Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9UKOPV)

• DOT Name: Diphthine methyl ester synthase (DPH5)
• Synonyms: EC 2.1.1.314; Diphthamide biosynthesis methyltransferase
• Gene Name: DPH5
• Related Disease:
  Neurodevelopmental disorder with short stature, prominent forehead, and feeding difficulties
  Ulcerative colitis
• UniProt ID: DPH5_HUMAN
• EC Number: 2.1.1.314
• Pfam ID: PF00590
• Sequence:
  MLYLIGLGLGDAKDITVKGLEVVRRCSRVYLEAYTSVLTVGKEALEEFYGRKLVVADREE
  VEQEADNILKDADISDVAFLVVGDPFGATTHSDLVLRATKLGIPYRVIHNASIMNAVGCC
  GLQLYKFGETVSIVFWTDTWRPESFFDKVKKNRQNGMHTLCLLDIKVKEQSLENLIKGRK
  IYEPPRYMSVNQAAQQLLEIVQNQRIRGEEPAVTEETLCVGLARVGADDQKIAAGTLRQM
  CTVDLGEPLHSLIITGGSIHPMEMEMLSLFSIPENSSESQSINGL
• Function: S-adenosyl-L-methionine-dependent methyltransferase that catalyzes four methylations of the modified target histidine residue in translation elongation factor 2 (EF-2), to form an intermediate called diphthine methyl ester. The four successive methylation reactions represent the second step of diphthamide biosynthesis.
• Reactome Pathway: Synthesis of diphthamide-EEF2 (R-HSA-5358493)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neurodevelopmental disorder with short stature, prominent forehead, and feeding difficulties	DIS9V7SK	Strong	Autosomal recessive	[1]
Ulcerative colitis	DIS8K27O	moderate	Genetic Variation	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Diphthine methyl ester synthase (DPH5).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Diphthine methyl ester synthase (DPH5).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Diphthine methyl ester synthase (DPH5).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Diphthine methyl ester synthase (DPH5).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Diphthine methyl ester synthase (DPH5).	[7]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Diphthine methyl ester synthase (DPH5).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Diphthine methyl ester synthase (DPH5).	[9]

References

• [1] A novel DPH5-related diphthamide-deficiency syndrome causing embryonic lethality or profound neurodevelopmental disorder. Genet Med. 2022 Jul;24(7):1567-1582. doi: 10.1016/j.gim.2022.03.014. Epub 2022 Apr 28.
• [2] Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations.Nat Genet. 2015 Sep;47(9):979-986. doi: 10.1038/ng.3359. Epub 2015 Jul 20.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [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] 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.
• [6] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [9] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.