Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4MP90J)

• DOT Name: NIF3-like protein 1 (NIF3L1)
• Synonyms: Amyotrophic lateral sclerosis 2 chromosomal region candidate gene 1 protein
• Gene Name: NIF3L1
• Related Disease:
  Amyotrophic lateral sclerosis type 2, juvenile
  Arteriosclerosis
  Atherosclerosis
  Bronchopulmonary dysplasia
  Dihydropteridine reductase deficiency
  Dilated cardiomyopathy
  Dilated cardiomyopathy 1A
  GTP cyclohydrolase I deficiency
  Hypopigmentation of the skin
  Juvenile-onset Parkinson disease
  Metabolic disorder
  Movement disorder
  Parkinson disease
  Neuroblastoma
  Type-1/2 diabetes
  Adult glioblastoma
  Arthritis
  Glioblastoma multiforme
  Neoplasm
  Non-insulin dependent diabetes
  Phenylketonuria
  Young-onset Parkinson disease
• UniProt ID: NIF3L_HUMAN
• Pfam ID: PF01784
• Sequence:
  MLSSCVRPVPTTVRFVDSLICNSSRSFMDLKALLSSLNDFASLSFAESWDNVGLLVEPSP
  PHTVNTLFLTNDLTEEVMEEVLQKKADLILSYHPPIFRPMKRITWNTWKERLVIRALENR
  VGIYSPHTAYDAAPQGVNNWLAKGLGACTSRPIHPSKAPNYPTEGNHRVEFNVNYTQDLD
  KVMSAVKGIDGVSVTSFSARTGNEEQTRINLNCTQKALMQVVDFLSRNKQLYQKTEILSL
  EKPLLLHTGMGRLCTLDESVSLATMIDRIKRHLKLSHIRLALGVGRTLESQVKVVALCAG
  SGSSVLQGVEADLYLTGEMSHHDTLDAASQGINVILCEHSNTERGFLSDLRDMLDSHLEN
  KINIILSETDRDPLQVV
• Function: May function as a transcriptional corepressor through its interaction with COPS2, negatively regulating the expression of genes involved in neuronal differentiation.

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Amyotrophic lateral sclerosis type 2, juvenile	DISYFHD8	Strong	Biomarker	[1]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[2]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[2]
Bronchopulmonary dysplasia	DISO0BY5	Strong	Genetic Variation	[3]
Dihydropteridine reductase deficiency	DIS1IC3E	Strong	Genetic Variation	[4]
Dilated cardiomyopathy	DISX608J	Strong	Biomarker	[5]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Altered Expression	[5]
GTP cyclohydrolase I deficiency	DISFIL4X	Strong	Genetic Variation	[6]
Hypopigmentation of the skin	DIS39YKC	Strong	Altered Expression	[7]
Juvenile-onset Parkinson disease	DISNT5BI	Strong	Altered Expression	[8]
Metabolic disorder	DIS71G5H	Strong	Biomarker	[6]
Movement disorder	DISOJJ2D	Strong	Genetic Variation	[9]
Parkinson disease	DISQVHKL	Strong	Biomarker	[10]
Neuroblastoma	DISVZBI4	moderate	Altered Expression	[11]
Type-1/2 diabetes	DISIUHAP	moderate	Altered Expression	[12]
Adult glioblastoma	DISVP4LU	Limited	Biomarker	[13]
Arthritis	DIST1YEL	Limited	Biomarker	[14]
Glioblastoma multiforme	DISK8246	Limited	Biomarker	[13]
Neoplasm	DISZKGEW	Limited	Biomarker	[13]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Genetic Variation	[15]
Phenylketonuria	DISCU56J	Limited	Biomarker	[16]
Young-onset Parkinson disease	DIS05LFS	Limited	Genetic Variation	[17]

16 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 NIF3-like protein 1 (NIF3L1).	[18]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of NIF3-like protein 1 (NIF3L1).	[19]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of NIF3-like protein 1 (NIF3L1).	[20]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of NIF3-like protein 1 (NIF3L1).	[21]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of NIF3-like protein 1 (NIF3L1).	[22]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of NIF3-like protein 1 (NIF3L1).	[23]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of NIF3-like protein 1 (NIF3L1).	[24]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of NIF3-like protein 1 (NIF3L1).	[25]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of NIF3-like protein 1 (NIF3L1).	[26]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of NIF3-like protein 1 (NIF3L1).	[26]
Phenobarbital	DMXZOCG	Approved	Phenobarbital decreases the expression of NIF3-like protein 1 (NIF3L1).	[27]
Menadione	DMSJDTY	Approved	Menadione affects the expression of NIF3-like protein 1 (NIF3L1).	[28]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of NIF3-like protein 1 (NIF3L1).	[29]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of NIF3-like protein 1 (NIF3L1).	[30]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of NIF3-like protein 1 (NIF3L1).	[31]
GALLICACID	DM6Y3A0	Investigative	GALLICACID increases the expression of NIF3-like protein 1 (NIF3L1).	[32]

