Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0TSHP4)

• DOT Name: Glutaminyl-peptide cyclotransferase (QPCT)
• Synonyms: EC 2.3.2.5; Glutaminyl cyclase; QC; sQC; Glutaminyl-tRNA cyclotransferase; Glutamyl cyclase; EC
• Gene Name: QPCT
• UniProt ID: QPCT_HUMAN
• PDB ID: 2AFM; 2AFO; 2AFS; 2AFU; 2AFW; 2AFX; 2AFZ; 2ZED; 2ZEE; 2ZEF; 2ZEG; 2ZEH; 2ZEL; 2ZEM; 2ZEN; 2ZEO; 2ZEP; 3PBB; 3PBE; 3SI0; 4YU9; 4YWY; 6GBX; 6YI1; 6YJY; 7CM0; 7COZ; 7CP0; 7D8E
• EC Number: 2.3.2.5
• Pfam ID: PF04389
• Sequence:
  MAGGRHRRVVGTLHLLLLVAALPWASRGVSPSASAWPEEKNYHQPAILNSSALRQIAEGT
  SISEMWQNDLQPLLIERYPGSPGSYAARQHIMQRIQRLQADWVLEIDTFLSQTPYGYRSF
  SNIISTLNPTAKRHLVLACHYDSKYFSHWNNRVFVGATDSAVPCAMMLELARALDKKLLS
  LKTVSDSKPDLSLQLIFFDGEEAFLHWSPQDSLYGSRHLAAKMASTPHPPGARGTSQLHG
  MDLLVLLDLIGAPNPTFPNFFPNSARWFERLQAIEHELHELGLLKDHSLEGRYFQNYSYG
  GVIQDDHIPFLRRGVPVLHLIPSPFPEVWHTMDDNEENLDESTIDNLNKILQVFVLEYLH
  L
• Function: Responsible for the biosynthesis of pyroglutamyl peptides. Has a bias against acidic and tryptophan residues adjacent to the N-terminal glutaminyl residue and a lack of importance of chain length after the second residue. Also catalyzes N-terminal pyroglutamate formation. In vitro, catalyzes pyroglutamate formation of N-terminally truncated form of APP amyloid-beta peptides [Glu-3]-amyloid-beta. May be involved in the N-terminal pyroglutamate formation of several amyloid-related plaque-forming peptides.
• Reactome Pathway: Neutrophil degranulation (R-HSA-6798695)
• BioCyc Pathway: MetaCyc:HS03941-MONOMER

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
DTI-015	DMXZRW0	Approved	Glutaminyl-peptide cyclotransferase (QPCT) affects the response to substance of DTI-015.	[16]

16 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 Glutaminyl-peptide cyclotransferase (QPCT).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Glutaminyl-peptide cyclotransferase (QPCT).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Glutaminyl-peptide cyclotransferase (QPCT).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Glutaminyl-peptide cyclotransferase (QPCT).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Glutaminyl-peptide cyclotransferase (QPCT).	[5]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Glutaminyl-peptide cyclotransferase (QPCT).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Glutaminyl-peptide cyclotransferase (QPCT).	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Glutaminyl-peptide cyclotransferase (QPCT).	[8]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Glutaminyl-peptide cyclotransferase (QPCT).	[9]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Glutaminyl-peptide cyclotransferase (QPCT).	[10]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Glutaminyl-peptide cyclotransferase (QPCT).	[11]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Glutaminyl-peptide cyclotransferase (QPCT).	[12]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of Glutaminyl-peptide cyclotransferase (QPCT).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Glutaminyl-peptide cyclotransferase (QPCT).	[14]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Glutaminyl-peptide cyclotransferase (QPCT).	[15]
OXYQUINOLINE	DMZVS9Y	Investigative	OXYQUINOLINE decreases the expression of Glutaminyl-peptide cyclotransferase (QPCT).	[6]

References

• [1] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [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] 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] 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] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [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] 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.
• [8] Oxidative Stress Alters miRNA and Gene Expression Profiles in Villous First Trimester Trophoblasts. Biomed Res Int. 2015;2015:257090. doi: 10.1155/2015/257090. Epub 2015 Aug 3.
• [9] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [10] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [11] Characterization of DOK1, a candidate tumor suppressor gene, in epithelial ovarian cancer. Mol Oncol. 2011 Oct;5(5):438-53. doi: 10.1016/j.molonc.2011.07.003. Epub 2011 Jul 26.
• [12] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [13] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [14] Gene expression changes associated with altered growth and differentiation in benzo[a]pyrene or arsenic exposed normal human epidermal keratinocytes. J Appl Toxicol. 2008 May;28(4):491-508.
• [15] Sulforaphane-induced apoptosis in human leukemia HL-60 cells through extrinsic and intrinsic signal pathways and altering associated genes expression assayed by cDNA microarray. Environ Toxicol. 2017 Jan;32(1):311-328.
• [16] Tumor necrosis factor-alpha-induced protein 3 as a putative regulator of nuclear factor-kappaB-mediated resistance to O6-alkylating agents in human glioblastomas. J Clin Oncol. 2006 Jan 10;24(2):274-87. doi: 10.1200/JCO.2005.02.9405. Epub 2005 Dec 19.