Details of Drug Off-Target (DOT)

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

• DOT Name: Nardilysin (NRDC)
• Synonyms: EC 3.4.24.61; N-arginine dibasic convertase; NRD convertase; NRD-C; Nardilysin convertase
• Gene Name: NRDC
• Related Disease:
  Acute coronary syndrome
  Acute myocardial infarction
  Alcohol dependence
  Alzheimer disease
  Breast cancer
  Breast carcinoma
  Carcinoma
  Carcinoma of esophagus
  Cerebral infarction
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Ductal breast carcinoma in situ
  Esophageal cancer
  Esophageal squamous cell carcinoma
  Intestinal neoplasm
  Intrahepatic cholangiocarcinoma
  Major depressive disorder
  Neoplasm
  Neoplasm of esophagus
  Neuroblastoma
  Pancreatic ductal carcinoma
  Pancreatitis
  Patent ductus arteriosus
  Stroke
  Hepatitis C virus infection
  Hepatocellular carcinoma
  Retinopathy
• UniProt ID: NRDC_HUMAN
• EC Number: 3.4.24.61
• Pfam ID: PF00675 ; PF05193 ; PF16187
• Sequence:
  MLRRVTVAAVCATRRKLCEAGRELAALWGIETRGRCEDSAAARPFPILAMPGRNKAKSTC
  SCPDLQPNGQDLGENSRVARLGADESEEEGRRGSLSNAGDPEIVKSPSDPKQYRYIKLQN
  GLQALLISDLSNMEGKTGNTTDDEEEEEVEEEEEDDDEDSGAEIEDDDEEGFDDEDEFDD
  EHDDDLDTEDNELEELEERAEARKKTTEKQSAAALCVGVGSFADPDDLPGLAHFLEHMVF
  MGSLKYPDENGFDAFLKKHGGSDNASTDCERTVFQFDVQRKYFKEALDRWAQFFIHPLMI
  RDAIDREVEAVDSEYQLARPSDANRKEMLFGSLARPGHPMGKFFWGNAETLKHEPRKNNI
  DTHARLREFWMRYYSSHYMTLVVQSKETLDTLEKWVTEIFSQIPNNGLPRPNFGHLTDPF
  DTPAFNKLYRVVPIRKIHALTITWALPPQQQHYRVKPLHYISWLVGHEGKGSILSFLRKK
  CWALALFGGNGETGFEQNSTYSVFSISITLTDEGYEHFYEVAYTVFQYLKMLQKLGPEKR
  IFEEIRKIEDNEFHYQEQTDPVEYVENMCENMQLYPLQDILTGDQLLFEYKPEVIGEALN
  QLVPQKANLVLLSGANEGKCDLKEKWFGTQYSIEDIENSWAELWNSNFELNPDLHLPAEN
  KYIATDFTLKAFDCPETEYPVKIVNTPQGCLWYKKDNKFKIPKAYIRFHLISPLIQKSAA
  NVVLFDIFVNILTHNLAEPAYEADVAQLEYKLVAGEHGLIIRVKGFNHKLPLLFQLIIDY
  LAEFNSTPAVFTMITEQLKKTYFNILIKPETLAKDVRLLILEYARWSMIDKYQALMDGLS
  LESLLSFVKEFKSQLFVEGLVQGNVTSTESMDFLKYVVDKLNFKPLEQEMPVQFQVVELP
  SGHHLCKVKALNKGDANSEVTVYYQSGTRSLREYTLMELLVMHMEEPCFDFLRTKQTLGY
  HVYPTCRNTSGILGFSVTVGTQATKYNSEVVDKKIEEFLSSFEEKIENLTEEAFNTQVTA
  LIKLKECEDTHLGEEVDRNWNEVVTQQYLFDRLAHEIEALKSFSKSDLVNWFKAHRGPGS
  KMLSVHVVGYGKYELEEDGTPSSEDSNSSCEVMQLTYLPTSPLLADCIIPITDIRAFTTT
  LNLLPYHKIVK
• Function: Cleaves peptide substrates on the N-terminus of arginine residues in dibasic pairs. Is a critical activator of BACE1- and ADAM17-mediated pro-neuregulin ectodomain shedding, involved in the positive regulation of axonal maturation and myelination. Required for proper functioning of 2-oxoglutarate dehydrogenase (OGDH).
• Tissue Specificity: Primarily in adult heart, skeletal muscle, and testis and at much lower levels in other tissues.

