Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTC1RAH3)

• DOT Name: Omega-amidase NIT2 (NIT2)
• Synonyms: EC 3.5.1.3; Nitrilase homolog 2
• Gene Name: NIT2
• Related Disease:
  Advanced cancer
  Alzheimer disease
  Colon cancer
  Colon carcinoma
  Neoplasm
• UniProt ID: NIT2_HUMAN
• EC Number: 3.5.1.3
• Pfam ID: PF00795
• Sequence:
  MTSFRLALIQLQISSIKSDNVTRACSFIREAATQGAKIVSLPECFNSPYGAKYFPEYAEK
  IPGESTQKLSEVAKECSIYLIGGSIPEEDAGKLYNTCAVFGPDGTLLAKYRKIHLFDIDV
  PGKITFQESKTLSPGDSFSTFDTPYCRVGLGICYDMRFAELAQIYAQRGCQLLVYPGAFN
  LTTGPAHWELLQRSRAVDNQVYVATASPARDDKASYVAWGHSTVVNPWGEVLAKAGTEEA
  IVYSDIDLKKLAEIRQQIPVFRQKRSDLYAVEMKKP
• Function: Has omega-amidase activity. The role of omega-amidase is to remove potentially toxic intermediates by converting 2-oxoglutaramate and 2-oxosuccinamate to biologically useful 2-oxoglutarate and oxaloacetate, respectively.
• Tissue Specificity: Detected in fetal brain (at protein level). Ubiquitous. Detected in heart, brain, placenta, lung, liver, skeletal muscle, kidney, pancreas, prostate, spleen, thymus, prostate, testis, ovary, small intestine and colon.
• KEGG Pathway:
  Alanine, aspartate and glutamate metabolism (hsa00250)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Neutrophil degranulation (R-HSA-6798695)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[2]
Colon cancer	DISVC52G	Strong	Biomarker	[3]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]

13 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 Omega-amidase NIT2 (NIT2).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Omega-amidase NIT2 (NIT2).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Omega-amidase NIT2 (NIT2).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Omega-amidase NIT2 (NIT2).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Omega-amidase NIT2 (NIT2).	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Omega-amidase NIT2 (NIT2).	[9]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Omega-amidase NIT2 (NIT2).	[10]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Omega-amidase NIT2 (NIT2).	[11]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Omega-amidase NIT2 (NIT2).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Omega-amidase NIT2 (NIT2).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Omega-amidase NIT2 (NIT2).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Omega-amidase NIT2 (NIT2).	[17]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Omega-amidase NIT2 (NIT2).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Omega-amidase NIT2 (NIT2).	[13]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Omega-amidase NIT2 (NIT2).	[14]

References

• [1] Growth inhibitory effect of the human NIT2 gene and its allelic imbalance in cancers.FEBS J. 2007 Jun;274(11):2946-56. doi: 10.1111/j.1742-4658.2007.05828.x. Epub 2007 May 4.
• [2] Genetic data and cognitively defined late-onset Alzheimer's disease subgroups.Mol Psychiatry. 2020 Nov;25(11):2942-2951. doi: 10.1038/s41380-018-0298-8. Epub 2018 Dec 4.
• [3] Downregulation of NIT2 inhibits colon cancer cell proliferation and induces cell cycle arrest through the caspase-3 and PARP pathways.Int J Mol Med. 2015 May;35(5):1317-22. doi: 10.3892/ijmm.2015.2125. Epub 2015 Mar 4.
• [4] 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.
• [5] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [6] 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.
• [7] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [8] 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.
• [9] 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.
• [10] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [11] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.