Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8BQWTE)

• DOT Name: Iodotyrosine deiodinase 1 (IYD)
• Synonyms: IYD-1; EC 1.21.1.1; Iodotyrosine dehalogenase 1
• Gene Name: IYD
• Related Disease:
  Ataxia-telangiectasia
  Congenital hypothyroidism
  Familial thyroid dyshormonogenesis 1
  Goiter
  Graves disease
  Hypothyroidism
  Thyroid cancer
  Thyroid dyshormonogenesis 4
  Thyroid gland carcinoma
  Thyroid gland follicular carcinoma
  Thyroid gland papillary carcinoma
  Thyroid gland undifferentiated (anaplastic) carcinoma
  Thyrotoxicosis
  Familial thyroid dyshormonogenesis
• UniProt ID: IYD1_HUMAN
• PDB ID: 4TTB; 4TTC; 5YAK
• EC Number: 1.21.1.1
• Pfam ID: PF00881
• Sequence:
  MYFLTPILVAILCILVVWIFKNADRSMEKKKGEPRTRAEARPWVDEDLKDSSDLHQAEED
  ADEWQESEENVEHIPFSHNHYPEKEMVKRSQEFYELLNKRRSVRFISNEQVPMEVIDNVI
  RTAGTAPSGAHTEPWTFVVVKDPDVKHKIRKIIEEEEEINYMKRMGHRWVTDLKKLRTNW
  IKEYLDTAPILILIFKQVHGFAANGKKKVHYYNEISVSIACGILLAALQNAGLVTVTTTP
  LNCGPRLRVLLGRPAHEKLLMLLPVGYPSKEATVPDLKRKPLDQIMVTV
• Function: Catalyzes the dehalogenation of halotyrosines such as 3-bromo-L-tyrosine, 3-chloro-L-tyrosine, 3-iodo-L-tyrosine and 3,5-diiodo-L-tyrosine. During thyroid hormone biosynthesis, facilitates iodide salvage by catalysing the oxidative NADPH-dependent deiodination of the halogenated by-products of thyroid hormone production, monoiodotyrosine (L-MIT) and diiodotyrosine (L-DIT). The scavanged iodide can then reenter the hormone-producing pathways. Acts more efficiently on 3-iodo-L-tyrosine than 3,5-diiodo-L-tyrosine.
• Tissue Specificity: Expressed at a high level in thyroid gland (at protein level). Expressed at a high level in thyroid gland and at lower level in kidney and trachea.
• KEGG Pathway: Thyroid hormone synthesis (hsa04918)
• Reactome Pathway: Thyroxine biosynthesis (R-HSA-209968)
• BioCyc Pathway: MetaCyc:ENSG00000009765-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Ataxia-telangiectasia	DISP3EVR	Strong	Altered Expression	[1]
Congenital hypothyroidism	DISL5XVU	Strong	Biomarker	[2]
Familial thyroid dyshormonogenesis 1	DISAXKZN	Strong	GermlineCausalMutation	[3]
Goiter	DISLCGI6	Strong	Genetic Variation	[4]
Graves disease	DISU4KOQ	Strong	Altered Expression	[1]
Hypothyroidism	DISR0H6D	Strong	Biomarker	[5]
Thyroid cancer	DIS3VLDH	Strong	Altered Expression	[1]
Thyroid dyshormonogenesis 4	DISBZ5RR	Strong	Autosomal recessive	[6]
Thyroid gland carcinoma	DISMNGZ0	Strong	Altered Expression	[1]
Thyroid gland follicular carcinoma	DISFK2QT	Strong	Altered Expression	[1]
Thyroid gland papillary carcinoma	DIS48YMM	Strong	Altered Expression	[1]
Thyroid gland undifferentiated (anaplastic) carcinoma	DISYBB1W	Strong	Altered Expression	[1]
Thyrotoxicosis	DISWH7BV	Strong	Altered Expression	[1]
Familial thyroid dyshormonogenesis	DISALTXN	Supportive	Autosomal recessive	[7]

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
3-iodotyrosine	DMNZMH6	Investigative	Iodotyrosine deiodinase 1 (IYD) increases the metabolism of 3-iodotyrosine.	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Iodotyrosine deiodinase 1 (IYD).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Iodotyrosine deiodinase 1 (IYD).	[9]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Iodotyrosine deiodinase 1 (IYD).	[10]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Iodotyrosine deiodinase 1 (IYD).	[10]
Triclosan	DMZUR4N	Approved	Triclosan decreases the activity of Iodotyrosine deiodinase 1 (IYD).	[11]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Iodotyrosine deiodinase 1 (IYD).	[12]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Iodotyrosine deiodinase 1 (IYD).	[13]
Benzbromarone	DMC3YUA	Approved	Benzbromarone decreases the activity of Iodotyrosine deiodinase 1 (IYD).	[11]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Iodotyrosine deiodinase 1 (IYD).	[15]

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 increases the methylation of Iodotyrosine deiodinase 1 (IYD).	[14]

References

• [1] Characterisation of DEHAL1 expression in thyroid pathologies.Eur J Endocrinol. 2007 Mar;156(3):295-301. doi: 10.1530/EJE-06-0596.
• [2] Next-generation sequencing analysis of twelve known causative genes in congenital hypothyroidism.Clin Chim Acta. 2017 May;468:76-80. doi: 10.1016/j.cca.2017.02.009. Epub 2017 Feb 16.
• [3] Genetic causes of congenital hypothyroidism due to dyshormonogenesis.Curr Opin Pediatr. 2011 Aug;23(4):421-8. doi: 10.1097/MOP.0b013e32834726a4.
• [4] Genetics and phenomics of hypothyroidism and goiter due to iodotyrosine deiodinase (DEHAL1) gene mutations.Mol Cell Endocrinol. 2010 Jun 30;322(1-2):91-8. doi: 10.1016/j.mce.2010.03.010. Epub 2010 Mar 16.
• [5] Towards the pre-clinical diagnosis of hypothyroidism caused by iodotyrosine deiodinase (DEHAL1) defects.Best Pract Res Clin Endocrinol Metab. 2014 Mar;28(2):151-9. doi: 10.1016/j.beem.2013.10.009. Epub 2013 Oct 29.
• [6] Mutations in the iodotyrosine deiodinase gene and hypothyroidism. N Engl J Med. 2008 Apr 24;358(17):1811-8. doi: 10.1056/NEJMoa0706819.
• [7] Congenital hypothyroidism. Orphanet J Rare Dis. 2010 Jun 10;5:17. doi: 10.1186/1750-1172-5-17.
• [8] 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.
• [9] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [10] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [11] Structure-activity relationships of 44 halogenated compounds for iodotyrosine deiodinase-inhibitory activity. Toxicology. 2013 Dec 6;314(1):22-9. doi: 10.1016/j.tox.2013.08.017. Epub 2013 Sep 3.
• [12] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [13] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [14] 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.
• [15] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [16] In vitro screening for chemical inhibition of the iodide recycling enzyme, iodotyrosine deiodinase. Toxicol In Vitro. 2021 Mar;71:105073. doi: 10.1016/j.tiv.2020.105073. Epub 2020 Dec 29.