Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJXOAN4)

• DOT Name: Procollagen C-endopeptidase enhancer 1 (PCOLCE)
• Synonyms: Procollagen COOH-terminal proteinase enhancer 1; PCPE-1; Procollagen C-proteinase enhancer 1; Type 1 procollagen C-proteinase enhancer protein; Type I procollagen COOH-terminal proteinase enhancer
• Gene Name: PCOLCE
• Related Disease:
  Arteriosclerosis
  Arthropathy
  Atherosclerosis
  Chronic kidney disease
  Liver cirrhosis
  Uterine fibroids
  Non-insulin dependent diabetes
  Chronic hepatitis B virus infection
• UniProt ID: PCOC1_HUMAN
• PDB ID: 1UAP; 6FZV; 6FZW
• Pfam ID: PF00431 ; PF01759
• Sequence:
  MLPAATASLLGPLLTACALLPFAQGQTPNYTRPVFLCGGDVKGESGYVASEGFPNLYPPN
  KECIWTITVPEGQTVSLSFRVFDLELHPACRYDALEVFAGSGTSGQRLGRFCGTFRPAPL
  VAPGNQVTLRMTTDEGTGGRGFLLWYSGRATSGTEHQFCGGRLEKAQGTLTTPNWPESDY
  PPGISCSWHIIAPPDQVIALTFEKFDLEPDTYCRYDSVSVFNGAVSDDSRRLGKFCGDAV
  PGSISSEGNELLVQFVSDLSVTADGFSASYKTLPRGTAKEGQGPGPKRGTEPKVKLPPKS
  QPPEKTEESPSAPDAPTCPKQCRRTGTLQSNFCASSLVVTATVKSMVREPGEGLAVTVSL
  IGAYKTGGLDLPSPPTGASLKFYVPCKQCPPMKKGVSYLLMGQVEENRGPVLPPESFVVL
  HRPNQDQILTNLSKRKCPSQPVRAAASQD
• Function: Binds to the C-terminal propeptide of type I procollagen and enhances procollagen C-proteinase activity.; C-terminal processed part of PCPE (CT-PCPE) may have an metalloproteinase inhibitory activity.
• Reactome Pathway:
  Crosslinking of collagen fibrils (R-HSA-2243919)
  Collagen biosynthesis and modifying enzymes (R-HSA-1650814)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[1]
Arthropathy	DISVEERK	Strong	Altered Expression	[2]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[1]
Chronic kidney disease	DISW82R7	Strong	Altered Expression	[3]
Liver cirrhosis	DIS4G1GX	Strong	Biomarker	[4]
Uterine fibroids	DISBZRMJ	Strong	Biomarker	[5]
Non-insulin dependent diabetes	DISK1O5Z	Disputed	Biomarker	[6]
Chronic hepatitis B virus infection	DISHL4NT	Limited	Altered Expression	[7]

14 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 Procollagen C-endopeptidase enhancer 1 (PCOLCE).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Procollagen C-endopeptidase enhancer 1 (PCOLCE).	[9]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Procollagen C-endopeptidase enhancer 1 (PCOLCE).	[10]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Procollagen C-endopeptidase enhancer 1 (PCOLCE).	[11]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Procollagen C-endopeptidase enhancer 1 (PCOLCE).	[12]
Selenium	DM25CGV	Approved	Selenium increases the expression of Procollagen C-endopeptidase enhancer 1 (PCOLCE).	[13]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of Procollagen C-endopeptidase enhancer 1 (PCOLCE).	[14]
Paclitaxel	DMLB81S	Approved	Paclitaxel increases the expression of Procollagen C-endopeptidase enhancer 1 (PCOLCE).	[15]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of Procollagen C-endopeptidase enhancer 1 (PCOLCE).	[16]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Procollagen C-endopeptidase enhancer 1 (PCOLCE).	[17]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Procollagen C-endopeptidase enhancer 1 (PCOLCE).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Procollagen C-endopeptidase enhancer 1 (PCOLCE).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Procollagen C-endopeptidase enhancer 1 (PCOLCE).	[20]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Procollagen C-endopeptidase enhancer 1 (PCOLCE).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Procollagen C-endopeptidase enhancer 1 (PCOLCE).	[18]

References

• [1] Procollagen C-endopeptidase Enhancer Protein 2 (PCPE2) Reduces Atherosclerosis in Mice by Enhancing Scavenger Receptor Class B1 (SR-BI)-mediated High-density Lipoprotein (HDL)-Cholesteryl Ester Uptake.J Biol Chem. 2015 Jun 19;290(25):15496-15511. doi: 10.1074/jbc.M115.646240. Epub 2015 May 6.
• [2] Epigenome-wide analysis of sperm cells identifies IL22 as a possible germ line risk locus for psoriatic arthritis.PLoS One. 2019 Feb 19;14(2):e0212043. doi: 10.1371/journal.pone.0212043. eCollection 2019.
• [3] Elevated serum levels of procollagen C-proteinase enhancer-1 in patients with chronic kidney disease is associated with a declining glomerular filtration rate.Nephrology (Carlton). 2019 Sep;24(9):938-942. doi: 10.1111/nep.13521. Epub 2019 Apr 29.
• [4] Gene Expression Patterns Associated With Histopathology in Toxic Liver Fibrosis.Toxicol Sci. 2016 Jan;149(1):67-88. doi: 10.1093/toxsci/kfv214. Epub 2015 Sep 22.
• [5] PCOLCE deletion and expression analyses in uterine leiomyomata.Cancer Genet Cytogenet. 2002 Sep;137(2):133-7. doi: 10.1016/s0165-4608(02)00547-2.
• [6] Shared genetic regulatory networks for cardiovascular disease and type 2 diabetes in multiple populations of diverse ethnicities in the United States.PLoS Genet. 2017 Sep 28;13(9):e1007040. doi: 10.1371/journal.pgen.1007040. eCollection 2017 Sep.
• [7] Evaluation of serum procollagen C-proteinase enhancer 1 level as a fibrosis marker in patients with chronic hepatitis B.Eur J Gastroenterol Hepatol. 2018 Aug;30(8):918-924. doi: 10.1097/MEG.0000000000001123.
• [8] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [9] 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.
• [10] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [11] 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.
• [12] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [13] 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.
• [14] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [15] Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell. 2009 Aug 21;138(4):645-659. doi: 10.1016/j.cell.2009.06.034. Epub 2009 Aug 13.
• [16] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [17] 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.
• [18] 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.
• [19] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [20] 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.
• [21] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.