Molecular Interaction Atlas (MIA) of This DOT

28 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute coronary syndrome	DIS7DYEW	Strong	Biomarker	[1]
Acute myocardial infarction	DISE3HTG	Strong	Altered Expression	[2]
Alcohol dependence	DIS4ZSCO	Strong	Biomarker	[3]
Alzheimer disease	DISF8S70	Strong	Biomarker	[4]
Breast cancer	DIS7DPX1	Strong	Biomarker	[5]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[5]
Carcinoma	DISH9F1N	Strong	Altered Expression	[5]
Carcinoma of esophagus	DISS6G4D	Strong	Biomarker	[6]
Cerebral infarction	DISR1WNP	Strong	Altered Expression	[7]
Colon cancer	DISVC52G	Strong	Biomarker	[8]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[8]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[8]
Ductal breast carcinoma in situ	DISLCJY7	Strong	Altered Expression	[5]
Esophageal cancer	DISGB2VN	Strong	Biomarker	[6]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[9]
Intestinal neoplasm	DISK0GUH	Strong	Genetic Variation	[8]
Intrahepatic cholangiocarcinoma	DIS6GOC8	Strong	Biomarker	[10]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[11]
Neoplasm	DISZKGEW	Strong	Biomarker	[6]
Neoplasm of esophagus	DISOLKAQ	Strong	Biomarker	[6]
Neuroblastoma	DISVZBI4	Strong	Altered Expression	[4]
Pancreatic ductal carcinoma	DIS26F9Q	Strong	Biomarker	[12]
Pancreatitis	DIS0IJEF	Strong	Biomarker	[12]
Patent ductus arteriosus	DIS9P8YS	Strong	Biomarker	[12]
Stroke	DISX6UHX	Strong	Biomarker	[7]
Hepatitis C virus infection	DISQ0M8R	moderate	Biomarker	[6]
Hepatocellular carcinoma	DIS0J828	moderate	Altered Expression	[6]
Retinopathy	DISB4B0F	moderate	Biomarker	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Nardilysin (NRDC).	[14]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Nardilysin (NRDC).	[15]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Nardilysin (NRDC).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Nardilysin (NRDC).	[18]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Nardilysin (NRDC).	[19]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Nardilysin (NRDC).	[20]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of Nardilysin (NRDC).	[18]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Nardilysin (NRDC).	[21]
Tributylstannanyl	DMHN7CB	Investigative	Tributylstannanyl decreases the expression of Nardilysin (NRDC).	[18]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Nardilysin (NRDC).	[17]

References

• [1] Increased serum nardilysin is associated with worse long-term outcome of ST-elevation myocardial infarction.Eur Rev Med Pharmacol Sci. 2018 Nov;22(22):7938-7944. doi: 10.26355/eurrev_201811_16421.
• [2] Nardilysin is a promising biomarker for the early diagnosis of acute coronary syndrome.Int J Cardiol. 2017 Sep 15;243:1-8. doi: 10.1016/j.ijcard.2017.04.047.
• [3] Genome-wide association discoveries of alcohol dependence.Am J Addict. 2014 Nov-Dec;23(6):526-39. doi: 10.1111/j.1521-0391.2014.12147.x.
• [4] Retinoic acid-induced upregulation of the metalloendopeptidase nardilysin is accelerated by co-expression of the brain-specific protein p42(IP4) (centaurin 1; ADAP1) in neuroblastoma cells.Neurochem Int. 2011 Nov;59(6):936-44. doi: 10.1016/j.neuint.2011.07.004. Epub 2011 Jul 23.
• [5] Elevated NRD1 metalloprotease expression plays a role in breast cancer growth and proliferation.Genes Chromosomes Cancer. 2011 Oct;50(10):837-47. doi: 10.1002/gcc.20905. Epub 2011 Jul 18.
• [6] Nardilysin promotes hepatocellular carcinoma through activation of signal transducer and activator of transcription 3.Cancer Sci. 2017 May;108(5):910-917. doi: 10.1111/cas.13204. Epub 2017 Apr 24.
• [7] Clinical determination of serum nardilysin levels in predicting 30-day mortality among adults with malignant cerebral infarction.Clin Chim Acta. 2019 Jul;494:8-13. doi: 10.1016/j.cca.2019.03.1608. Epub 2019 Mar 11.
• [8] Nardilysin controls intestinal tumorigenesis through HDAC1/p53-dependent transcriptional regulation.JCI Insight. 2018 Apr 19;3(8):e91316. doi: 10.1172/jci.insight.91316. eCollection 2018 Apr 19.
• [9] NRD1, which encodes nardilysin protein, promotes esophageal cancer cell invasion through induction of MMP2 and MMP3 expression.Cancer Sci. 2014 Jan;105(1):134-40. doi: 10.1111/cas.12316. Epub 2013 Nov 29.
• [10] Serum Nardilysin, a Surrogate Marker for Epithelial-Mesenchymal Transition, Predicts Prognosis of Intrahepatic Cholangiocarcinoma after Surgical Resection.Clin Cancer Res. 2019 Jan 15;25(2):619-628. doi: 10.1158/1078-0432.CCR-18-0124. Epub 2018 Oct 23.
• [11] Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions.Nat Neurosci. 2019 Mar;22(3):343-352. doi: 10.1038/s41593-018-0326-7. Epub 2019 Feb 4.
• [12] Nardilysin inhibits pancreatitis and suppresses pancreatic ductal adenocarcinoma initiation in mice.Gut. 2019 May;68(5):882-892. doi: 10.1136/gutjnl-2017-315425. Epub 2018 May 24.
• [13] Regulation of ADAM10 and ADAM17 by Sorafenib Inhibits Epithelial-to-Mesenchymal Transition in Epstein-Barr Virus-Infected Retinal Pigment Epithelial Cells.Invest Ophthalmol Vis Sci. 2015 Aug;56(9):5162-73. doi: 10.1167/iovs.14-16058.
• [14] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [15] 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.
• [16] 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.
• [17] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [18] Inhibition of CXCL12-mediated chemotaxis of Jurkat cells by direct immunotoxicants. Arch Toxicol. 2016 Jul;90(7):1685-94. doi: 10.1007/s00204-015-1585-7. Epub 2015 Aug 28.
• [19] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [20] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [21] 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.