Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTM2665Z)

• DOT Name: Furin (FURIN)
• Synonyms: EC 3.4.21.75; Dibasic-processing enzyme; Paired basic amino acid residue-cleaving enzyme; PACE
• Gene Name: FURIN
• UniProt ID: FURIN_HUMAN
• PDB ID: 4OMC ; 4OMD ; 4RYD ; 4Z2A ; 5JMO ; 5JXG ; 5JXH ; 5JXI ; 5JXJ ; 5MIM ; 6A8Y ; 6EQV ; 6EQW ; 6EQX ; 6HLB ; 6HLD ; 6HLE ; 6HZA ; 6HZB ; 6HZC ; 6HZD ; 6YD2 ; 6YD3 ; 6YD4 ; 6YD7 ; 7LCU ; 7O1U ; 7O1W ; 7O1Y ; 7O20 ; 7O22 ; 7QXY ; 7QXZ ; 7QY0 ; 7QY1 ; 7QY2 ; 8B4V ; 8B4W ; 8B4X
• EC Number: 3.4.21.75
• Pfam ID: PF01483 ; PF00082 ; PF16470
• Sequence:
  MELRPWLLWVVAATGTLVLLAADAQGQKVFTNTWAVRIPGGPAVANSVARKHGFLNLGQI
  FGDYYHFWHRGVTKRSLSPHRPRHSRLQREPQVQWLEQQVAKRRTKRDVYQEPTDPKFPQ
  QWYLSGVTQRDLNVKAAWAQGYTGHGIVVSILDDGIEKNHPDLAGNYDPGASFDVNDQDP
  DPQPRYTQMNDNRHGTRCAGEVAAVANNGVCGVGVAYNARIGGVRMLDGEVTDAVEARSL
  GLNPNHIHIYSASWGPEDDGKTVDGPARLAEEAFFRGVSQGRGGLGSIFVWASGNGGREH
  DSCNCDGYTNSIYTLSISSATQFGNVPWYSEACSSTLATTYSSGNQNEKQIVTTDLRQKC
  TESHTGTSASAPLAAGIIALTLEANKNLTWRDMQHLVVQTSKPAHLNANDWATNGVGRKV
  SHSYGYGLLDAGAMVALAQNWTTVAPQRKCIIDILTEPKDIGKRLEVRKTVTACLGEPNH
  ITRLEHAQARLTLSYNRRGDLAIHLVSPMGTRSTLLAARPHDYSADGFNDWAFMTTHSWD
  EDPSGEWVLEIENTSEANNYGTLTKFTLVLYGTAPEGLPVPPESSGCKTLTSSQACVVCE
  EGFSLHQKSCVQHCPPGFAPQVLDTHYSTENDVETIRASVCAPCHASCATCQGPALTDCL
  SCPSHASLDPVEQTCSRQSQSSRESPPQQQPPRLPPEVEAGQRLRAGLLPSHLPEVVAGL
  SCAFIVLVFVTVFLVLQLRSGFSFRGVKVYTMDRGLISYKGLPPEAWQEECPSDSEEDEG
  RGERTAFIKDQSAL
• Function: Ubiquitous endoprotease within constitutive secretory pathways capable of cleavage at the RX(K/R)R consensus motif. Mediates processing of TGFB1, an essential step in TGF-beta-1 activation. Converts through proteolytic cleavage the non-functional Brain natriuretic factor prohormone into its active hormone BNP(1-32). By mediating processing of accessory subunit ATP6AP1/Ac45 of the V-ATPase, regulates the acidification of dense-core secretory granules in islets of Langerhans cells; (Microbial infection) Cleaves and activates diphtheria toxin DT; (Microbial infection) Cleaves and activates anthrax toxin protective antigen (PA); (Microbial infection) Cleaves and activates HIV-1 virus Envelope glycoprotein gp160; (Microbial infection) Required for H7N1 and H5N1 influenza virus infection probably by cleaving hemagglutinin; (Microbial infection) Able to cleave S.pneumoniae serine-rich repeat protein PsrP; (Microbial infection) Facilitates human coronaviruses EMC and SARS-CoV-2 infections by proteolytically cleaving the spike protein at the monobasic S1/S2 cleavage site. This cleavage is essential for spike protein-mediated cell-cell fusion and entry into human lung cells; (Microbial infection) Facilitates mumps virus infection by proteolytically cleaving the viral fusion protein F.
• Tissue Specificity: Seems to be expressed ubiquitously.
• KEGG Pathway: Viral life cycle - HIV-1 (hsa03250)
• Reactome Pathway:
  Collagen degradation (R-HSA-1442490)
  Elastic fibre formation (R-HSA-1566948)
  Activation of Matrix Metalloproteinases (R-HSA-1592389)
  Removal of aminoterminal propeptides from gamma-carboxylated proteins (R-HSA-159782)
  NGF processing (R-HSA-167060)
  Synthesis and processing of ENV and VPU (R-HSA-171286)
  Signaling by PDGF (R-HSA-186797)
  Pre-NOTCH Processing in Golgi (R-HSA-1912420)
  TGF-beta receptor signaling activates SMADs (R-HSA-2173789)
  SMAD2/SMAD3 (R-HSA-2173796)
  Uptake and function of anthrax toxins (R-HSA-5210891)
  Formation of the cornified envelope (R-HSA-6809371)
  Assembly of active LPL and LIPC lipase complexes (R-HSA-8963889)
  CD163 mediating an anti-inflammatory response (R-HSA-9662834)
  Potential therapeutics for SARS (R-HSA-9679191)
  Attachment and Entry (R-HSA-9694614)
  Induction of Cell-Cell Fusion (R-HSA-9733458)
  Amyloid fiber formation (R-HSA-977225)
  Signaling by NODAL (R-HSA-1181150)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Paclitaxel	DMLB81S	Approved	Furin (FURIN) decreases the response to substance of Paclitaxel.	[15]

