Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRD1OTR)

• DOT Name: Troponin C, skeletal muscle (TNNC2)
• Gene Name: TNNC2
• Related Disease:
  Congenital myopathy 15
  Hypertrophic cardiomyopathy
• UniProt ID: TNNC2_HUMAN
• PDB ID: 7KAA
• Pfam ID: PF13499
• Sequence:
  MTDQQAEARSYLSEEMIAEFKAAFDMFDADGGGDISVKELGTVMRMLGQTPTKEELDAII
  EEVDEDGSGTIDFEEFLVMMVRQMKEDAKGKSEEELAECFRIFDRNADGYIDPEELAEIF
  RASGEHVTDEEIESLMKDGDKNNDGRIDFDEFLKMMEGVQ
• Function: Troponin is the central regulatory protein of striated muscle contraction. Tn consists of three components: Tn-I which is the inhibitor of actomyosin ATPase, Tn-T which contains the binding site for tropomyosin and Tn-C. The binding of calcium to Tn-C abolishes the inhibitory action of Tn on actin filaments.
• KEGG Pathway:
  Calcium sig.ling pathway (hsa04020)
  Motor proteins (hsa04814)
  Cytoskeleton in muscle cells (hsa04820)
• Reactome Pathway: Striated Muscle Contraction (R-HSA-390522)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Congenital myopathy 15	DISKRRQ0	Limited	Autosomal dominant	[1]
Hypertrophic cardiomyopathy	DISQG2AI	No Known	Autosomal dominant	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Troponin C, skeletal muscle (TNNC2).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Troponin C, skeletal muscle (TNNC2).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Troponin C, skeletal muscle (TNNC2).	[5]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Troponin C, skeletal muscle (TNNC2).	[6]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Troponin C, skeletal muscle (TNNC2).	[8]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Troponin C, skeletal muscle (TNNC2).	[9]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Troponin C, skeletal muscle (TNNC2).	[10]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Troponin C, skeletal muscle (TNNC2).	[11]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Troponin C, skeletal muscle (TNNC2).	[13]

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 C, skeletal muscle (TNNC2).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Troponin C, skeletal muscle (TNNC2).	[12]

References

• [1] 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.
• [2] 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.
• [3] Antiepileptic drugs are endocrine disruptors for the human fetal testis ex vivo. Toxicol Sci. 2023 Sep 28;195(2):169-183. doi: 10.1093/toxsci/kfad076.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [7] 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.
• [8] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [9] 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.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] 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.
• [12] 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.
• [13] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.