References

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• [2] Induction of vascular GTP-cyclohydrolase I and endogenous tetrahydrobiopterin synthesis protect against inflammation-induced endothelial dysfunction in human atherosclerosis.Circulation. 2011 Oct 25;124(17):1860-70. doi: 10.1161/CIRCULATIONAHA.111.029272. Epub 2011 Oct 3.
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• [4] BH(4) deficiency identified in a neonatal screening program for hyperphenylalaninemia.J Pediatr (Rio J). 2018 Mar-Apr;94(2):170-176. doi: 10.1016/j.jped.2017.04.005. Epub 2017 Aug 9.
• [5] Suppressed expression of GTP cyclohydrolase I mRNA and accelerated expression of inducible nitric oxide synthase mRNA in endomyocardial biopsy specimens from patients with dilated cardiomyopathy.Clin Chim Acta. 2005 Mar;353(1-2):103-7. doi: 10.1016/j.cccn.2004.10.004.
• [6] A novel GTPCH deficiency mouse model exhibiting tetrahydrobiopterin-related metabolic disturbance and infancy-onset motor impairments.Metabolism. 2019 May;94:96-104. doi: 10.1016/j.metabol.2019.02.001. Epub 2019 Feb 10.
• [7] Defective tetrahydrobiopterin and catecholamine biosynthesis in the depigmentation disorder vitiligo.Biochim Biophys Acta. 1994 May 25;1226(2):181-92. doi: 10.1016/0925-4439(94)90027-2.
• [8] GTP cyclohydrolase I activity in mononuclear blood cells in juvenile parkinsonism.Neurosci Lett. 1995 May 5;190(2):140-2. doi: 10.1016/0304-3940(95)11511-t.
• [9] Mutation analysis of the parkin gene in Russian families with autosomal recessive juvenile parkinsonism.Mov Disord. 2003 Aug;18(8):914-9. doi: 10.1002/mds.10467.
• [10] Biochemistry of postmortem brains in Parkinson's disease: historical overview and future prospects. J Neural Transm Suppl. 2007;(72):113-20.
• [11] Characterization of GTP cyclohydrolase I gene expression in the human neuroblastoma SKN-BE(2)M17: enhanced transcription in response to cAMP is conferred by the proximal promoter.J Neurochem. 2001 Nov;79(3):576-87. doi: 10.1046/j.1471-4159.2001.00583.x.
• [12] In vivo activation of AMP-activated protein kinase attenuates diabetes-enhanced degradation of GTP cyclohydrolase I.Diabetes. 2009 Aug;58(8):1893-901. doi: 10.2337/db09-0267. Epub 2009 Jun 15.
• [13] Reactive species balance via GTP cyclohydrolase I regulates glioblastoma growth and tumor initiating cell maintenance.Neuro Oncol. 2018 Jul 5;20(8):1055-1067. doi: 10.1093/neuonc/noy012.
• [14] Induction of inducible nitric oxide synthase, argininosuccinate synthase, and GTP cyclohydrolase I in arthritic joints of human tumor necrosis factor-alpha transgenic mice.J Rheumatol. 2003 Apr;30(4):652-9.
• [15] GTP cyclohydrolase I gene polymorphisms are associated with endothelial dysfunction and oxidative stress in patients with type 2 diabetes mellitus.PLoS One. 2014 Nov 4;9(11):e108587. doi: 10.1371/journal.pone.0108587. eCollection 2014.
• [16] Comparison of epidermal keratinocytes and dermal fibroblasts as potential target cells for somatic gene therapy of phenylketonuria.Mol Genet Metab. 2002 Aug;76(4):313-8. doi: 10.1016/s1096-7192(02)00101-4.
• [17] Low frequency of Parkin, Tyrosine Hydroxylase, and GTP Cyclohydrolase I gene mutations in a Danish population of early-onset Parkinson's Disease.Eur J Neurol. 2006 Apr;13(4):385-90. doi: 10.1111/j.1468-1331.2006.01249.x.
• [18] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [19] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [20] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [21] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [22] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [23] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [24] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [25] 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.
• [26] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [27] Proteomic analysis of hepatic effects of phenobarbital in mice with humanized liver. Arch Toxicol. 2022 Oct;96(10):2739-2754. doi: 10.1007/s00204-022-03338-7. Epub 2022 Jul 26.
• [28] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [29] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [30] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [31] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [32] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.