Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTI64BU4)

• DOT Name: Proprotein convertase subtilisin/kexin type 6 (PCSK6)
• Synonyms: EC 3.4.21.-; Paired basic amino acid cleaving enzyme 4; Subtilisin-like proprotein convertase 4; SPC4; Subtilisin/kexin-like protease PACE4
• Gene Name: PCSK6
• UniProt ID: PCSK6_HUMAN
• EC Number: 3.4.21.-
• Pfam ID: PF14843 ; PF01483 ; PF00082 ; PF16470
• Sequence:
  MPPRAPPAPGPRPPPRAAAATDTAAGAGGAGGAGGAGGPGFRPLAPRPWRWLLLLALPAA
  CSAPPPRPVYTNHWAVQVLGGPAEADRVAAAHGYLNLGQIGNLEDYYHFYHSKTFKRSTL
  SSRGPHTFLRMDPQVKWLQQQEVKRRVKRQVRSDPQALYFNDPIWSNMWYLHCGDKNSRC
  RSEMNVQAAWKRGYTGKNVVVTILDDGIERNHPDLAPNYDSYASYDVNGNDYDPSPRYDA
  SNENKHGTRCAGEVAASANNSYCIVGIAYNAKIGGIRMLDGDVTDVVEAKSLGIRPNYID
  IYSASWGPDDDGKTVDGPGRLAKQAFEYGIKKGRQGLGSIFVWASGNGGREGDYCSCDGY
  TNSIYTISVSSATENGYKPWYLEECASTLATTYSSGAFYERKIVTTDLRQRCTDGHTGTS
  VSAPMVAGIIALALEANSQLTWRDVQHLLVKTSRPAHLKASDWKVNGAGHKVSHFYGFGL
  VDAEALVVEAKKWTAVPSQHMCVAASDKRPRSIPLVQVLRTTALTSACAEHSDQRVVYLE
  HVVVRTSISHPRRGDLQIYLVSPSGTKSQLLAKRLLDLSNEGFTNWEFMTVHCWGEKAEG
  QWTLEIQDLPSQVRNPEKQGKLKEWSLILYGTAEHPYHTFSAHQSRSRMLELSAPELEPP
  KAALSPSQVEVPEDEEDYTAQSTPGSANILQTSVCHPECGDKGCDGPNADQCLNCVHFSL
  GSVKTSRKCVSVCPLGYFGDTAARRCRRCHKGCETCSSRAATQCLSCRRGFYHHQEMNTC
  VTLCPAGFYADESQKNCLKCHPSCKKCVDEPEKCTVCKEGFSLARGSCIPDCEPGTYFDS
  ELIRCGECHHTCGTCVGPGREECIHCAKNFHFHDWKCVPACGEGFYPEEMPGLPHKVCRR
  CDENCLSCAGSSRNCSRCKTGFTQLGTSCITNHTCSNADETFCEMVKSNRLCERKLFIQF
  CCRTCLLAG
• Function: Serine endoprotease that processes various proproteins by cleavage at paired basic amino acids, recognizing the RXXX[KR]R consensus motif. Likely functions in the constitutive secretory pathway, with unique restricted distribution in both neuroendocrine and non-neuroendocrine tissues.
• Tissue Specificity: Each PACE4 isoform exhibits a unique restricted distribution. Isoform PACE4A-I is expressed in heart, brain, placenta, lung, skeletal muscle, kidney, pancreas, but at comparatively higher levels in the liver. Isoform PACE4A-II is at least expressed in placenta. Isoform PACE4B was only found in the embryonic kidney cell line from which it was isolated. Isoform PACE4C and isoform PACE4D are expressed in placenta. Isoform PACE4E-I is expressed in cerebellum, placenta and pituitary. Isoform PACE4E-II is at least present in cerebellum.
• Reactome Pathway:
  NGF processing (R-HSA-167060)
  Formation of the cornified envelope (R-HSA-6809371)
  Assembly of active LPL and LIPC lipase complexes (R-HSA-8963889)
  Signaling by NODAL (R-HSA-1181150)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Proprotein convertase subtilisin/kexin type 6 (PCSK6).	[1]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Proprotein convertase subtilisin/kexin type 6 (PCSK6).	[7]

16 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 Proprotein convertase subtilisin/kexin type 6 (PCSK6).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Proprotein convertase subtilisin/kexin type 6 (PCSK6).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Proprotein convertase subtilisin/kexin type 6 (PCSK6).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Proprotein convertase subtilisin/kexin type 6 (PCSK6).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Proprotein convertase subtilisin/kexin type 6 (PCSK6).	[6]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Proprotein convertase subtilisin/kexin type 6 (PCSK6).	[8]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Proprotein convertase subtilisin/kexin type 6 (PCSK6).	[8]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Proprotein convertase subtilisin/kexin type 6 (PCSK6).	[9]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Proprotein convertase subtilisin/kexin type 6 (PCSK6).	[10]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Proprotein convertase subtilisin/kexin type 6 (PCSK6).	[11]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Proprotein convertase subtilisin/kexin type 6 (PCSK6).	[12]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Proprotein convertase subtilisin/kexin type 6 (PCSK6).	[12]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of Proprotein convertase subtilisin/kexin type 6 (PCSK6).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Proprotein convertase subtilisin/kexin type 6 (PCSK6).	[14]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Proprotein convertase subtilisin/kexin type 6 (PCSK6).	[15]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Proprotein convertase subtilisin/kexin type 6 (PCSK6).	[16]

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] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [3] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [4] 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.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [7] 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.
• [8] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [9] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [10] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [11] Progesterone regulation of implantation-related genes: new insights into the role of oestrogen. Cell Mol Life Sci. 2007 Apr;64(7-8):1009-32.
• [12] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [13] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [14] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [15] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [16] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.