Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOJ7BXR)

• DOT Name: Diphthine--ammonia ligase (DPH6)
• Synonyms: EC 6.3.1.14; ATP-binding domain-containing protein 4; Diphthamide synthase; Diphthamide synthetase; Protein DPH6 homolog
• Gene Name: DPH6
• UniProt ID: DPH6_HUMAN
• EC Number: 6.3.1.14
• Pfam ID: PF01902
• Sequence:
  MRVAALISGGKDSCYNMMQCIAAGHQIVALANLRPAENQVGSDELDSYMYQTVGHHAIDL
  YAEAMALPLYRRTIRGRSLDTRQVYTKCEGDEVEDLYELLKLVKEKEEVEGISVGAILSD
  YQRIRVENVCKRLNLQPLAYLWQRNQEDLLREMISSNIQAMIIKVAALGLDPDKHLGKTL
  DQMEPYLIELSKKYGVHVCGEGGEYETFTLDCPLFKKKIIVDSSEVVIHSADAFAPVAYL
  RFLELHLEDKVSSVPDNYRTSNYIYNF
• Function: Amidase that may catalyze the last step of diphthamide biosynthesis using ammonium and ATP. Diphthamide biosynthesis consists in the conversion of an L-histidine residue in the translation elongation factor (EEF2) to diphthamide.
• Reactome Pathway: Synthesis of diphthamide-EEF2 (R-HSA-5358493)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Diphthine--ammonia ligase (DPH6).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Diphthine--ammonia ligase (DPH6).	[2]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Diphthine--ammonia ligase (DPH6).	[3]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Diphthine--ammonia ligase (DPH6).	[4]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Diphthine--ammonia ligase (DPH6).	[5]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Diphthine--ammonia ligase (DPH6).	[6]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Diphthine--ammonia ligase (DPH6).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Diphthine--ammonia ligase (DPH6).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Diphthine--ammonia ligase (DPH6).	[9]

References

• [1] 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.
• [2] 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.
• [3] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [4] 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.
• [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] 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.
• [7] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [8] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [9] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.