Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQIG7BL)

• DOT Name: Deoxyhypusine synthase (DHPS)
• Synonyms: DHS; EC 2.5.1.46
• Gene Name: DHPS
• Related Disease: Neurodevelopmental disorder with seizures and speech and walking impairment
• UniProt ID: DHYS_HUMAN
• PDB ID: 1DHS; 1RLZ; 1ROZ; 1RQD; 6P4V; 6PGR; 6WKZ; 6WL6; 6XXH; 6XXI; 6XXJ; 6XXK; 6XXL; 6XXM; 7A6S; 7A6T; 8A0E; 8A0F; 8A0G
• EC Number: 2.5.1.46
• Pfam ID: PF01916
• Sequence:
  MEGSLEREAPAGALAAVLKHSSTLPPESTQVRGYDFNRGVNYRALLEAFGTTGFQATNFG
  RAVQQVNAMIEKKLEPLSQDEDQHADLTQSRRPLTSCTIFLGYTSNLISSGIRETIRYLV
  QHNMVDVLVTTAGGVEEDLIKCLAPTYLGEFSLRGKELRENGINRIGNLLVPNENYCKFE
  DWLMPILDQMVMEQNTEGVKWTPSKMIARLGKEINNPESVYYWAQKNHIPVFSPALTDGS
  LGDMIFFHSYKNPGLVLDIVEDLRLINTQAIFAKCTGMIILGGGVVKHHIANANLMRNGA
  DYAVYINTAQEFDGSDSGARPDEAVSWGKIRVDAQPVKVYADASLVFPLLVAETFAQKMD
  AFMHEKNED
• Function: Catalyzes the NAD-dependent oxidative cleavage of spermidine and the subsequent transfer of the butylamine moiety of spermidine to the epsilon-amino group of a critical lysine residue of the eIF-5A precursor protein to form the intermediate deoxyhypusine residue. This is the first 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:HS01810-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neurodevelopmental disorder with seizures and speech and walking impairment	DISILZ09	Strong	Autosomal recessive	[1]

14 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 Deoxyhypusine synthase (DHPS).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Deoxyhypusine synthase (DHPS).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Deoxyhypusine synthase (DHPS).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Deoxyhypusine synthase (DHPS).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Deoxyhypusine synthase (DHPS).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Deoxyhypusine synthase (DHPS).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Deoxyhypusine synthase (DHPS).	[8]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Deoxyhypusine synthase (DHPS).	[9]
Selenium	DM25CGV	Approved	Selenium increases the expression of Deoxyhypusine synthase (DHPS).	[10]
Nicotine	DMWX5CO	Approved	Nicotine decreases the expression of Deoxyhypusine synthase (DHPS).	[11]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Deoxyhypusine synthase (DHPS).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Deoxyhypusine synthase (DHPS).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Deoxyhypusine synthase (DHPS).	[16]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Deoxyhypusine synthase (DHPS).	[17]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Deoxyhypusine synthase (DHPS).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Deoxyhypusine synthase (DHPS).	[13]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Deoxyhypusine synthase (DHPS).	[14]

References

• [1] Recessive Rare Variants in Deoxyhypusine Synthase, an Enzyme Involved in the Synthesis of Hypusine, Are Associated with a Neurodevelopmental Disorder. Am J Hum Genet. 2019 Feb 7;104(2):287-298. doi: 10.1016/j.ajhg.2018.12.017. Epub 2019 Jan 17.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [5] Gamma-irradiation and doxorubicin treatment of normal human cells cause cell cycle arrest via different pathways. Mol Cells. 2005 Dec 31;20(3):331-8.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [8] 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.
• [9] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [10] 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.
• [11] Nicotinic modulation of gene expression in SH-SY5Y neuroblastoma cells. Brain Res. 2006 Oct 20;1116(1):39-49.
• [12] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [13] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [14] 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.
• [15] 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.
• [16] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [17] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.