Details of Drug Off-Target (DOT)

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

• DOT Name: Transthyretin
• Synonyms: ATTR; Prealbumin; TBPA
• Gene Name: TTR
• Related Disease:
  Obsolete hereditary ATTR amyloidosis
  Transthyretin amyloidosis
  Heart arrhythmia
  ATTRV122I amyloidosis
• UniProt ID: TTHY_HUMAN
• PDB ID: 1BM7 ; 1BMZ ; 1BZ8 ; 1BZD ; 1BZE ; 1DVQ ; 1DVS ; 1DVT ; 1DVU ; 1DVX ; 1DVY ; 1DVZ ; 1E3F ; 1E4H ; 1E5A ; 1ETA ; 1ETB ; 1F41 ; 1F86 ; 1FH2 ; 1FHN ; 1G1O ; 1GKO ; 1ICT ; 1III ; 1IIK ; 1IJN ; 1QAB ; 1QWH ; 1RLB ; 1SOK ; 1SOQ ; 1THA ; 1THC ; 1TLM ; 1TSH ; 1TT6 ; 1TTA ; 1TTB ; 1TTC ; 1TTR ; 1TYR ; 1TZ8 ; 1U21 ; 1X7S ; 1X7T ; 1Y1D ; 1Z7J ; 1ZCR ; 1ZD6 ; 2B14 ; 2B15 ; 2B16 ; 2B77 ; 2B9A ; 2F7I ; 2F8I ; 2FBR ; 2FLM ; 2G3X ; 2G3Z ; 2G4E ; 2G4G ; 2G5U ; 2G9K ; 2GAB ; 2H4E ; 2M5N ; 2NBO ; 2NBP ; 2NOY ; 2PAB ; 2QEL ; 2QGB ; 2QGC ; 2QGD ; 2QGE ; 2ROX ; 2ROY ; 2TRH ; 2TRY ; 2WQA ; 3A4D ; 3A4E ; 3A4F ; 3B56 ; 3BSZ ; 3BT0 ; 3CBR ; 3CFM ; 3CFN ; 3CFQ ; 3CFT ; 3CN0 ; 3CN1 ; 3CN2 ; 3CN3 ; 3CN4 ; 3CXF ; 3D2T ; 3D7P ; 3DGD ; 3DID ; 3DJR ; 3DJS ; 3DJT ; 3DJZ ; 3DK0 ; 3DK2 ; 3DO4 ; 3ESN ; 3ESO ; 3ESP ; 3FC8 ; 3FCB ; 3GLZ ; 3GPS ; 3GRB ; 3GRG ; 3GS0 ; 3GS4 ; 3GS7 ; 3HJ0 ; 3I9A ; 3I9I ; 3I9P ; 3IMR ; 3IMS ; 3IMT ; 3IMU ; 3IMV ; 3IMW ; 3IPB ; 3IPE ; 3KGS ; 3KGT ; 3KGU ; 3M1O ; 3NEE ; 3NEO ; 3NES ; 3NEX ; 3NG5 ; 3OZK ; 3OZL ; 3P3R ; 3P3S ; 3P3T ; 3P3U ; 3SSG ; 3TCT ; 3TFB ; 3U2I ; 3U2J ; 3W3B ; 4ABQ ; 4ABU ; 4ABV ; 4ABW ; 4AC2 ; 4AC4 ; 4ACT ; 4ANK ; 4D7B ; 4DER ; 4DES ; 4DET ; 4DEU ; 4DEW ; 4FI6 ; 4FI7 ; 4FI8 ; 4HIQ ; 4HIS ; 4HJS ; 4HJT ; 4HJU ; 4I85 ; 4I87 ; 4I89 ; 4IIZ ; 4IK6 ; 4IK7 ; 4IKI ; 4IKJ ; 4IKK ; 4IKL ; 4KY2 ; 4L1S ; 4L1T ; 4MAS ; 4MRB ; 4MRC ; 4N85 ; 4N86 ; 4N87 ; 4PM1 ; 4PME ; 4PMF ; 4PVL ; 4PVM ; 4PVN ; 4PWE ; 4PWF ; 4PWG ; 4PWH ; 4PWI ; 4PWJ ; 4PWK ; 4QRF ; 4QXV ; 4QYA ; 4TKW ; 4TL4 ; 4TL5 ; 4TLK ; 4TLS ; 4TLT ; 4TLU ; 4TM9 ; 4TNE ; 4TNF ; 4TNG ; 4TQ8 ; 4TQH ; 4TQI ; 4TQP ; 4WNJ ; 4WNS ; 4WO0 ; 4Y9B ; 4Y9C ; 4Y9E ; 4Y9F ; 4Y9G ; 4YDM ; 4YDN ; 5A6I ; 5AKS ; 5AKT ; 5AKV ; 5AL0 ; 5AL8 ; 5AYT ; 5BOJ ; 5CLX ; 5CLY ; 5CLZ ; 5CM1 ; 5CN3 ; 5CNH ; 5CR1 ; 5DEJ ; 5DWP ; 5E23 ; 5E4A ; 5E4O ; 5EN3 ; 5EZP ; 5FO2 ; 5FW6 ; 5FW7 ; 5FW8 ; 5H0V ; 5H0W ; 5H0X ; 5H0Y ; 5H0Z ; 