Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYWPPM3)

• DOT Name: Tachykinin-4 (TAC4)
• Synonyms: Preprotachykinin-C; PPT-C
• Gene Name: TAC4
• Related Disease:
  Crohn disease
  Inflammatory bowel disease
  Multiple sclerosis
  Familial cold autoinflammatory syndrome
  Fibromyalgia
  Hepatitis B virus infection
  Nasal polyp
  Uterine fibroids
  Asthma
  Astrocytoma
  Glioma
  Melanoma
  Neoplasm
  Osteoarthritis
  Rheumatoid arthritis
• UniProt ID: TKN4_HUMAN
• PDB ID: 2MOC
• Sequence:
  MLPCLALLLLMELSVCTVAGDGGEEQTLSTEAETWVIVALEEGAGPSIQLQLQEVKTGKA
  SQFFGLMGKRVGGRPLIQPRRKKAYQLEHTFQGLLGKRSLFTEGREDEAQGSE
• Function: Tachykinins are active peptides which excite neurons, evoke behavioral responses, are potent vasodilators and secretagogues, and contract (directly or indirectly) many smooth muscles. Endokinin-A induces thermal hyperalgesia and pain-related behavior such as scratching following intrathecal administration in rats. These effects are suppressed by treatment with endokinin-C. Endokinin-A/B reduces arterial blood pressure and increases sperm motility.
• Tissue Specificity: Expressed at low levels in the uterus of both pregnant and non-pregnant women. Isoform 1 is found only in the adrenal gland and fetal liver. Isoform 2 is found in heart, liver, bone marrow, prostate, adrenal gland and testis. Isoform 3 and isoform 4 are expressed predominantly in adrenal gland and placenta.
• KEGG Pathway: Neuroactive ligand-receptor interaction (hsa04080)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Crohn disease	DIS2C5Q8	Definitive	Altered Expression	[1]
Inflammatory bowel disease	DISGN23E	Definitive	Biomarker	[1]
Multiple sclerosis	DISB2WZI	Definitive	Genetic Variation	[2]
Familial cold autoinflammatory syndrome	DISAPE70	Strong	Biomarker	[3]
Fibromyalgia	DISZJDS2	Strong	Biomarker	[4]
Hepatitis B virus infection	DISLQ2XY	Strong	Biomarker	[5]
Nasal polyp	DISLP3XE	Strong	Altered Expression	[6]
Uterine fibroids	DISBZRMJ	Strong	Biomarker	[7]
Asthma	DISW9QNS	Limited	Biomarker	[8]
Astrocytoma	DISL3V18	Limited	Biomarker	[9]
Glioma	DIS5RPEH	Limited	Biomarker	[9]
Melanoma	DIS1RRCY	Limited	Biomarker	[10]
Neoplasm	DISZKGEW	Limited	Biomarker	[10]
Osteoarthritis	DIS05URM	Limited	Altered Expression	[11]
Rheumatoid arthritis	DISTSB4J	Limited	Altered Expression	[11]

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 Tachykinin-4 (TAC4).	[12]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Tachykinin-4 (TAC4).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Tachykinin-4 (TAC4).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Tachykinin-4 (TAC4).	[13]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Tachykinin-4 (TAC4).	[15]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Tachykinin-4 (TAC4).	[17]

References

• [1] Distinct differences in tachykinin gene expression in ulcerative colitis, Crohn's disease and diverticular disease: a role for hemokinin-1?.Neurogastroenterol Motil. 2011 May;23(5):475-83, e179-80. doi: 10.1111/j.1365-2982.2011.01685.x. Epub 2011 Feb 22.
• [2] 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.
• [3] Hemokinin-1 is an important mediator of pain in mouse models of neuropathic and inflammatory mechanisms.Brain Res Bull. 2019 Apr;147:165-173. doi: 10.1016/j.brainresbull.2019.01.015. Epub 2019 Jan 18.
• [4] Mast Cells, Neuroinflammation and Pain in Fibromyalgia Syndrome.Front Cell Neurosci. 2019 Aug 2;13:353. doi: 10.3389/fncel.2019.00353. eCollection 2019.
• [5] Hemokinin-1 as an adjuvant molecule enhancing humoral and memory responses to HBsAg DNA vaccination.Viral Immunol. 2012 Aug;25(4):289-96. doi: 10.1089/vim.2012.0015.
• [6] Hemokinin-1 stimulates C-C motif chemokine ligand 24 production in macrophages to enhance eosinophilic inflammation in nasal polyps.Int Forum Allergy Rhinol. 2019 Nov;9(11):1334-1345. doi: 10.1002/alr.22430. Epub 2019 Sep 23.
• [7] Altered expression of the tachykinins substance P/neurokinin A/hemokinin-1 and their preferred neurokinin 1/neurokinin 2 receptors in uterine leiomyomata.Fertil Steril. 2016 Nov;106(6):1521-1529. doi: 10.1016/j.fertnstert.2016.07.007. Epub 2016 Jul 25.
• [8] Upregulation of Mas-related G Protein coupled receptor X2 in asthmatic lung mast cells and its activation by the novel neuropeptide hemokinin-1.Respir Res. 2018 Jan 3;19(1):1. doi: 10.1186/s12931-017-0698-3.
• [9] Hemokinin-1 has Substance P-like function in U-251 MG astrocytoma cells: a pharmacological and functional study.J Neuroimmunol. 2005 Jul;164(1-2):48-56. doi: 10.1016/j.jneuroim.2005.03.016.
• [10] Human hemokinin-1 promotes migration of melanoma cells and increases MMP-2 and MT1-MMP expression by activating tumor cell NK1 receptors.Peptides. 2016 Sep;83:8-15. doi: 10.1016/j.peptides.2016.07.004. Epub 2016 Jul 22.
• [11] Inhibition of hexokinases holds potential as treatment strategy for rheumatoid arthritis.Arthritis Res Ther. 2019 Apr 3;21(1):87. doi: 10.1186/s13075-019-1865-3.
• [12] 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.
• [13] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [14] 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.
• [15] 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.
• [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] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.