Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDRAT3F)

• DOT Name: Deoxyhypusine hydroxylase (DOHH)
• Synonyms: hDOHH; EC 1.14.99.29; Deoxyhypusine dioxygenase; Deoxyhypusine monooxygenase; HEAT-like repeat-containing protein 1
• Gene Name: DOHH
• Related Disease:
  B-cell neoplasm
  Adult glioblastoma
  Adult lymphoma
  Advanced cancer
  Glioblastoma multiforme
  Lymphoma
  Pediatric lymphoma
  Prostate cancer
  Prostate carcinoma
  B-cell lymphoma
  Mantle cell lymphoma
  Neurodevelopmental disorder with microcephaly, cerebral atrophy, and visual impairment
  Small lymphocytic lymphoma
• UniProt ID: DOHH_HUMAN
• PDB ID: 4D4Z; 4D50
• EC Number: 1.14.99.29
• Pfam ID: PF13646
• Sequence:
  MVTEQEVDAIGQTLVDPKQPLQARFRALFTLRGLGGPGAIAWISQAFDDDSALLKHELAY
  CLGQMQDARAIPMLVDVLQDTRQEPMVRHEAGEALGAIGDPEVLEILKQYSSDPVIEVAE
  TCQLAVRRLEWLQQHGGEPAAGPYLSVDPAPPAEERDVGRLREALLDESRPLFERYRAMF
  ALRNAGGEEAALALAEGLHCGSALFRHEVGYVLGQLQHEAAVPQLAAALARCTENPMVRH
  ECAEALGAIARPACLAALQAHADDPERVVRESCEVALDMYEHETGRAFQYADGLEQLRGA
  PS
• Function: Catalyzes the hydroxylation of the N(6)-(4-aminobutyl)-L-lysine intermediate produced by deoxyhypusine synthase/DHPS on a critical lysine of the eukaryotic translation initiation factor 5A/eIF-5A. This is the second step of the post-translational modification of that lysine into an unusual amino acid residue named hypusine. Hypusination is unique to mature eIF-5A factor and is essential for its function.
• Reactome Pathway: Hypusine synthesis from eIF5A-lysine (R-HSA-204626)
• BioCyc Pathway: MetaCyc:HS05318-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
B-cell neoplasm	DISVY326	Definitive	Biomarker	[1]
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[2]
Adult lymphoma	DISK8IZR	Strong	Biomarker	[3]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[4]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[2]
Lymphoma	DISN6V4S	Strong	Biomarker	[3]
Pediatric lymphoma	DIS51BK2	Strong	Biomarker	[3]
Prostate cancer	DISF190Y	moderate	Altered Expression	[5]
Prostate carcinoma	DISMJPLE	moderate	Altered Expression	[5]
B-cell lymphoma	DISIH1YQ	Limited	Biomarker	[6]
Mantle cell lymphoma	DISFREOV	Limited	Genetic Variation	[6]
Neurodevelopmental disorder with microcephaly, cerebral atrophy, and visual impairment	DIS55JFQ	Limited	Autosomal recessive	[7]
Small lymphocytic lymphoma	DIS30POX	Limited	Genetic Variation	[6]

2 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 Deoxyhypusine hydroxylase (DOHH).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Deoxyhypusine hydroxylase (DOHH).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Deoxyhypusine hydroxylase (DOHH).	[9]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Deoxyhypusine hydroxylase (DOHH).	[10]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Deoxyhypusine hydroxylase (DOHH).	[11]
Selenium	DM25CGV	Approved	Selenium increases the expression of Deoxyhypusine hydroxylase (DOHH).	[12]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Deoxyhypusine hydroxylase (DOHH).	[10]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Deoxyhypusine hydroxylase (DOHH).	[12]
APR-246	DMNFADH	Phase 2	APR-246 affects the expression of Deoxyhypusine hydroxylase (DOHH).	[13]

References

• [1] Anti-CD20 antibody (IDEC-C2B8, rituximab) enhances efficacy of cytotoxic drugs on neoplastic lymphocytes in vitro: role of cytokines, complement, and caspases.Haematologica. 2002 Jan;87(1):33-43.
• [2] Expression of eukaryotic initiation factor 5A and hypusine forming enzymes in glioblastoma patient samples: implications for new targeted therapies.PLoS One. 2012;7(8):e43468. doi: 10.1371/journal.pone.0043468. Epub 2012 Aug 21.
• [3] Serological identification of HSP105 as a novel non-Hodgkin lymphoma therapeutic target.Blood. 2011 Oct 20;118(16):4421-30. doi: 10.1182/blood-2011-06-364570. Epub 2011 Aug 22.
• [4] Synergistic drug combination GC7/DFMO suppresses hypusine/spermidine-dependent eIF5A activation and induces apoptotic cell death in neuroblastoma.Biochem J. 2018 Jan 31;475(2):531-545. doi: 10.1042/BCJ20170597.
• [5] Regulation of expression of deoxyhypusine hydroxylase (DOHH), the enzyme that catalyzes the activation of eIF5A, by miR-331-3p and miR-642-5p in prostate cancer cells.J Biol Chem. 2012 Oct 12;287(42):35251-35259. doi: 10.1074/jbc.M112.374686. Epub 2012 Aug 20.
• [6] Targeting B-cell malignancies with the beta-emitting anti-CD37 radioimmunoconjugate (177)Lu-NNV003.Eur J Nucl Med Mol Imaging. 2019 Oct;46(11):2311-2321. doi: 10.1007/s00259-019-04417-1. Epub 2019 Jul 15.
• [7] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [8] 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.
• [9] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [10] 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.
• [11] 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.
• [12] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [13] Mutant p53 reactivation by PRIMA-1MET induces multiple signaling pathways converging on apoptosis. Oncogene. 2010 Mar 4;29(9):1329-38. doi: 10.1038/onc.2009.425. Epub 2009 Nov 30.
• [14] 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.