5HJG ; 5IHH ; 5JID ; 5JIM ; 5JIQ ; 5K1J ; 5K1N ; 5L4F ; 5L4I ; 5L4J ; 5L4M ; 5LLL ; 5LLV ; 5N5Q ; 5N62 ; 5N7C ; 5NFE ; 5NFW ; 5OQ0 ; 5TTR ; 5TZL ; 5U48 ; 5U49 ; 5U4A ; 5U4B ; 5U4C ; 5U4D ; 5U4E ; 5U4F ; 5U4G ; 6D0W ; 6E6Z ; 6E70 ; 6E71 ; 6E72 ; 6E73 ; 6E74 ; 6E75 ; 6E76 ; 6E77 ; 6E78 ; 6EOY ; 6EP1 ; 6FFT ; 6FWD ; 6FXU ; 6FZL ; 6GR7 ; 6GRP ; 6IMX ; 6IMY ; 6KGB ; 6R66 ; 6R67 ; 6R68 ; 6R6I ; 6SDZ ; 6SUG ; 6SUH ; 6TI9 ; 6TJN ; 6TXV ; 6TXW ; 6U0Q ; 6XTK ; 7ACU ; 7DT3 ; 7DT5 ; 7DT6 ; 7DT8 ; 7EJQ ; 7EJR ; 7ERH ; 7ERI ; 7ERJ ; 7ERK ; 7OB4 ; 7Q3I ; 7Q9L ; 7Q9N ; 7Q9O ; 7QC5 ; 7THA ; 7W9Q ; 7W9R ; 7WL6 ; 7Y1I ; 7Y6J ; 7YBR ; 7YCQ ; 7Z60 ; 8ADE ; 8AWI ; 8AWW ; 8E7D ; 8E7E ; 8E7H ; 8E7I ; 8E7J ; 8HEJ ; 8HY4 ; 8IG1 ; 8II1 ; 8II2 ; 8II3 ; 8II4 ; 8PKE ; 8PKF ; 8PKG ; 8W42 ; 8W43 ; 8W44 ; 8W45 ; 8W46 ; 8W47 ; 8W48
• Pfam ID: PF00576
• Sequence:
  MASHRLLLLCLAGLVFVSEAGPTGTGESKCPLMVKVLDAVRGSPAINVAVHVFRKAADDT
  WEPFASGKTSESGELHGLTTEEEFVEGIYKVEIDTKSYWKALGISPFHEHAEVVFTANDS
  GPRRYTIAALLSPYSYSTTAVVTNPKE
• Function: Thyroid hormone-binding protein. Probably transports thyroxine from the bloodstream to the brain.
• Tissue Specificity: Detected in serum and cerebrospinal fluid (at protein level). Highly expressed in choroid plexus epithelial cells. Detected in retina pigment epithelium and liver.
• KEGG Pathway: Thyroid hormone synthesis (hsa04918)
• Reactome Pathway:
  The canonical retinoid cycle in rods (twilight vision) (R-HSA-2453902)
  Non-integrin membrane-ECM interactions (R-HSA-3000171)
  Neutrophil degranulation (R-HSA-6798695)
  Retinoid metabolism and transport (R-HSA-975634)
  Amyloid fiber formation (R-HSA-977225)
  Retinoid cycle disease events (R-HSA-2453864)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Obsolete hereditary ATTR amyloidosis	DIS45HVQ	Definitive	Autosomal dominant	[1]
Transthyretin amyloidosis	DISJP3J0	Definitive	Autosomal dominant	[2]
Heart arrhythmia	DISLKUNL	Strong	Autosomal dominant	[3]
ATTRV122I amyloidosis	DISUVZO0	Supportive	Autosomal dominant	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Transthyretin.	[5]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Transthyretin.	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Transthyretin.	[16]