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 Furin (FURIN).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Furin (FURIN).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Furin (FURIN).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Furin (FURIN).	[4]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Furin (FURIN).	[6]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of Furin (FURIN).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Furin (FURIN).	[9]
KENPAULLONE	DMAGVXW	Patented	KENPAULLONE decreases the expression of Furin (FURIN).	[10]
Batimastat	DM92VRP	Preclinical	Batimastat decreases the activity of Furin (FURIN).	[11]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Furin (FURIN).	[12]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride decreases the expression of Furin (FURIN).	[13]
Cordycepin	DM72Y01	Investigative	Cordycepin decreases the expression of Furin (FURIN).	[14]
Apomorphine SL	DMPH7EO	Investigative	Apomorphine SL decreases the expression of Furin (FURIN).	[10]

1 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 Furin (FURIN).	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Glucosamine	DM4ZLFD	Approved	Glucosamine decreases the cleavage of Furin (FURIN).	[8]

References

• [1] 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.
• [2] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [3] 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.
• [4] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [5] 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.
• [6] Transcriptomic Analysis of Stem Cells Treated with Moringin or Cannabidiol: Analogies and Differences in Inflammation Pathways. Int J Mol Sci. 2019 Nov 30;20(23):6039. doi: 10.3390/ijms20236039.
• [7] Expression profile analysis of human peripheral blood mononuclear cells in response to aspirin. Arch Immunol Ther Exp (Warsz). 2005 Mar-Apr;53(2):151-8.
• [8] 10mM glucosamine prevents activation of proADAMTS5 (aggrecanase-2) in transfected cells by interference with post-translational modification of furin. Osteoarthritis Cartilage. 2010 Mar;18(3):455-63. doi: 10.1016/j.joca.2009.10.014. Epub 2009 Nov 4.
• [9] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [10] A HAMP promoter bioassay system for identifying chemical compounds that modulate hepcidin expression. Exp Hematol. 2015 May;43(5):404-413.e5. doi: 10.1016/j.exphem.2015.01.005. Epub 2015 Jan 26.
• [11] Elastin-derived peptides enhance angiogenesis by promoting endothelial cell migration and tubulogenesis through upregulation of MT1-MMP. J Cell Sci. 2005 Jan 15;118(Pt 2):343-56. doi: 10.1242/jcs.01613. Epub 2005 Jan 4.
• [12] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [13] Classification of heavy-metal toxicity by human DNA microarray analysis. Environ Sci Technol. 2007 May 15;41(10):3769-74.
• [14] COVID-19 disease and malignant cancers: The impact for the furin gene expression in susceptibility to SARS-CoV-2. Int J Biol Sci. 2021 Sep 21;17(14):3954-3967. doi: 10.7150/ijbs.63072. eCollection 2021.
• [15] cDNA microarray analysis of isogenic paclitaxel- and doxorubicin-resistant breast tumor cell lines reveals distinct drug-specific genetic signatures of resistance. Breast Cancer Res Treat. 2006 Mar;96(1):17-39. doi: 10.1007/s10549-005-9026-6. Epub 2005 Dec 2.