Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4PAKUY)

• DOT Name: Neurturin (NRTN)
• Gene Name: NRTN
• Related Disease:
  Depression
  Extrapulmonary tuberculosis
  Hirschsprung disease
  Movement disorder
  Pancreatic cancer
  Paraganglioma
  Pheochromocytoma
  Psoriasis
  Encephalitis
  Hyperglycemia
  Neoplasm
  Type-1/2 diabetes
• UniProt ID: NRTN_HUMAN
• PDB ID: 5MR4; 5MR5; 5MR9; 5NMZ; 6GL7; 6Q2O; 6Q2R
• Pfam ID: PF00019
• Sequence:
  MQRWKAAALASVLCSSVLSIWMCREGLLLSHRLGPALVPLHRLPRTLDARIARLAQYRAL
  LQGAPDAMELRELTPWAGRPPGPRRRAGPRRRRARARLGARPCGLRELEVRVSELGLGYA
  SDETVLFRYCAGACEAAARVYDLGLRRLRQRRRLRRERVRAQPCCRPTAYEDEVSFLDAH
  SRYHTVHELSARECACV
• Function: Supports the survival of sympathetic neurons in culture. May regulate the development and maintenance of the CNS. Might control the size of non-neuronal cell population such as haemopoietic cells.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  PI3K-Akt sig.ling pathway (hsa04151)
• Reactome Pathway:
  RAF/MAP kinase cascade (R-HSA-5673001)
  RET signaling (R-HSA-8853659)
  NCAM1 interactions (R-HSA-419037)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Depression	DIS3XJ69	Strong	Altered Expression	[1]
Extrapulmonary tuberculosis	DIS6KM28	Strong	Biomarker	[2]
Hirschsprung disease	DISUUSM1	Strong	Biomarker	[3]
Movement disorder	DISOJJ2D	Strong	Biomarker	[4]
Pancreatic cancer	DISJC981	Strong	Altered Expression	[5]
Paraganglioma	DIS2XXH5	Strong	Biomarker	[6]
Pheochromocytoma	DIS56IFV	Strong	Biomarker	[6]
Psoriasis	DIS59VMN	Strong	Biomarker	[7]
Encephalitis	DISLD1RL	moderate	Altered Expression	[8]
Hyperglycemia	DIS0BZB5	Disputed	Biomarker	[9]
Neoplasm	DISZKGEW	Limited	Biomarker	[5]
Type-1/2 diabetes	DISIUHAP	Limited	Biomarker	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Neurturin (NRTN).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Neurturin (NRTN).	[22]

16 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 Neurturin (NRTN).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Neurturin (NRTN).	[13]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Neurturin (NRTN).	[12]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Neurturin (NRTN).	[14]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Neurturin (NRTN).	[15]
Decitabine	DMQL8XJ	Approved	Decitabine decreases the expression of Neurturin (NRTN).	[16]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Neurturin (NRTN).	[17]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of Neurturin (NRTN).	[18]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol increases the expression of Neurturin (NRTN).	[19]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Neurturin (NRTN).	[20]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Neurturin (NRTN).	[21]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Neurturin (NRTN).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Neurturin (NRTN).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Neurturin (NRTN).	[24]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Neurturin (NRTN).	[25]
Arachidonic acid	DMUOQZD	Investigative	Arachidonic acid decreases the expression of Neurturin (NRTN).	[26]

References

• [1] Abdominal pain and the neurotrophic system in ulcerative colitis.Inflamm Bowel Dis. 2014 Dec;20(12):2330-9. doi: 10.1097/MIB.0000000000000207.
• [2] Prevalence of nontuberculous mycobacteria among extrapulmonary tuberculosis cases in tertiary care centers in Northern India.Biomed Res Int. 2015;2015:465403. doi: 10.1155/2015/465403. Epub 2015 Mar 26.
• [3] Novel mutations at RET ligand genes preventing receptor activation are associated to Hirschsprung's disease.J Mol Med (Berl). 2011 May;89(5):471-80. doi: 10.1007/s00109-010-0714-2. Epub 2011 Jan 5.
• [4] AAV2-Neurturin for Parkinson's Disease: What Lessons Have We Learned?.Methods Mol Biol. 2016;1382:485-90. doi: 10.1007/978-1-4939-3271-9_32.
• [5] The neurotrophic factor neurturin contributes toward an aggressive cancer cell phenotype, neuropathic pain and neuronal plasticity in pancreatic cancer.Carcinogenesis. 2014 Jan;35(1):103-13. doi: 10.1093/carcin/bgt312. Epub 2013 Sep 25.
• [6] Expression analysis of RET and the GDNF/GFRalpha-1 and NTN/GFRalpha-2 ligand complexes in pheochromocytomas and paragangliomas.Int J Mol Med. 2000 Oct;6(4):469-74. doi: 10.3892/ijmm.6.4.469.
• [7] Role of neurturin in spontaneous itch and increased nonpeptidergic intraepidermal fiber density in a mouse model of psoriasis.Pain. 2017 Nov;158(11):2196-2202. doi: 10.1097/j.pain.0000000000001025.
• [8] Analysis of neurotrophic and antioxidant factors related to midbrain dopamine neuronal loss and brain inflammation in the cerebrospinal fluid of the elderly.Exp Gerontol. 2018 Sep;110:54-60. doi: 10.1016/j.exger.2018.05.009. Epub 2018 May 19.
• [9] Neurturin and a GLP-1 Analogue Act Synergistically to Alleviate Diabetes in Zucker Diabetic Fatty Rats.Diabetes. 2017 Jul;66(7):2007-2018. doi: 10.2337/db16-0916. Epub 2017 Apr 13.
• [10] A bicistronic vector with destabilized mRNA secondary structure yields scalable higher titer expression of human neurturin in E. coli.Biotechnol Bioeng. 2017 Aug;114(8):1753-1761. doi: 10.1002/bit.26299. Epub 2017 May 18.
• [11] 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.
• [12] 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.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] Prenatal arsenic exposure and shifts in the newborn proteome: interindividual differences in tumor necrosis factor (TNF)-responsive signaling. Toxicol Sci. 2014 Jun;139(2):328-37. doi: 10.1093/toxsci/kfu053. Epub 2014 Mar 27.
• [15] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [16] DNA methylation inhibits p53-mediated survivin repression. Oncogene. 2009 May 14;28(19):2046-50. doi: 10.1038/onc.2009.62. Epub 2009 Apr 13.
• [17] Gene expression profiling in Ishikawa cells: a fingerprint for estrogen active compounds. Toxicol Appl Pharmacol. 2009 Apr 1;236(1):85-96.
• [18] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [19] The genomic response of a human uterine endometrial adenocarcinoma cell line to 17alpha-ethynyl estradiol. Toxicol Sci. 2009 Jan;107(1):40-55.
• [20] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [21] 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.
• [22] 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.
• [23] 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.
• [24] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.
• [25] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [26] Arachidonic acid-induced gene expression in colon cancer cells. Carcinogenesis. 2006 Oct;27(10):1950-60.