Details of Drug Off-Target (DOT)

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

• DOT Name: Nitric oxide synthase-interacting protein (NOSIP)
• Synonyms: E3 ubiquitin-protein ligase NOSIP; EC 2.3.2.27; RING-type E3 ubiquitin transferase NOSIP; eNOS-interacting protein
• Gene Name: NOSIP
• Related Disease:
  Nephropathy
  Congenital diaphragmatic hernia
  Isolated congenital microcephaly
  Mental disorder
  Primitive neuroectodermal tumor
  Intellectual disability
  Schizophrenia
• UniProt ID: NOSIP_HUMAN
• PDB ID: 8C6J
• EC Number: 2.3.2.27
• Pfam ID: PF15906
• Sequence:
  MTRHGKNCTAGAVYTYHEKKKDTAASGYGTQNIRLSRDAVKDFDCCCLSLQPCHDPVVTP
  DGYLYEREAILEYILHQKKEIARQMKAYEKQRGTRREEQKELQRAASQDHVRGFLEKESA
  IVSRPLNPFTAKALSGTSPDDVQPGPSVGPPSKDKDKVLPSFWIPSLTPEAKATKLEKPS
  RTVTCPMSGKPLRMSDLTPVHFTPLDSSVDRVGLITRSERYVCAVTRDSLSNATPCAVLR
  PSGAVVTLECVEKLIRKDMVDPVTGDKLTDRDIIVLQRGGTGFAGSGVKLQAEKSRPVMQ
  A
• Function: E3 ubiquitin-protein ligase that is essential for proper development of the forebrain, the eye, and the face. Catalyzes monoubiquitination of serine/threonine-protein phosphatase 2A (PP2A) catalytic subunit PPP2CA/PPP2CB. Negatively regulates nitric oxide production by inducing NOS1 and NOS3 translocation to actin cytoskeleton and inhibiting their enzymatic activity.
• Tissue Specificity: Expressed in heart, brain and lung. Present in endothelial cells (at protein level).
• Reactome Pathway: NOSIP mediated eNOS trafficking (R-HSA-203754)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Nephropathy	DISXWP4P	Definitive	Biomarker	[1]
Congenital diaphragmatic hernia	DIS0IPVU	Strong	Altered Expression	[2]
Isolated congenital microcephaly	DISUXHZ6	Strong	Altered Expression	[3]
Mental disorder	DIS3J5R8	Strong	Biomarker	[3]
Primitive neuroectodermal tumor	DISFHXHA	moderate	Altered Expression	[4]
Intellectual disability	DISMBNXP	Disputed	Genetic Variation	[5]
Schizophrenia	DISSRV2N	Limited	Genetic Variation	[6]

5 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 Nitric oxide synthase-interacting protein (NOSIP).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Nitric oxide synthase-interacting protein (NOSIP).	[15]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Nitric oxide synthase-interacting protein (NOSIP).	[17]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Nitric oxide synthase-interacting protein (NOSIP).	[18]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Nitric oxide synthase-interacting protein (NOSIP).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Nitric oxide synthase-interacting protein (NOSIP).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Nitric oxide synthase-interacting protein (NOSIP).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Nitric oxide synthase-interacting protein (NOSIP).	[10]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Nitric oxide synthase-interacting protein (NOSIP).	[11]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Nitric oxide synthase-interacting protein (NOSIP).	[12]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Nitric oxide synthase-interacting protein (NOSIP).	[13]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Nitric oxide synthase-interacting protein (NOSIP).	[14]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Nitric oxide synthase-interacting protein (NOSIP).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Nitric oxide synthase-interacting protein (NOSIP).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Nitric oxide synthase-interacting protein (NOSIP).	[20]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Nitric oxide synthase-interacting protein (NOSIP).	[21]

References

• [1] Intragraft Antiviral-Specific Gene Expression as a Distinctive Transcriptional Signature for Studies in Polyomavirus-Associated Nephropathy.Transplantation. 2016 Oct;100(10):2062-70. doi: 10.1097/TP.0000000000001214.
• [2] Expression of Nitric Oxide Synthase Interacting Protein (NOSIP) is Decreased in the Pulmonary Vasculature of Nitrofen-Induced Congenital Diaphragmatic Hernia.Eur J Pediatr Surg. 2019 Feb;29(1):102-107. doi: 10.1055/s-0038-1675772. Epub 2018 Dec 10.
• [3] Nosip functions during vertebrate eye and cranial cartilage development.Dev Dyn. 2018 Sep;247(9):1070-1082. doi: 10.1002/dvdy.24659. Epub 2018 Sep 9.
• [4] Nitric oxide synthase (NOS)-interacting protein interacts with neuronal NOS and regulates its distribution and activity.J Neurosci. 2004 Nov 17;24(46):10454-65. doi: 10.1523/JNEUROSCI.2265-04.2004.
• [5] Differential DNA methylation at birth associated with mental disorder in individuals with 22q11.2 deletion syndrome.Transl Psychiatry. 2017 Aug 29;7(8):e1221. doi: 10.1038/tp.2017.181.
• [6] Genome-Wide Association Study Detected Novel Susceptibility Genes for Schizophrenia and Shared Trans-Populations/Diseases Genetic Effect.Schizophr Bull. 2019 Jun 18;45(4):824-834. doi: 10.1093/schbul/sby140.
• [7] 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.
• [8] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [9] 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.
• [10] 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.
• [11] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [12] A genomic approach to predict synergistic combinations for breast cancer treatment. Pharmacogenomics J. 2013 Feb;13(1):94-104. doi: 10.1038/tpj.2011.48. Epub 2011 Nov 15.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [15] 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.
• [16] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [17] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [18] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [19] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [20] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [21] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.