Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTY2Z48T)

• DOT Name: Meprin A subunit alpha (MEP1A)
• Synonyms: EC 3.4.24.18; Endopeptidase-2; N-benzoyl-L-tyrosyl-P-amino-benzoic acid hydrolase subunit alpha; PABA peptide hydrolase; PPH alpha
• Gene Name: MEP1A
• Related Disease:
  Advanced cancer
  Neoplasm
  Autosomal recessive polycystic kidney disease
  Colitis
  Colon cancer
  Colonic neoplasm
  Colorectal neoplasm
  Inflammatory bowel disease
  Polycystic ovarian syndrome
  Ulcerative colitis
  Colorectal carcinoma
  Prostate cancer
  Prostate carcinoma
• UniProt ID: MEP1A_HUMAN
• PDB ID: 7UAB; 7UAC; 7UAE; 7UAF; 7UAI
• EC Number: 3.4.24.18
• Pfam ID: PF01400 ; PF00008 ; PF00629 ; PF21355
• Sequence:
  MAWIRSTCILFFTLLFAHIAAVPIKYLPEENVHDADFGEQKDISEINLAAGLDLFQGDIL
  LQKSRNGLRDPNTRWTFPIPYILADNLGLNAKGAILYAFEMFRLKSCVDFKPYEGESSYI
  IFQQFDGCWSEVGDQHVGQNISIGQGCAYKAIIEHEILHALGFYHEQSRTDRDDYVNIWW
  DQILSGYQHNFDTYDDSLITDLNTPYDYESLMHYQPFSFNKNASVPTITAKIPEFNSIIG
  QRLDFSAIDLERLNRMYNCTTTHTLLDHCTFEKANICGMIQGTRDDTDWAHQDSAQAGEV
  DHTLLGQCTGAGYFMQFSTSSGSAEEAALLESRILYPKRKQQCLQFFYKMTGSPSDRLVV
  WVRRDDSTGNVRKLVKVQTFQGDDDHNWKIAHVVLKEEQKFRYLFQGTKGDPQNSTGGIY
  LDDITLTETPCPTGVWTVRNFSQVLENTSKGDKLQSPRFYNSEGYGFGVTLYPNSRESSG
  YLRLAFHVCSGENDAILEWPVENRQVIITILDQEPDVRNRMSSSMVFTTSKSHTSPAIND
  TVIWDRPSRVGTYHTDCNCFRSIDLGWSGFISHQMLKRRSFLKNDDLIIFVDFEDITHLS
  QTEVPTKGKRLSPQGLILQGQEQQVSEEGSGKAMLEEALPVSLSQGQPSRQKRSVENTGP
  LEDHNWPQYFRDPCDPNPCQNDGICVNVKGMASCRCISGHAFFYTGERCQAVQVHGSVLG
  MVIGGTAGVIFLTFSIIAILSQRPRK
• KEGG Pathway: Protein digestion and absorption (hsa04974)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Definitive	Biomarker	[1]
Neoplasm	DISZKGEW	Definitive	Biomarker	[2]
Autosomal recessive polycystic kidney disease	DISPUS40	Strong	Biomarker	[3]
Colitis	DISAF7DD	Strong	Altered Expression	[4]
Colon cancer	DISVC52G	Strong	Biomarker	[5]
Colonic neoplasm	DISSZ04P	Strong	Biomarker	[5]
Colorectal neoplasm	DISR1UCN	Strong	Biomarker	[6]
Inflammatory bowel disease	DISGN23E	Strong	Genetic Variation	[4]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Genetic Variation	[7]
Ulcerative colitis	DIS8K27O	Strong	Altered Expression	[4]
Colorectal carcinoma	DIS5PYL0	moderate	Biomarker	[8]
Prostate cancer	DISF190Y	Limited	Altered Expression	[9]
Prostate carcinoma	DISMJPLE	Limited	Altered Expression	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Meprin A subunit alpha (MEP1A).	[10]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Meprin A subunit alpha (MEP1A).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Meprin A subunit alpha (MEP1A).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Meprin A subunit alpha (MEP1A).	[11]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Meprin A subunit alpha (MEP1A).	[12]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of Meprin A subunit alpha (MEP1A).	[13]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Meprin A subunit alpha (MEP1A).	[14]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Meprin A subunit alpha (MEP1A).	[15]

References

• [1] Metalloproteinase meprin regulates migration and invasion of human hepatocarcinoma cells and is a mediator of the oncoprotein Reptin.Oncotarget. 2017 Jan 31;8(5):7839-7851. doi: 10.18632/oncotarget.13975.
• [2] Combination therapy for the treatment of pancreatic cancer through hyaluronic acid-decorated nanoparticles loaded with quercetin and gemcitabine: A preliminary in vitro study.J Cell Physiol. 2019 Apr;234(4):4959-4969. doi: 10.1002/jcp.27297. Epub 2018 Oct 18.
• [3] Fine mapping of MEP1A, the gene encoding the alpha subunit of the metalloendopeptidase meprin, to human chromosome 6P21.Biochem Biophys Res Commun. 1995 Nov 13;216(2):630-5. doi: 10.1006/bbrc.1995.2668.
• [4] TNF--induced down-regulation of CDX2 suppresses MEP1A expression in colitis.Biochim Biophys Acta. 2012 Jun;1822(6):843-51. doi: 10.1016/j.bbadis.2012.01.012. Epub 2012 Feb 3.
• [5] Global gene expression analysis of rat colon cancers induced by a food-borne carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine.Carcinogenesis. 2004 Aug;25(8):1495-505. doi: 10.1093/carcin/bgh155. Epub 2004 Apr 1.
• [6] Activation of human meprin-alpha in a cell culture model of colorectal cancer is triggered by the plasminogen-activating system.J Biol Chem. 2002 Oct 25;277(43):40650-8. doi: 10.1074/jbc.M206203200. Epub 2002 Aug 19.
• [7] Association of MEP1A gene variants with insulin metabolism in central European women with polycystic ovary syndrome.Gene. 2014 Mar 10;537(2):245-52. doi: 10.1016/j.gene.2013.12.055. Epub 2014 Jan 2.
• [8] Correction to: Metalloproteases meprin- (MEP1A) is a prognostic biomarker and promotes proliferation and invasion of colorectal cancer.BMC Cancer. 2018 Jan 11;18(1):70. doi: 10.1186/s12885-017-3767-6.
• [9] A genetic screen in Drosophila for regulators of human prostate cancer progression.Biochem Biophys Res Commun. 2014 Sep 5;451(4):548-55. doi: 10.1016/j.bbrc.2014.08.015. Epub 2014 Aug 10.
• [10] 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.
• [11] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [12] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [13] Inorganic arsenic exposure promotes malignant progression by HDAC6-mediated down-regulation of HTRA1. J Appl Toxicol. 2023 Aug;43(8):1214-1224. doi: 10.1002/jat.4457. Epub 2023 Mar 11.
• [14] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [15] 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.
• [16] 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.
• [17] 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.