Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPBRJ54)

• DOT Name: Neuroendocrine convertase 1 (PCSK1)
• Synonyms: NEC 1; EC 3.4.21.93; Prohormone convertase 1; Proprotein convertase 1; PC1
• Gene Name: PCSK1
• Related Disease: Obesity due to prohormone convertase I deficiency
• UniProt ID: NEC1_HUMAN
• EC Number: 3.4.21.93
• Pfam ID: PF01483 ; PF00082 ; PF12177 ; PF16470
• Sequence:
  MERRAWSLQCTAFVLFCAWCALNSAKAKRQFVNEWAAEIPGGPEAASAIAEELGYDLLGQ
  IGSLENHYLFKHKNHPRRSRRSAFHITKRLSDDDRVIWAEQQYEKERSKRSALRDSALNL
  FNDPMWNQQWYLQDTRMTAALPKLDLHVIPVWQKGITGKGVVITVLDDGLEWNHTDIYAN
  YDPEASYDFNDNDHDPFPRYDPTNENKHGTRCAGEIAMQANNHKCGVGVAYNSKVGGIRM
  LDGIVTDAIEASSIGFNPGHVDIYSASWGPNDDGKTVEGPGRLAQKAFEYGVKQGRQGKG
  SIFVWASGNGGRQGDNCDCDGYTDSIYTISISSASQQGLSPWYAEKCSSTLATSYSSGDY
  TDQRITSADLHNDCTETHTGTSASAPLAAGIFALALEANPNLTWRDMQHLVVWTSEYDPL
  ANNPGWKKNGAGLMVNSRFGFGLLNAKALVDLADPRTWRSVPEKKECVVKDNDFEPRALK
  ANGEVIIEIPTRACEGQENAIKSLEHVQFEATIEYSRRGDLHVTLTSAAGTSTVLLAERE
  RDTSPNGFKNWDFMSVHTWGENPIGTWTLRITDMSGRIQNEGRIVNWKLILHGTSSQPEH
  MKQPRVYTSYNTVQNDRRGVEKMVDPGEEQPTQENPKENTLVSKSPSSSSVGGRRDELEE
  GAPSQAMLRLLQSAFSKNSPPKQSPKKSPSAKLNIPYENFYEALEKLNKPSQLKDSEDSL
  YNDYVDVFYNTKPYKHRDDRLLQALVDILNEEN
• Function: Involved in the processing of hormone and other protein precursors at sites comprised of pairs of basic amino acid residues. Substrates include POMC, renin, enkephalin, dynorphin, somatostatin, insulin and AGRP.
• Reactome Pathway:
  Insulin processing (R-HSA-264876)
  Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) (R-HSA-381771)
  Synthesis, secretion, and inactivation of Glucose-dependent Insulinotropic Polypeptide (GIP) (R-HSA-400511)
  Synthesis, secretion, and deacylation of Ghrelin (R-HSA-422085)
  Peptide hormone biosynthesis (R-HSA-209952)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Obesity due to prohormone convertase I deficiency	DIS2GLUH	Definitive	Autosomal recessive	[1]

13 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 Neuroendocrine convertase 1 (PCSK1).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Neuroendocrine convertase 1 (PCSK1).	[3]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Neuroendocrine convertase 1 (PCSK1).	[4]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Neuroendocrine convertase 1 (PCSK1).	[5]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Neuroendocrine convertase 1 (PCSK1).	[6]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Neuroendocrine convertase 1 (PCSK1).	[7]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of Neuroendocrine convertase 1 (PCSK1).	[8]
Liothyronine	DM6IR3P	Approved	Liothyronine decreases the expression of Neuroendocrine convertase 1 (PCSK1).	[9]
Gatifloxacin	DMSL679	Approved	Gatifloxacin increases the expression of Neuroendocrine convertase 1 (PCSK1).	[10]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Neuroendocrine convertase 1 (PCSK1).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Neuroendocrine convertase 1 (PCSK1).	[4]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Neuroendocrine convertase 1 (PCSK1).	[13]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Neuroendocrine convertase 1 (PCSK1).	[14]

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 decreases the methylation of Neuroendocrine convertase 1 (PCSK1).	[11]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] 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.
• [4] Bisphenol A effects on gene expression in adipocytes from children: association with metabolic disorders. J Mol Endocrinol. 2015 Jun;54(3):289-303.
• [5] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [6] Aberrantly expressed genes in HaCaT keratinocytes chronically exposed to arsenic trioxide. Biomark Insights. 2011 Feb 8;6:7-16.
• [7] Epigenetic silencing of novel tumor suppressors in malignant melanoma. Cancer Res. 2006 Dec 1;66(23):11187-93. doi: 10.1158/0008-5472.CAN-06-1274.
• [8] Expression profile analysis of colon cancer cells in response to sulindac or aspirin. Biochem Biophys Res Commun. 2002 Mar 29;292(2):498-512.
• [9] Thyroid hormone regulation of prohormone convertase 1 (PC1): regional expression in rat brain and in vitro characterization of negative thyroid hormone response elements. J Mol Endocrinol. 2004 Aug;33(1):21-33. doi: 10.1677/jme.0.0330021.
• [10] Combined contributions of over-secreted glucagon-like peptide 1 and suppressed insulin secretion to hyperglycemia induced by gatifloxacin in rats. Toxicol Appl Pharmacol. 2013 Feb 1;266(3):375-84. doi: 10.1016/j.taap.2012.11.015. Epub 2012 Nov 28.
• [11] 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.
• [12] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [13] 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.
• [14] 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.