Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0QU3JY)

• DOT Name: 2-(3-amino-3-carboxypropyl)histidine synthase subunit 1 (DPH1)
• Synonyms: EC 2.5.1.108; Diphthamide biosynthesis protein 1; Diphtheria toxin resistance protein 1; Ovarian cancer-associated gene 1 protein; S-adenosyl-L-methionine:L-histidine 3-amino-3-carboxypropyltransferase 1
• Gene Name: DPH1
• Related Disease:
  Anal intraepithelial neoplasia
  Cervical cancer
  Cervical carcinoma
  Cervical Intraepithelial neoplasia
  Colorectal carcinoma
  Cranioectodermal dysplasia
  Cranioectodermal dysplasia 1
  Developmental delay with short stature, dysmorphic facial features, and sparse hair
  Developmental delay with short stature, dysmorphic facial features, and sparse hair 1
  Epithelial ovarian cancer
  Human papillomavirus infection
  Intellectual disability
  Neoplasm
  Obsolete craniofacial dysplasia-short stature-ectodermal anomalies-intellectual disability syndrome
  Obstructive lung disease
  Ovarian neoplasm
  Ritscher-Schinzel syndrome
  Acute myelogenous leukaemia
  Asthma
  Neurodevelopmental disorder
  Ovarian cancer
• UniProt ID: DPH1_HUMAN
• EC Number: 2.5.1.108
• Pfam ID: PF01866
• Sequence:
  MAALVVSGAAEQGGRDGPGRGRAPRGRVANQIPPEILKNPQLQAAIRVLPSNYNFEIPKT
  IWRIQQAQAKKVALQMPEGLLLFACTIVDILERFTEAEVMVMGDVTYGACCVDDFTARAL
  GADFLVHYGHSCLIPMDTSAQDFRVLYVFVDIRIDTTHLLDSLRLTFPPATALALVSTIQ
  FVSTLQAAAQELKAEYRVSVPQCKPLSPGEILGCTSPRLSKEVEAVVYLGDGRFHLESVM
  IANPNVPAYRYDPYSKVLSREHYDHQRMQAARQEAIATARSAKSWGLILGTLGRQGSPKI
  LEHLESRLRALGLSFVRLLLSEIFPSKLSLLPEVDVWVQVACPRLSIDWGTAFPKPLLTP
  YEAAVALRDISWQQPYPMDFYAGSSLGPWTVNHGQDRRPHAPGRPARGKVQEGSARPPSA
  VACEDCSCRDEKVAPLAP
• Function: Catalyzes 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 a tumor suppressor.
• Tissue Specificity: Expressed in heart, brain, placenta, lung, liver, skeletal muscle, kidney, pancreas, spleen, thymus, mammary gland, colon, small intestine, testis and ovary. Reduced expression in primary breast and ovarian tumors.
• Reactome Pathway: Synthesis of diphthamide-EEF2 (R-HSA-5358493)

