Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOJGM38)

• DOT Name: Tachykinin-3 (TAC3)
• Synonyms: ZNEUROK1
• Gene Name: TAC3
• Related Disease:
  Multiple sclerosis
  Precocious puberty
  Congenital hypogonadotropic hypogonadism
  High blood pressure
  Hypogonadism
  Hypogonadotropic hypogonadism 10 with or without anosmia
  Hypogonadotropic hypogonadism 7 with or without anosmia
  Klinefelter syndrome
  Leiomyoma
  Myotonic dystrophy type 1
  Neoplasm
  Obesity
  Polycystic ovarian syndrome
  Pre-eclampsia
  Type-1 diabetes
  Uterine fibroids
  Zika virus infection
  Cryptorchidism
  Myotonic dystrophy type 2
  Non-insulin dependent diabetes
  Hypogonadotropic hypogonadism
  Asthma
  Eclampsia
  Glaucoma/ocular hypertension
• UniProt ID: TKNK_HUMAN
• PDB ID: 1P9F
• Pfam ID: PF03823
• Sequence:
  MRIMLLFTAILAFSLAQSFGAVCKEPQEEVVPGGGRSKRDPDLYQLLQRLFKSHSSLEGL
  LKALSQASTDPKESTSPEKRDMHDFFVGLMGKRSVQPDSPTDVNQENVPSFGILKYPPRA
  E
• Function: Tachykinins are active peptides which excite neurons, evoke behavioral responses, are potent vasodilators and secretagogues, and contract (directly or indirectly) many smooth muscles. Is a critical central regulator of gonadal function.
• KEGG Pathway: Neuroactive ligand-receptor interaction (hsa04080)
• Reactome Pathway:
  G alpha (q) signalling events (R-HSA-416476)
  Tachykinin receptors bind tachykinins (R-HSA-380095)

Molecular Interaction Atlas (MIA) of This DOT

24 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Multiple sclerosis	DISB2WZI	Definitive	Biomarker	[1]
Precocious puberty	DISYI2XZ	Definitive	Altered Expression	[2]
Congenital hypogonadotropic hypogonadism	DISEV092	Strong	Biomarker	[3]
High blood pressure	DISY2OHH	Strong	Altered Expression	[4]
Hypogonadism	DISICMNI	Strong	Biomarker	[5]
Hypogonadotropic hypogonadism 10 with or without anosmia	DISJBI0M	Strong	Autosomal recessive	[3]
Hypogonadotropic hypogonadism 7 with or without anosmia	DISPBWEU	Strong	Autosomal recessive	[5]
Klinefelter syndrome	DISOUI7W	Strong	Biomarker	[6]
Leiomyoma	DISLDDFN	Strong	Altered Expression	[7]
Myotonic dystrophy type 1	DISJC0OX	Strong	Biomarker	[8]
Neoplasm	DISZKGEW	Strong	Biomarker	[9]
Obesity	DIS47Y1K	Strong	Biomarker	[8]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Altered Expression	[10]
Pre-eclampsia	DISY7Q29	Strong	Altered Expression	[11]
Type-1 diabetes	DIS7HLUB	Strong	Biomarker	[8]
Uterine fibroids	DISBZRMJ	Strong	Altered Expression	[7]
Zika virus infection	DISQUCTY	Strong	Biomarker	[12]
Cryptorchidism	DISYUD2P	moderate	Biomarker	[13]
Myotonic dystrophy type 2	DIS5ZWF1	moderate	Genetic Variation	[14]
Non-insulin dependent diabetes	DISK1O5Z	moderate	Biomarker	[14]
Hypogonadotropic hypogonadism	DIS8JSKR	Supportive	Autosomal dominant	[5]
Asthma	DISW9QNS	Limited	Biomarker	[15]
Eclampsia	DISWPO8U	Limited	Altered Expression	[16]
Glaucoma/ocular hypertension	DISLBXBY	Limited	Biomarker	[17]

8 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 Tachykinin-3 (TAC3).	[18]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Tachykinin-3 (TAC3).	[19]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Tachykinin-3 (TAC3).	[21]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Tachykinin-3 (TAC3).	[22]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Tachykinin-3 (TAC3).	[19]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Tachykinin-3 (TAC3).	[23]
Amphotericin B	DMTAJQE	Approved	Amphotericin B increases the expression of Tachykinin-3 (TAC3).	[24]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Tachykinin-3 (TAC3).	[25]

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 Tachykinin-3 (TAC3).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Tachykinin-3 (TAC3).	[26]

