Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKAICP5)

• DOT Name: Gamma-glutamylcyclotransferase (GGCT)
• Synonyms: EC 4.3.2.9; Cytochrome c-releasing factor 21
• Gene Name: GGCT
• UniProt ID: GGCT_HUMAN
• PDB ID: 2I5T; 2PN7; 2Q53; 2RBH; 3CRY
• EC Number: 4.3.2.9
• Pfam ID: PF13772
• Sequence:
  MANSGCKDVTGPDEESFLYFAYGSNLLTERIHLRNPSAAFFCVARLQDFKLDFGNSQGKT
  SQTWHGGIATIFQSPGDEVWGVVWKMNKSNLNSLDEQEGVKSGMYVVIEVKVATQEGKEI
  TCRSYLMTNYESAPPSPQYKKIICMGAKENGLPLEYQEKLKAIEPNDYTGKVSEEIEDII
  KKGETQTL
• Function: Catalyzes the formation of 5-oxoproline from gamma-glutamyl dipeptides and may play a significant role in glutathione homeostasis. Induces release of cytochrome c from mitochondria with resultant induction of apoptosis.
• KEGG Pathway:
  Glutathione metabolism (hsa00480)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Glutathione synthesis and recycling (R-HSA-174403)

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
Vinblastine	DM5TVS3	Approved	Gamma-glutamylcyclotransferase (GGCT) affects the response to substance of Vinblastine.	[13]

11 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 Gamma-glutamylcyclotransferase (GGCT).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin affects the expression of Gamma-glutamylcyclotransferase (GGCT).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Gamma-glutamylcyclotransferase (GGCT).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Gamma-glutamylcyclotransferase (GGCT).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Gamma-glutamylcyclotransferase (GGCT).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Gamma-glutamylcyclotransferase (GGCT).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Gamma-glutamylcyclotransferase (GGCT).	[7]
Nicotine	DMWX5CO	Approved	Nicotine increases the splicing of Gamma-glutamylcyclotransferase (GGCT).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Gamma-glutamylcyclotransferase (GGCT).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Gamma-glutamylcyclotransferase (GGCT).	[11]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone decreases the expression of Gamma-glutamylcyclotransferase (GGCT).	[12]

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 increases the methylation of Gamma-glutamylcyclotransferase (GGCT).	[9]

References

• [1] Design principles of concentration-dependent transcriptome deviations in drug-exposed differentiating stem cells. Chem Res Toxicol. 2014 Mar 17;27(3):408-20.
• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [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] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [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] Characterizing the genetic basis for nicotine induced cancer development: a transcriptome sequencing study. PLoS One. 2013 Jun 18;8(6):e67252.
• [9] 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.
• [10] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [11] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [12] Evaluation of an in vitro model of androgen ablation and identification of the androgen responsive proteome in LNCaP cells. Proteomics. 2007 Jan;7(1):47-63.
• [13] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.