).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Transmembrane and coiled-coil domain-containing protein 3 (TMCO3).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Transmembrane and coiled-coil domain-containing protein 3 (TMCO3).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Transmembrane and coiled-coil domain-containing protein 3 (TMCO3).	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Transmembrane and coiled-coil domain-containing protein 3 (TMCO3).	[9]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Transmembrane and coiled-coil domain-containing protein 3 (TMCO3).	[9]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Transmembrane and coiled-coil domain-containing protein 3 (TMCO3).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Transmembrane and coiled-coil domain-containing protein 3 (TMCO3).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Transmembrane and coiled-coil domain-containing protein 3 (TMCO3).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Transmembrane and coiled-coil domain-containing protein 3 (TMCO3).	[11]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Transmembrane and coiled-coil domain-containing protein 3 (TMCO3).	[13]

References

• [1] Mutations in the TMCO3 Gene are Associated with Cornea Guttata and Anterior Polar Cataract.Sci Rep. 2016 Aug 3;6:31021. doi: 10.1038/srep31021.
• [2] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [3] 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.
• [4] 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.
• [5] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [6] 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.
• [7] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [8] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [9] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [10] 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.
• [11] 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.
• [12] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [13] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [14] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.