10 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 Transthyretin.	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Transthyretin.	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Transthyretin.	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Transthyretin.	[10]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Transthyretin.	[11]
Indomethacin	DMSC4A7	Approved	Indomethacin decreases the expression of Transthyretin.	[13]
Benzylpenicillin	DMS9503	Phase 3	Benzylpenicillin decreases the expression of Transthyretin.	[13]
PJ34	DMXO6YH	Preclinical	PJ34 increases the expression of Transthyretin.	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Transthyretin.	[18]
OXYQUINOLINE	DMZVS9Y	Investigative	OXYQUINOLINE increases the expression of Transthyretin.	[10]

7 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Triclosan	DMZUR4N	Approved	Triclosan affects the binding of Transthyretin.	[12]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the binding of Transthyretin.	[12]
Liothyronine	DM6IR3P	Approved	Liothyronine affects the binding of Transthyretin.	[14]
Diflunisal	DM7EN8I	Approved	Diflunisal affects the binding of Transthyretin.	[15]
L-thyroxine	DM83HWL	Investigative	L-thyroxine affects the binding of Transthyretin.	[19]
1-anilinonaphthalene-8-sulfonic acid	DMNGY0E	Investigative	1-anilinonaphthalene-8-sulfonic acid affects the binding of Transthyretin.	[20]
3,5-dibromo-2-(2,4-dibromophenoxy)phenol	DMCEY6O	Investigative	3,5-dibromo-2-(2,4-dibromophenoxy)phenol affects the binding of Transthyretin.	[14]

References

• [1] 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.
• [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] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [4] The V122I cardiomyopathy variant of transthyretin increases the velocity of rate-limiting tetramer dissociation, resulting in accelerated amyloidosis. Proc Natl Acad Sci U S A. 2001 Dec 18;98(26):14943-8. doi: 10.1073/pnas.261419998.
• [5] 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.
• [6] 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.
• [7] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [10] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [11] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [12] Assessment of endocrine disruption and oxidative potential of bisphenol-A, triclosan, nonylphenol, diethylhexyl phthalate, galaxolide, and carbamazepine, common contaminants of municipal biosolids. Toxicol In Vitro. 2018 Apr;48:342-349. doi: 10.1016/j.tiv.2018.02.003. Epub 2018 Feb 7.
• [13] Evaluation of developmental toxicity using undifferentiated human embryonic stem cells. J Appl Toxicol. 2015 Feb;35(2):205-18.
• [14] Structure-based investigation on the binding interaction of hydroxylated polybrominated diphenyl ethers with thyroxine transport proteins. Toxicology. 2010 Nov 9;277(1-3):20-8. doi: 10.1016/j.tox.2010.08.012. Epub 2010 Sep 8.
• [15] In vivo stabilization of mutant human transthyretin in transgenic mice. Amyloid. 2007 Sep;14(3):227-36. doi: 10.1080/13506120701464396.
• [16] 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.
• [17] PARP inhibitor activates the intrinsic pathway of apoptosis in primary lung cancer cells. Cancer Invest. 2014 Aug;32(7):339-48. doi: 10.3109/07357907.2014.919303. Epub 2014 Jun 4.
• [18] 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.
• [19] Assessing the role of ortho-substitution on polychlorinated biphenyl binding to transthyretin, a thyroxine transport protein. Toxicol Appl Pharmacol. 2000 Jan 1;162(1):10-21. doi: 10.1006/taap.1999.8826.
• [20] Sulfated metabolites of polychlorinated biphenyls are high-affinity ligands for the thyroid hormone transport protein transthyretin. Environ Health Perspect. 2013 Jun;121(6):657-62. doi: 10.1289/ehp.1206198. Epub 2013 Apr 12.