Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT59Q6C4)

• DOT Name: Diphthamide biosynthesis protein 3 (DPH3)
• Synonyms: CSL-type zinc finger-containing protein 2; DelGEF-interacting protein 1; DelGIP1
• Gene Name: DPH3
• Related Disease:
  Melanoma
  Cutaneous squamous cell carcinoma
  Melanocytic nevus
  Skin cancer
• UniProt ID: DPH3_HUMAN
• PDB ID: 2JR7
• Pfam ID: PF05207
• Sequence:
  MAVFHDEVEIEDFQYDEDSETYFYPCPCGDNFSITKEDLENGEDVATCPSCSLIIKVIYD
  KDQFVCGETVPAPSANKELVKC
• Function: Required for the first step of diphthamide biosynthesis, a post-translational modification of histidine which occurs in elongation factor 2. DPH1 and DPH2 transfer a 3-amino-3-carboxypropyl (ACP) group from S-adenosyl-L-methionine (SAM) to a histidine residue, the reaction is assisted by a reduction system comprising DPH3 and a NADH-dependent reductase. Acts as an electron donor to reduce the Fe-S cluster in DPH1-DPH2 keeping the [4Fe-4S] clusters in the active and reduced state. Restores iron to DPH1-DPH2 iron-sulfur clusters which have degraded from [4Fe-4S] to [3Fe-4S] by donating an iron atom to reform [4Fe-4S] clusters, in a manner dependent on the presence of elongation factor 2 and SAM. Associates with the elongator complex and is required for tRNA Wobble base modifications mediated by the elongator complex. The elongator complex is required for multiple tRNA modifications, including mcm5U (5-methoxycarbonylmethyl uridine), mcm5s 2U (5-methoxycarbonylmethyl-2-thiouridine), and ncm5U (5-carbamoylmethyl uridine).
• Tissue Specificity: Widely expressed with highest levels in small intestine, spleen, thymus, heart, liver and lung.
• Reactome Pathway: Synthesis of diphthamide-EEF2 (R-HSA-5358493)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Melanoma	DIS1RRCY	Strong	Biomarker	[1]
Cutaneous squamous cell carcinoma	DIS3LXUG	Limited	Genetic Variation	[2]
Melanocytic nevus	DISYS32D	Limited	Genetic Variation	[2]
Skin cancer	DISTM18U	Limited	Genetic Variation	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Diphthamide biosynthesis protein 3 (DPH3).	[3]

7 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 Diphthamide biosynthesis protein 3 (DPH3).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Diphthamide biosynthesis protein 3 (DPH3).	[5]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Diphthamide biosynthesis protein 3 (DPH3).	[6]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Diphthamide biosynthesis protein 3 (DPH3).	[7]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Diphthamide biosynthesis protein 3 (DPH3).	[8]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Diphthamide biosynthesis protein 3 (DPH3).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Diphthamide biosynthesis protein 3 (DPH3).	[10]

References

• [1] Silencing of diphthamide synthesis 3 (Dph3) reduces metastasis of murine melanoma.PLoS One. 2012;7(11):e49988. doi: 10.1371/journal.pone.0049988. Epub 2012 Nov 20.
• [2] Frequent DPH3 promoter mutations in skin cancers.Oncotarget. 2015 Nov 3;6(34):35922-30. doi: 10.18632/oncotarget.5771.
• [3] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [4] 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.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [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] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [8] 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.
• [9] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [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.