Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTP0RJ4Y)

• DOT Name: Proprotein convertase subtilisin/kexin type 5 (PCSK5)
• Synonyms: EC 3.4.21.-; Proprotein convertase 5; PC5; Proprotein convertase 6; PC6; hPC6; Subtilisin/kexin-like protease PC5
• Gene Name: PCSK5
• UniProt ID: PCSK5_HUMAN
• EC Number: 3.4.21.-
• Pfam ID: PF14843 ; PF01483 ; PF00082 ; PF16470
• Sequence:
  MGWGSRCCCPGRLDLLCVLALLGGCLLPVCRTRVYTNHWAVKIAGGFPEANRIASKYGFI
  NIGQIGALKDYYHFYHSRTIKRSVISSRGTHSFISMEPKVEWIQQQVVKKRTKRDYDFSR
  AQSTYFNDPKWPSMWYMHCSDNTHPCQSDMNIEGAWKRGYTGKNIVVTILDDGIERTHPD
  LMQNYDALASCDVNGNDLDPMPRYDASNENKHGTRCAGEVAAAANNSHCTVGIAFNAKIG
  GVRMLDGDVTDMVEAKSVSFNPQHVHIYSASWGPDDDGKTVDGPAPLTRQAFENGVRMGR
  RGLGSVFVWASGNGGRSKDHCSCDGYTNSIYTISISSTAESGKKPWYLEECSSTLATTYS
  SGESYDKKIITTDLRQRCTDNHTGTSASAPMAAGIIALALEANPFLTWRDVQHVIVRTSR
  AGHLNANDWKTNAAGFKVSHLYGFGLMDAEAMVMEAEKWTTVPRQHVCVESTDRQIKTIR
  PNSAVRSIYKASGCSDNPNRHVNYLEHVVVRITITHPRRGDLAIYLTSPSGTRSQLLANR
  LFDHSMEGFKNWEFMTIHCWGERAAGDWVLEVYDTPSQLRNFKTPGKLKEWSLVLYGTSV
  QPYSPTNEFPKVERFRYSRVEDPTDDYGTEDYAGPCDPECSEVGCDGPGPDHCNDCLHYY
  YKLKNNTRICVSSCPPGHYHADKKRCRKCAPNCESCFGSHGDQCMSCKYGYFLNEETNSC
  VTHCPDGSYQDTKKNLCRKCSENCKTCTEFHNCTECRDGLSLQGSRCSVSCEDGRYFNGQ
  DCQPCHRFCATCAGAGADGCINCTEGYFMEDGRCVQSCSISYYFDHSSENGYKSCKKCDI
  SCLTCNGPGFKNCTSCPSGYLLDLGMCQMGAICKDGEYVDEHGHCQTCEASCAKCQGPTQ
  EDCTTCPMTRIFDDGRCVSNCPSWKFEFENQCHPCHHTCQRCQGSGPTHCTSCGADNYGR
  EHFLYQGECGDSCPEGHYATEGNTCLPCPDNCELCHSVHVCTRCMKGYFIAPTNHTCQKL
  ECGQGEVQDPDYEECVPCEEGCLGCSLDDPGTCTSCAMGYYRFDHHCYKTCPEKTYSEEV
  ECKACDSNCGSCDQNGCYWCEEGFFLLGGSCVRKCGPGFYGDQEMGECESCHRACETCTG
  PGHDECSSCQEGLQLLRGMCVHATKTQEEGKFWNDILRKLQPCHSSCKTCNGSATLCTSC
  PKGAYLLAQACVSSCPQGTWPSVRSGSCENCTEACAICSGADLCKKCQMQPGHPLFLHEG
  RCYSKCPEGSYAEDGICERCSSPCRTCEGNATNCHSCEGGHVLHHGVCQENCPERHVAVK
  GVCKHCPEMCQDCIHEKTCKECTPEFFLHDDMCHQSCPRGFYADSRHCVPCHKDCLECSG
  PKADDCELCLESSWVLYDGLCLEECPAGTYYEKETKECRDCHKSCLTCSSSGTCTTCQKG
  LIMNPRGSCMANEKCSPSEYWDEDAPGCKPCHVKCFHCMGPAEDQCQTCPMNSLLLNTTC
  VKDCPEGYYADEDSNRCAHCHSSCRTCEGRHSRQCHSCRPGWFQLGKECLLQCREGYYAD
  NSTGRCERCNRSCKGCQGPRPTDCLSCDRFFFLLRSKGECHRSCPDHYYVEQSTQTCERC
  HPTCDQCKGKGALNCLSCVWSYHLMGGICTSDCLVGEYRVGEGEKFNCEKCHESCMECKG
  PGAKNCTLCPANLVLHMDDSHCLHCCNTSDPPSAQECCDCQDTTDECILRTSKVRPATEH
  FKTALFITSSMMLVLLLGAAVVVWKKSRGRVQPAAKAGYEKLADPNKSYSSYKSSYREST
  SFEEDQVIEYRDRDYDEDDDDDIVYMGQDGTVYRKFKYGLLDDDDIDELEYDDESYSYYQ
• 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 and regulated secretory pathways. Plays an essential role in pregnancy establishment by proteolytic activation of a number of important factors such as BMP2, CALD1 and alpha-integrins.
• Tissue Specificity: Expressed in T-lymphocytes.
• Reactome Pathway:
  Assembly of active LPL and LIPC lipase complexes (R-HSA-8963889)
  NGF processing (R-HSA-167060)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Proprotein convertase subtilisin/kexin type 5 (PCSK5).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Proprotein convertase subtilisin/kexin type 5 (PCSK5).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Proprotein convertase subtilisin/kexin type 5 (PCSK5).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Proprotein convertase subtilisin/kexin type 5 (PCSK5).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Proprotein convertase subtilisin/kexin type 5 (PCSK5).	[5]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Proprotein convertase subtilisin/kexin type 5 (PCSK5).	[6]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Proprotein convertase subtilisin/kexin type 5 (PCSK5).	[7]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Proprotein convertase subtilisin/kexin type 5 (PCSK5).	[8]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Proprotein convertase subtilisin/kexin type 5 (PCSK5).	[9]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Proprotein convertase subtilisin/kexin type 5 (PCSK5).	[10]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Proprotein convertase subtilisin/kexin type 5 (PCSK5).	[11]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Proprotein convertase subtilisin/kexin type 5 (PCSK5).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Proprotein convertase subtilisin/kexin type 5 (PCSK5).	[13]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Proprotein convertase subtilisin/kexin type 5 (PCSK5).	[14]
PMID28870136-Compound-48	DMPIM9L	Patented	PMID28870136-Compound-48 increases the expression of Proprotein convertase subtilisin/kexin type 5 (PCSK5).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Proprotein convertase subtilisin/kexin type 5 (PCSK5).	[16]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Proprotein convertase subtilisin/kexin type 5 (PCSK5).	[17]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [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] 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.
• [4] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [7] Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005 Jul 1;106(1):304-10.
• [8] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [9] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [10] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [13] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [14] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [15] Global expression profiling of theophylline response genes in macrophages: evidence of airway anti-inflammatory regulation. Respir Res. 2005 Aug 8;6(1):89. doi: 10.1186/1465-9921-6-89.
• [16] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [17] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.