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Anal intraepithelial neoplasia	DISJ0JW3	Strong	Altered Expression	[1]
Cervical cancer	DISFSHPF	Strong	Altered Expression	[1]
Cervical carcinoma	DIST4S00	Strong	Altered Expression	[1]
Cervical Intraepithelial neoplasia	DISXP757	Strong	Altered Expression	[1]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[2]
Cranioectodermal dysplasia	DISW7Y64	Strong	Genetic Variation	[3]
Cranioectodermal dysplasia 1	DISN81L4	Strong	Genetic Variation	[3]
Developmental delay with short stature, dysmorphic facial features, and sparse hair	DIS34K5T	Strong	Biomarker	[4]
Developmental delay with short stature, dysmorphic facial features, and sparse hair 1	DISV92FX	Strong	Autosomal recessive	[5]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[1]
Human papillomavirus infection	DISX61LX	Strong	Altered Expression	[1]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[6]
Neoplasm	DISZKGEW	Strong	Biomarker	[7]
Obsolete craniofacial dysplasia-short stature-ectodermal anomalies-intellectual disability syndrome	DISJRSEA	Strong	Autosomal recessive	[8]
Obstructive lung disease	DIS4IIDZ	Strong	Genetic Variation	[8]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[1]
Ritscher-Schinzel syndrome	DIS5TSUC	Strong	Genetic Variation	[3]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[9]
Asthma	DISW9QNS	moderate	Genetic Variation	[10]
Neurodevelopmental disorder	DIS372XH	Limited	Genetic Variation	[11]
Ovarian cancer	DISZJHAP	Limited	Altered Expression	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of 2-(3-amino-3-carboxypropyl)histidine synthase subunit 1 (DPH1).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of 2-(3-amino-3-carboxypropyl)histidine synthase subunit 1 (DPH1).	[16]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of 2-(3-amino-3-carboxypropyl)histidine synthase subunit 1 (DPH1).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of 2-(3-amino-3-carboxypropyl)histidine synthase subunit 1 (DPH1).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of 2-(3-amino-3-carboxypropyl)histidine synthase subunit 1 (DPH1).	[14]
Menadione	DMSJDTY	Approved	Menadione affects the expression of 2-(3-amino-3-carboxypropyl)histidine synthase subunit 1 (DPH1).	[15]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of 2-(3-amino-3-carboxypropyl)histidine synthase subunit 1 (DPH1).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of 2-(3-amino-3-carboxypropyl)histidine synthase subunit 1 (DPH1).	[18]

References

• [1] OVCA1 expression and its correlation with the expression levels of cyclin D1 and p16 in cervical cancer and intraepithelial neoplasia.Oncol Lett. 2017 May;13(5):2929-2936. doi: 10.3892/ol.2017.5848. Epub 2017 Mar 13.
• [2] Diphthamide Biosynthesis 1 is a Novel Oncogene in Colorectal Cancer Cells and is Regulated by MiR-218-5p.Cell Physiol Biochem. 2017;44(2):505-514. doi: 10.1159/000485087. Epub 2017 Nov 17.
• [3] Matching two independent cohorts validates DPH1 as a gene responsible for autosomal recessive intellectual disability with short stature, craniofacial, and ectodermal anomalies. Hum Mutat. 2015 Oct;36(10):1015-9. doi: 10.1002/humu.22843. Epub 2015 Aug 17.
• [4] Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families. Cell Rep. 2015 Jan 13;10(2):148-61. doi: 10.1016/j.celrep.2014.12.015. Epub 2014 Dec 31.
• [5] Ovca1 regulates cell proliferation, embryonic development, and tumorigenesis. Genes Dev. 2004 Feb 1;18(3):320-32. doi: 10.1101/gad.1162204. Epub 2004 Jan 26.
• [6] A novel homozygous DPH1 mutation causes intellectual disability and unique craniofacial features.J Hum Genet. 2018 Apr;63(4):487-491. doi: 10.1038/s10038-017-0404-9. Epub 2018 Feb 6.
• [7] The tumor suppressor OVCA1 is a short half-life protein degraded by the ubiquitin-proteasome pathway.Oncol Lett. 2019 Feb;17(2):2328-2334. doi: 10.3892/ol.2018.9852. Epub 2018 Dec 19.
• [8] Novel compound heterozygous DPH1 mutations in a patient with the unique clinical features of airway obstruction and external genital abnormalities. J Hum Genet. 2018 Apr;63(4):529-532. doi: 10.1038/s10038-017-0399-2. Epub 2018 Jan 23.
• [9] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [10] Genome-Wide Association Study Identifies Novel Loci Associated With Diisocyanate-Induced Occupational Asthma.Toxicol Sci. 2015 Jul;146(1):192-201. doi: 10.1093/toxsci/kfv084. Epub 2015 Apr 26.
• [11] DPH1 syndrome: two novel variants and structural and functional analyses of seven missense variants identified in syndromic patients.Eur J Hum Genet. 2020 Jan;28(1):64-75. doi: 10.1038/s41431-019-0374-9. Epub 2019 Mar 15.
• [12] 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.
• [13] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [14] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [15] 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.
• [16] 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.
• [17] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [18] 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.