Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4SK7DK)

• DOT Name: Atrial natriuretic peptide-converting enzyme (CORIN)
• Synonyms: EC 3.4.21.-; Corin; Heart-specific serine proteinase ATC2; Pro-ANP-converting enzyme; Transmembrane protease serine 10
• Gene Name: CORIN
• Related Disease:
  Advanced cancer
  Cardiac disease
  Cardiac failure
  Cardiovascular disease
  Congenital heart disease
  Congestive heart failure
  Crohn disease
  Dilated cardiomyopathy 1A
  Fetal growth restriction
  Inflammatory bowel disease
  Non-alcoholic fatty liver disease
  Pre-eclampsia
  Ulcerative colitis
  High blood pressure
  Eclampsia
  Neoplasm
  Preeclampsia/eclampsia 5
  Small-cell lung cancer
• UniProt ID: CORIN_HUMAN
• EC Number: 3.4.21.-
• Pfam ID: PF01392 ; PF00057 ; PF15494 ; PF00089
• Sequence:
  MKQSPALAPEERCRRAGSPKPVLRADDNNMGNGCSQKLATANLLRFLLLVLIPCICALVL
  LLVILLSYVGTLQKVYFKSNGSEPLVTDGEIQGSDVILTNTIYNQSTVVSTAHPDQHVPA
  WTTDASLPGDQSHRNTSACMNITHSQCQMLPYHATLTPLLSVVRNMEMEKFLKFFTYLHR
  LSCYQHIMLFGCTLAFPECIIDGDDSHGLLPCRSFCEAAKEGCESVLGMVNYSWPDFLRC
  SQFRNQTESSNVSRICFSPQQENGKQLLCGRGENFLCASGICIPGKLQCNGYNDCDDWSD
  EAHCNCSENLFHCHTGKCLNYSLVCDGYDDCGDLSDEQNCDCNPTTEHRCGDGRCIAMEW
  VCDGDHDCVDKSDEVNCSCHSQGLVECRNGQCIPSTFQCDGDEDCKDGSDEENCSVIQTS
  CQEGDQRCLYNPCLDSCGGSSLCDPNNSLNNCSQCEPITLELCMNLPYNSTSYPNYFGHR
  TQKEASISWESSLFPALVQTNCYKYLMFFSCTILVPKCDVNTGEHIPPCRALCEHSKERC
  ESVLGIVGLQWPEDTDCSQFPEENSDNQTCLMPDEYVEECSPSHFKCRSGQCVLASRRCD
  GQADCDDDSDEENCGCKERDLWECPSNKQCLKHTVICDGFPDCPDYMDEKNCSFCQDDEL
  ECANHACVSRDLWCDGEADCSDSSDEWDCVTLSINVNSSSFLMVHRAATEHHVCADGWQE
  ILSQLACKQMGLGEPSVTKLIQEQEKEPRWLTLHSNWESLNGTTLHELLVNGQSCESRSK
  ISLLCTKQDCGRRPAARMNKRILGGRTSRPGRWPWQCSLQSEPSGHICGCVLIAKKWVLT
  VAHCFEGRENAAVWKVVLGINNLDHPSVFMQTRFVKTIILHPRYSRAVVDYDISIVELSE
  DISETGYVRPVCLPNPEQWLEPDTYCYITGWGHMGNKMPFKLQEGEVRIISLEHCQSYFD
  MKTITTRMICAGYESGTVDSCMGDSGGPLVCEKPGGRWTLFGLTSWGSVCFSKVLGPGVY
  SNVSYFVEWIKRQIYIQTFLLN
• Function: Serine-type endopeptidase involved in atrial natriuretic peptide (NPPA) and brain natriuretic peptide (NPPB) processing. Converts through proteolytic cleavage the non-functional propeptides NPPA and NPPB into their active hormones, ANP and BNP(1-32) respectively, thereby regulating blood pressure in the heart and promoting natriuresis, diuresis and vasodilation. Proteolytic cleavage of pro-NPPA also plays a role in female pregnancy by promoting trophoblast invasion and spiral artery remodeling in uterus. Also acts as a regulator of sodium reabsorption in kidney; [Isoform 2]: Has weaker endopeptidase activity compared to isoform 1.
• Tissue Specificity: Highly expressed in heart. Expressed in heart myocytes. Also expressed in pregnant uterus. Detected in blood, in plasma as well as in serum (at protein level).
• Reactome Pathway: Physiological factors (R-HSA-5578768)

