Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT80NN7R)

• DOT Name: Troponin T, cardiac muscle (TNNT2)
• Synonyms: TnTc; Cardiac muscle troponin T; cTnT
• Gene Name: TNNT2
• Related Disease:
  Dilated cardiomyopathy
  Dilated cardiomyopathy 1D
  Hypertrophic cardiomyopathy
  Hypertrophic cardiomyopathy 2
  Hypertrophic cardiomyopathy 3
  Cardiomyopathy, familial restrictive, 3
  Left ventricular noncompaction
  Obsolete familial isolated dilated cardiomyopathy
  Obsolete familial isolated restrictive cardiomyopathy
  Arrhythmogenic right ventricular cardiomyopathy
• UniProt ID: TNNT2_HUMAN
• PDB ID: 1J1D; 1J1E; 4Y99; 6KN7; 6KN8; 7UTI; 7UTL
• Pfam ID: PF00992
• Sequence:
  MSDIEEVVEEYEEEEQEEAAVEEEEDWREDEDEQEEAAEEDAEAEAETEETRAEEDEEEE
  EAKEAEDGPMEESKPKPRSFMPNLVPPKIPDGERVDFDDIHRKRMEKDLNELQALIEAHF
  ENRKKEEEELVSLKDRIERRRAERAEQQRIRNEREKERQNRLAEERARREEEENRRKAED
  EARKKKALSNMMHFGGYIQKQAQTERKSGKRQTEREKKKKILAERRKVLAIDHLNEDQLR
  EKAKELWQSIYNLEAEKFDLQEKFKQQKYEINVLRNRINDNQKVSKTRGKAKVTGRWK
• Function: Troponin T is the tropomyosin-binding subunit of troponin, the thin filament regulatory complex which confers calcium-sensitivity to striated muscle actomyosin ATPase activity.
• Tissue Specificity: Heart. The fetal heart shows a greater expression in the atrium than in the ventricle, while the adult heart shows a greater expression in the ventricle than in the atrium. Isoform 6 predominates in normal adult heart. Isoforms 1, 7 and 8 are expressed in fetal heart. Isoform 7 is also expressed in failing adult heart.
• KEGG Pathway:
  Cardiac muscle contraction (hsa04260)
  Adrenergic sig.ling in cardiomyocytes (hsa04261)
  Motor proteins (hsa04814)
  Cytoskeleton in muscle cells (hsa04820)
  Hypertrophic cardiomyopathy (hsa05410)
  Dilated cardiomyopathy (hsa05414)
• Reactome Pathway: Striated Muscle Contraction (R-HSA-390522)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Dilated cardiomyopathy	DISX608J	Definitive	Autosomal dominant	[1]
Dilated cardiomyopathy 1D	DISYL3CY	Definitive	Autosomal dominant	[2]
Hypertrophic cardiomyopathy	DISQG2AI	Definitive	Autosomal dominant	[1]
Hypertrophic cardiomyopathy 2	DISLGA2M	Definitive	Autosomal dominant	[2]
Hypertrophic cardiomyopathy 3	DISBVV0E	Definitive	Autosomal dominant	[3]
Cardiomyopathy, familial restrictive, 3	DIS0X7HF	Strong	Autosomal dominant	[4]
Left ventricular noncompaction	DISJ4QEG	Supportive	Autosomal dominant	[5]
Obsolete familial isolated dilated cardiomyopathy	DIS4FXO4	Supportive	Autosomal dominant	[6]
Obsolete familial isolated restrictive cardiomyopathy	DIS51KNV	Supportive	Autosomal dominant	[7]
Arrhythmogenic right ventricular cardiomyopathy	DIS3V2BE	No Known	Autosomal dominant	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Troponin T, cardiac muscle (TNNT2).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Troponin T, cardiac muscle (TNNT2).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Troponin T, cardiac muscle (TNNT2).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Troponin T, cardiac muscle (TNNT2).	[11]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Troponin T, cardiac muscle (TNNT2).	[13]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Troponin T, cardiac muscle (TNNT2).	[14]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Troponin T, cardiac muscle (TNNT2).	[15]
Tacrolimus	DMZ7XNQ	Approved	Tacrolimus increases the expression of Troponin T, cardiac muscle (TNNT2).	[16]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Troponin T, cardiac muscle (TNNT2).	[17]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Troponin T, cardiac muscle (TNNT2).	[19]
Ribavirin	DMEYLH9	Phase 1 Trial	Ribavirin decreases the expression of Troponin T, cardiac muscle (TNNT2).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Troponin T, cardiac muscle (TNNT2).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Troponin T, cardiac muscle (TNNT2).	[22]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Troponin T, cardiac muscle (TNNT2).	[23]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Troponin T, cardiac muscle (TNNT2).	[24]
cinnamaldehyde	DMZDUXG	Investigative	cinnamaldehyde decreases the expression of Troponin T, cardiac muscle (TNNT2).	[24]
acrolein	DMAMCSR	Investigative	acrolein decreases the expression of Troponin T, cardiac muscle (TNNT2).	[24]
1,6-hexamethylene diisocyanate	DMLB3RT	Investigative	1,6-hexamethylene diisocyanate decreases the expression of Troponin T, cardiac muscle (TNNT2).	[24]
NSC-1771	DMNXDGQ	Investigative	NSC-1771 decreases the expression of Troponin T, cardiac muscle (TNNT2).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Troponin T, cardiac muscle (TNNT2).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Troponin T, cardiac muscle (TNNT2).	[18]

References

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• [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] Mutations in sarcomere protein genes as a cause of dilated cardiomyopathy. N Engl J Med. 2000 Dec 7;343(23):1688-96. doi: 10.1056/NEJM200012073432304.
• [4] Idiopathic restrictive cardiomyopathy in children is caused by mutations in cardiac sarcomere protein genes. Heart. 2008 Nov;94(11):1478-84. doi: 10.1136/hrt.2007.134684. Epub 2008 May 8.
• [5] Severe familial left ventricular non-compaction cardiomyopathy due to a novel troponin T (TNNT2) mutation. Cardiovasc Res. 2010 Jun 1;86(3):452-60. doi: 10.1093/cvr/cvq009. Epub 2010 Jan 18.
• [6] Novel cardiac troponin T mutation as a cause of familial dilated cardiomyopathy. Circulation. 2001 Oct 30;104(18):2188-93. doi: 10.1161/hc4301.098285.
• [7] Infantile restrictive cardiomyopathy resulting from a mutation in the cardiac troponin T gene. Pediatrics. 2006 May;117(5):1830-3. doi: 10.1542/peds.2005-2301.
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• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] 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.
• [13] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [14] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
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• [17] A novel long noncoding RNA AK001796 acts as an oncogene and is involved in cell growth inhibition by resveratrol in lung cancer. Toxicol Appl Pharmacol. 2015 Jun 1;285(2):79-88.
• [18] 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.
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• [20] Inhibition of cardiomyocyte differentiation of human induced pluripotent stem cells by Ribavirin: Implication for its cardiac developmental toxicity. Toxicology. 2020 Apr 15;435:152422. doi: 10.1016/j.tox.2020.152422. Epub 2020 Feb 26.
• [21] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [22] Genome-wide gene expression profiling of low-dose, long-term exposure of human osteosarcoma cells to bisphenol A and its analogs bisphenols AF and S. Toxicol In Vitro. 2015 Aug;29(5):1060-9.
• [23] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [24] Gene expressions changes in bronchial epithelial cells: markers for respiratory sensitizers and exploration of the NRF2 pathway. Toxicol In Vitro. 2014 Mar;28(2):209-17.