References

• [1] The neuropeptide genes TAC1, TAC3, TAC4, VIP and PACAP(ADCYAP1), and susceptibility to multiple sclerosis.J Neuroimmunol. 2007 Feb;183(1-2):208-13. doi: 10.1016/j.jneuroim.2006.11.002. Epub 2006 Dec 18.
• [2] The usefulness of circulating levels of leptin, kisspeptin, and neurokinin B in obese girls with precocious puberty.Gynecol Endocrinol. 2018 Jul;34(7):627-630. doi: 10.1080/09513590.2017.1423467. Epub 2018 Jan 5.
• [3] TAC3 and TACR3 defects cause hypothalamic congenital hypogonadotropic hypogonadism in humans. J Clin Endocrinol Metab. 2010 May;95(5):2287-95. doi: 10.1210/jc.2009-2600. Epub 2010 Mar 1.
• [4] Excessive placental secretion of neurokinin B during the third trimester causes pre-eclampsia.Nature. 2000 Jun 15;405(6788):797-800. doi: 10.1038/35015579.
• [5] TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for Neurokinin B in the central control of reproduction. Nat Genet. 2009 Mar;41(3):354-358. doi: 10.1038/ng.306. Epub 2008 Dec 11.
• [6] Neurokinin B and its receptor in hypogonadotropic hypogonadism.Front Horm Res. 2010;39:133-141. doi: 10.1159/000312699. Epub 2010 Apr 8.
• [7] Differentially regulated expression of neurokinin B (NKB)/NK3 receptor system in uterine leiomyomata.Hum Reprod. 2013 Jul;28(7):1799-808. doi: 10.1093/humrep/det128. Epub 2013 May 8.
• [8] Effects of Orchidectomy and Testosterone Replacement on Numbers of Kisspeptin-, Neurokinin B-, and Dynorphin A-Immunoreactive Neurones in the Arcuate Nucleus of the Hypothalamus in Obese and Diabetic Rats.J Neuroendocrinol. 2017 Feb;29(2). doi: 10.1111/jne.12453.
• [9] Neurokinin-immunoreactivity in human neuroblastomas. Evidence for selective expression of the preprotachykinin (PPT) II gene.FEBS Lett. 1990 Dec 17;277(1-2):83-7. doi: 10.1016/0014-5793(90)80814-y.
• [10] Altered expression of the kisspeptin/KISS1R and neurokinin B/NK3R systems in mural granulosa and cumulus cells of patients with polycystic ovarian syndrome.J Assist Reprod Genet. 2019 Jan;36(1):113-120. doi: 10.1007/s10815-018-1338-7. Epub 2018 Oct 31.
• [11] Third trimester plasma neurokinin B levels in women with and without preeclampsia.J Matern Fetal Neonatal Med. 2008 Feb;21(2):95-100. doi: 10.1080/14767050701836784.
• [12] Zika virus induces abnormal cranial osteogenesis by negatively affecting cranial neural crest development.Infect Genet Evol. 2019 Apr;69:176-189. doi: 10.1016/j.meegid.2019.01.023. Epub 2019 Jan 19.
• [13] Isolated cryptorchidism: no evidence for involvement of genes underlying isolated hypogonadotropic hypogonadism.Mol Cell Endocrinol. 2011 Jul 20;341(1-2):35-8. doi: 10.1016/j.mce.2011.05.015. Epub 2011 Jun 1.
• [14] High-fat diet and type 2 diabetes induced disruption of the oestrous cycle and alteration of hormonal profiles, but did not affect subpopulations of KNDy neurones in female rats.J Neuroendocrinol. 2018 Nov;30(11):e12651. doi: 10.1111/jne.12651. Epub 2018 Nov 7.
• [15] T-helper cell type 2 (Th2) and non-Th2 molecular phenotypes of asthma using sputum transcriptomics in U-BIOPRED.Eur Respir J. 2017 Feb 8;49(2):1602135. doi: 10.1183/13993003.02135-2016. Print 2017 Feb.
• [16] Neurokinin B and pre-eclampsia: a decade of discovery.Reprod Biol Endocrinol. 2010 Jan 14;8:4. doi: 10.1186/1477-7827-8-4.
• [17] A novel gene (oculomedin) induced by mechanical stretching in human trabecular cells of the eye.Biochem Biophys Res Commun. 1999 Jun 7;259(2):349-51. doi: 10.1006/bbrc.1999.0797.
• [18] 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.
• [19] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [20] 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.
• [21] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [22] 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.
• [23] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [24] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [25] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [26] 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.