Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9P91XR)

• DOT Name: 2-(3-amino-3-carboxypropyl)histidine synthase subunit 2 (DPH2)
• Synonyms: Diphthamide biosynthesis protein 2; Diphtheria toxin resistance protein 2; S-adenosyl-L-methionine:L-histidine 3-amino-3-carboxypropyltransferase 2
• Gene Name: DPH2
• Related Disease: Diphtheria
• UniProt ID: DPH2_HUMAN
• Pfam ID: PF01866
• Sequence:
  MESMFSSPAEAALQRETGVPGLLTPLPDLDGVYELERVAGFVRDLGCERVALQFPDQLLG
  DAVAVAARLEETTGSKMFILGDTAYGSCCVDVLGAEQAGAQALIHFGPACLSPPARPLPV
  AFVLRQRSVALELCVKAFEAQNPDPKAPVVLLSEPACAHALEALATLLRPRYLDLLVSSP
  AFPQPVGSLSPEPMPLERFGRRFPLAPGRRLEEYGAFYVGGSKASPDPDLDPDLSRLLLG
  WAPGQPFSSCCPDTGKTQDEGARAGRLRARRRYLVERARDARVVGLLAGTLGVAQHREAL
  AHLRNLTQAAGKRSYVLALGRPTPAKLANFPEVDVFVLLACPLGALAPQLSGSFFQPILA
  PCELEAACNPAWPPPGLAPHLTHYADLLPGSPFHVALPPPESELWETPDVSLITGDLRPP
  PAWKSSNDHGSLALTPRPQLELAESSPAASFLSSRSWQGLEPRLGQTPVTEAVSGRRGIA
  IAYEDEGSG
• 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. Facilitates the reduction of the catalytic iron-sulfur cluster found in the DPH1 subunit.
• Tissue Specificity: Strongly expressed in skeletal muscle. Moderately expressed in heart, small intestine, liver, pancreas, testis and colon. Weakly expressed in brain, placenta, kidney, spleen, thymus, prostate, ovary and lymphocytes.
• Reactome Pathway: Synthesis of diphthamide-EEF2 (R-HSA-5358493)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Diphtheria	DISZWM55	Limited	Genetic Variation	[1]

9 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 2-(3-amino-3-carboxypropyl)histidine synthase subunit 2 (DPH2).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of 2-(3-amino-3-carboxypropyl)histidine synthase subunit 2 (DPH2).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of 2-(3-amino-3-carboxypropyl)histidine synthase subunit 2 (DPH2).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of 2-(3-amino-3-carboxypropyl)histidine synthase subunit 2 (DPH2).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of 2-(3-amino-3-carboxypropyl)histidine synthase subunit 2 (DPH2).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of 2-(3-amino-3-carboxypropyl)histidine synthase subunit 2 (DPH2).	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of 2-(3-amino-3-carboxypropyl)histidine synthase subunit 2 (DPH2).	[8]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of 2-(3-amino-3-carboxypropyl)histidine synthase subunit 2 (DPH2).	[9]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of 2-(3-amino-3-carboxypropyl)histidine synthase subunit 2 (DPH2).	[10]

References

• [1] OVCA1: tumor suppressor gene.Curr Opin Genet Dev. 2005 Feb;15(1):49-54. doi: 10.1016/j.gde.2004.12.006.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] 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.
• [6] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [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] 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.
• [9] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.