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Cardiac disease	DISVO1I5	Strong	Genetic Variation	[2]
Cardiac failure	DISDC067	Strong	Altered Expression	[3]
Cardiovascular disease	DIS2IQDX	Strong	Biomarker	[4]
Congenital heart disease	DISQBA23	Strong	Biomarker	[4]
Congestive heart failure	DIS32MEA	Strong	Altered Expression	[3]
Crohn disease	DIS2C5Q8	Strong	Biomarker	[1]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Altered Expression	[5]
Fetal growth restriction	DIS5WEJ5	Strong	Biomarker	[6]
Inflammatory bowel disease	DISGN23E	Strong	Genetic Variation	[1]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Biomarker	[7]
Pre-eclampsia	DISY7Q29	Strong	SusceptibilityMutation	[8]
Ulcerative colitis	DIS8K27O	Strong	Biomarker	[1]
High blood pressure	DISY2OHH	Disputed	Genetic Variation	[9]
Eclampsia	DISWPO8U	Limited	Genetic Variation	[10]
Neoplasm	DISZKGEW	Limited	Biomarker	[11]
Preeclampsia/eclampsia 5	DIS5W07Z	Limited	Unknown	[8]
Small-cell lung cancer	DISK3LZD	Limited	Biomarker	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Atrial natriuretic peptide-converting enzyme (CORIN).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Atrial natriuretic peptide-converting enzyme (CORIN).	[14]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Atrial natriuretic peptide-converting enzyme (CORIN).	[15]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Atrial natriuretic peptide-converting enzyme (CORIN).	[17]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Atrial natriuretic peptide-converting enzyme (CORIN).	[18]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Atrial natriuretic peptide-converting enzyme (CORIN).	[19]
Mitoxantrone	DMM39BF	Approved	Mitoxantrone decreases the expression of Atrial natriuretic peptide-converting enzyme (CORIN).	[15]
Daunorubicin	DMQUSBT	Approved	Daunorubicin decreases the expression of Atrial natriuretic peptide-converting enzyme (CORIN).	[15]
Testosterone Undecanoate	DMZO10Y	Approved	Testosterone Undecanoate increases the expression of Atrial natriuretic peptide-converting enzyme (CORIN).	[20]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Atrial natriuretic peptide-converting enzyme (CORIN).	[22]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Atrial natriuretic peptide-converting enzyme (CORIN).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Atrial natriuretic peptide-converting enzyme (CORIN).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Atrial natriuretic peptide-converting enzyme (CORIN).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Atrial natriuretic peptide-converting enzyme (CORIN).	[24]

References

• [1] Stool DNA testing for the detection of colorectal neoplasia in patients with inflammatory bowel disease.Aliment Pharmacol Ther. 2013 Mar;37(5):546-54. doi: 10.1111/apt.12218. Epub 2013 Jan 24.
• [2] A corin variant identified in hypertensive patients that alters cytoplasmic tail and reduces cell surface expression and activity.Sci Rep. 2014 Dec 9;4:7378. doi: 10.1038/srep07378.
• [3] Differential expression of the pro-natriuretic peptide convertases corin and furin in experimental heart failure and atrial fibrosis.Am J Physiol Regul Integr Comp Physiol. 2013 Jan 15;304(2):R102-9. doi: 10.1152/ajpregu.00233.2012. Epub 2012 Nov 14.
• [4] Localization of the mosaic transmembrane serine protease corin to heart myocytes.Eur J Biochem. 2000 Dec;267(23):6931-7. doi: 10.1046/j.1432-1033.2000.01806.x.
• [5] Natriuretic Peptide Processing in Patients with and Without Left Ventricular Dysfunction.Int Heart J. 2019 Jan 25;60(1):115-120. doi: 10.1536/ihj.18-012. Epub 2018 Dec 5.
• [6] Corin, an enzyme with a putative role in spiral artery remodeling, is up-regulated in late secretory endometrium and first trimester decidua.Hum Reprod. 2013 May;28(5):1172-80. doi: 10.1093/humrep/det028. Epub 2013 Feb 21.
• [7] Non-alcoholic fatty liver disease - histological scoring systems: a large cohort single-center, evaluation study.APMIS. 2017 Nov;125(11):962-973. doi: 10.1111/apm.12742.
• [8] Role of corin in trophoblast invasion and uterine spiral artery remodelling in pregnancy. Nature. 2012 Mar 21;484(7393):246-50. doi: 10.1038/nature10897.
• [9] Association of rs2271037 and rs3749585 polymorphisms in CORIN with susceptibility to hypertension in a Chinese Han population: A case-control study.Gene. 2018 Apr 20;651:79-85. doi: 10.1016/j.gene.2018.01.080. Epub 2018 Jan 31.
• [10] PCSK6-mediated corin activation is essential for normal blood pressure.Nat Med. 2015 Sep;21(9):1048-53. doi: 10.1038/nm.3920. Epub 2015 Aug 10.
• [11] Comparative analysis of copy number variations in ulcerative colitis associated and sporadic colorectal neoplasia.BMC Cancer. 2016 Apr 14;16:271. doi: 10.1186/s12885-016-2303-4.
• [12] Corin-mediated processing of pro-atrial natriuretic peptide in human small cell lung cancer cells.Cancer Res. 2003 Dec 1;63(23):8318-22.
• [13] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [14] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [15] Identification of genomic biomarkers for anthracycline-induced cardiotoxicity in human iPSC-derived cardiomyocytes: an in vitro repeated exposure toxicity approach for safety assessment. Arch Toxicol. 2016 Nov;90(11):2763-2777.
• [16] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [17] 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.
• [18] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [19] Unique transcriptome, pathways, and networks in the human endometrial fibroblast response to progesterone in endometriosis. Biol Reprod. 2011 Apr;84(4):801-15.
• [20] Levonorgestrel enhances spermatogenesis suppression by testosterone with greater alteration in testicular gene expression in men. Biol Reprod. 2009 Mar;80(3):484-92.
• [21] 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.
• [22] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [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] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.