Details of Drug Off-Target (DOT)

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

• DOT Name: Thyroxine 5-deiodinase (DIO3)
• Synonyms: EC 1.21.99.3; 5DIII; DIOIII; Type 3 DI; Type III iodothyronine deiodinase
• Gene Name: DIO3
• UniProt ID: IOD3_HUMAN
• EC Number: 1.21.99.3
• Pfam ID: PF00837
• Sequence:
  MPRQATSRLVVGEGEGSQGASGPAATMLRSLLLHSLRLCAQTASCLVLFPRFLGTAFMLW
  LLDFLCIRKHFLGRRRRGQPEPEVELNSEGEEVPPDDPPICVSDDNRLCTLASLKAVWHG
  QKLDFFKQAHEGGPAPNSEVVLPDGFQSQHILDYAQGNRPLVLNFGSCTUPPFMARMSAF
  QRLVTKYQRDVDFLIIYIEEAHPSDGWVTTDSPYIIPQHRSLEDRVSAARVLQQGAPGCA
  LVLDTMANSSSSAYGAYFERLYVIQSGTIMYQGGRGPDGYQVSELRTWLERYDEQLHGAR
  PRRV
• Function: Responsible for the deiodination of T4 (3,5,3',5'-tetraiodothyronine) into RT3 (3,3',5'-triiodothyronine) and of T3 (3,5,3'-triiodothyronine) into T2 (3,3'-diiodothyronine). RT3 and T2 are inactive metabolites. May play a role in preventing premature exposure of developing fetal tissues to adult levels of thyroid hormones. Can regulate circulating fetal thyroid hormone concentrations throughout gestation. Essential role for regulation of thyroid hormone inactivation during embryological development.
• Tissue Specificity: Expressed in placenta and several fetal tissues.
• KEGG Pathway: Thyroid hormone sig.ling pathway (hsa04919)
• Reactome Pathway: Regulation of thyroid hormone activity (R-HSA-350864)
• BioCyc Pathway: MetaCyc:HS11928-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Thyroxine 5-deiodinase (DIO3).	[1]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Thyroxine 5-deiodinase (DIO3).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the activity of Thyroxine 5-deiodinase (DIO3).	[2]
Estradiol	DMUNTE3	Approved	Estradiol increases the activity of Thyroxine 5-deiodinase (DIO3).	[2]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Thyroxine 5-deiodinase (DIO3).	[3]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the activity of Thyroxine 5-deiodinase (DIO3).	[2]
Alitretinoin	DMME8LH	Approved	Alitretinoin increases the activity of Thyroxine 5-deiodinase (DIO3).	[2]
Liothyronine	DM6IR3P	Approved	Liothyronine increases the expression of Thyroxine 5-deiodinase (DIO3).	[4]
Bicalutamide	DMZMSPF	Approved	Bicalutamide increases the expression of Thyroxine 5-deiodinase (DIO3).	[5]
Masoprocol	DMMVNZ0	Approved	Masoprocol decreases the activity of Thyroxine 5-deiodinase (DIO3).	[6]
Vemurafenib	DM62UG5	Approved	Vemurafenib decreases the expression of Thyroxine 5-deiodinase (DIO3).	[7]
Ergocalciferol	DMHO0AR	Approved	Ergocalciferol decreases the activity of Thyroxine 5-deiodinase (DIO3).	[6]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Thyroxine 5-deiodinase (DIO3).	[8]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the activity of Thyroxine 5-deiodinase (DIO3).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Thyroxine 5-deiodinase (DIO3).	[9]
SB 203580	DMAET6F	Terminated	SB 203580 decreases the expression of Thyroxine 5-deiodinase (DIO3).	[7]
SSR-69071	DMWL4MI	Terminated	SSR-69071 decreases the activity of Thyroxine 5-deiodinase (DIO3).	[6]
U0126	DM31OGF	Investigative	U0126 decreases the expression of Thyroxine 5-deiodinase (DIO3).	[7]
Morin	DM2OGZ5	Investigative	Morin decreases the activity of Thyroxine 5-deiodinase (DIO3).	[6]
Linoleic acid	DMDGPY9	Investigative	Linoleic acid decreases the activity of Thyroxine 5-deiodinase (DIO3).	[6]
Alpha-linolenic acid	DMY64HE	Investigative	Alpha-linolenic acid decreases the activity of Thyroxine 5-deiodinase (DIO3).	[6]
BADGE	DMCK5DG	Investigative	BADGE decreases the activity of Thyroxine 5-deiodinase (DIO3).	[6]
CYCLOPAMINE	DMEM2SW	Investigative	CYCLOPAMINE decreases the expression of Thyroxine 5-deiodinase (DIO3).	[7]
2,3-dichloro-1,4-naphthoquinone	DMPCGSD	Investigative	2,3-dichloro-1,4-naphthoquinone decreases the activity of Thyroxine 5-deiodinase (DIO3).	[6]

References

• [1] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [2] Regulation of type III iodothyronine deiodinase expression in human cell lines. Endocrinology. 2006 Dec;147(12):5845-54. doi: 10.1210/en.2006-0590. Epub 2006 Aug 24.
• [3] Disturbance of the Dlk1-Dio3 imprinted domain may underlie placental Dio3 suppression and extracellular thyroid hormone disturbance in placenta-derived JEG-3 cells following decabromodiphenyl ether (BDE209) exposure. Toxicology. 2021 Jun 30;458:152837. doi: 10.1016/j.tox.2021.152837. Epub 2021 Jun 21.
• [4] Monitoring of deiodinase deficiency based on transcriptomic responses in SH-SY5Y cells. Arch Toxicol. 2013 Jun;87(6):1103-13. doi: 10.1007/s00204-013-1018-4. Epub 2013 Feb 10.
• [5] Microarray analysis of bicalutamide action on telomerase activity, p53 pathway and viability of prostate carcinoma cell lines. J Pharm Pharmacol. 2005 Jan;57(1):83-92.
• [6] Screening the ToxCast Phase 1, Phase 2, and e1k Chemical Libraries for Inhibitors of Iodothyronine Deiodinases. Toxicol Sci. 2019 Apr 1;168(2):430-442. doi: 10.1093/toxsci/kfy302.
• [7] MAPK and SHH pathways modulate type 3 deiodinase expression in papillary thyroid carcinoma. Endocr Relat Cancer. 2016 Mar;23(3):135-46. doi: 10.1530/ERC-15-0162.
• [8] 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.
• [9] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [10] 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.