Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXV3RYX)

• DOT Name: Prolyl hydroxylase EGLN3 (EGLN3)
• Synonyms: EC 1.14.11.-; Egl nine homolog 3; EC 1.14.11.29; HPH-1; Hypoxia-inducible factor prolyl hydroxylase 3; HIF-PH3; HIF-prolyl hydroxylase 3; HPH-3; Prolyl hydroxylase domain-containing protein 3; PHD3
• Gene Name: EGLN3
• UniProt ID: EGLN3_HUMAN
• EC Number: 1.14.11.-; 1.14.11.29
• Pfam ID: PF13640
• Sequence:
  MPLGHIMRLDLEKIALEYIVPCLHEVGFCYLDNFLGEVVGDCVLERVKQLHCTGALRDGQ
  LAGPRAGVSKRHLRGDQITWIGGNEEGCEAISFLLSLIDRLVLYCGSRLGKYYVKERSKA
  MVACYPGNGTGYVRHVDNPNGDGRCITCIYYLNKNWDAKLHGGILRIFPEGKSFIADVEP
  IFDRLLFFWSDRRNPHEVQPSYATRYAMTVWYFDAEERAEAKKKFRNLTRKTESALTED
• Function: Prolyl hydroxylase that mediates hydroxylation of proline residues in target proteins, such as PKM, TELO2, ATF4 and HIF1A. Target proteins are preferentially recognized via a LXXLAP motif. Cellular oxygen sensor that catalyzes, under normoxic conditions, the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins. Hydroxylates a specific proline found in each of the oxygen-dependent degradation (ODD) domains (N-terminal, NODD, and C-terminal, CODD) of HIF1A. Also hydroxylates HIF2A. Has a preference for the CODD site for both HIF1A and HIF2A. Hydroxylation on the NODD site by EGLN3 appears to require prior hydroxylation on the CODD site. Hydroxylated HIFs are then targeted for proteasomal degradation via the von Hippel-Lindau ubiquitination complex. Under hypoxic conditions, the hydroxylation reaction is attenuated allowing HIFs to escape degradation resulting in their translocation to the nucleus, heterodimerization with HIF1B, and increased expression of hypoxy-inducible genes. ELGN3 is the most important isozyme in limiting physiological activation of HIFs (particularly HIF2A) in hypoxia. Also hydroxylates PKM in hypoxia, limiting glycolysis. Under normoxia, hydroxylates and regulates the stability of ADRB2. Regulator of cardiomyocyte and neuronal apoptosis. In cardiomyocytes, inhibits the anti-apoptotic effect of BCL2 by disrupting the BAX-BCL2 complex. In neurons, has a NGF-induced proapoptotic effect, probably through regulating CASP3 activity. Also essential for hypoxic regulation of neutrophilic inflammation. Plays a crucial role in DNA damage response (DDR) by hydroxylating TELO2, promoting its interaction with ATR which is required for activation of the ATR/CHK1/p53 pathway. Also mediates hydroxylation of ATF4, leading to decreased protein stability of ATF4 (Probable).
• Tissue Specificity: Widely expressed at low levels. Expressed at higher levels in adult heart (cardiac myocytes, aortic endothelial cells and coronary artery smooth muscle), lung and placenta, and in fetal spleen, heart and skeletal muscle. Also expressed in pancreas. Localized to pancreatic acini and islet cells.
• KEGG Pathway:
  HIF-1 sig.ling pathway (hsa04066)
  Pathways in cancer (hsa05200)
  Re.l cell carcinoma (hsa05211)
• Reactome Pathway: Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha (R-HSA-1234176)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Prolyl hydroxylase EGLN3 (EGLN3).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Prolyl hydroxylase EGLN3 (EGLN3).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Prolyl hydroxylase EGLN3 (EGLN3).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Prolyl hydroxylase EGLN3 (EGLN3).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Prolyl hydroxylase EGLN3 (EGLN3).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Prolyl hydroxylase EGLN3 (EGLN3).	[5]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Prolyl hydroxylase EGLN3 (EGLN3).	[2]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Prolyl hydroxylase EGLN3 (EGLN3).	[6]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Prolyl hydroxylase EGLN3 (EGLN3).	[7]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Prolyl hydroxylase EGLN3 (EGLN3).	[8]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Prolyl hydroxylase EGLN3 (EGLN3).	[9]
Amphotericin B	DMTAJQE	Approved	Amphotericin B decreases the expression of Prolyl hydroxylase EGLN3 (EGLN3).	[10]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Prolyl hydroxylase EGLN3 (EGLN3).	[11]
HMPL-004	DM29XGY	Phase 3	HMPL-004 increases the expression of Prolyl hydroxylase EGLN3 (EGLN3).	[12]
Bardoxolone methyl	DMODA2X	Phase 3	Bardoxolone methyl affects the expression of Prolyl hydroxylase EGLN3 (EGLN3).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Prolyl hydroxylase EGLN3 (EGLN3).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Prolyl hydroxylase EGLN3 (EGLN3).	[16]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of Prolyl hydroxylase EGLN3 (EGLN3).	[17]
Okadaic acid	DM47CO1	Investigative	Okadaic acid increases the expression of Prolyl hydroxylase EGLN3 (EGLN3).	[18]

References

• [1] 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.
• [2] 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.
• [3] 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.
• [4] 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.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [7] 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.
• [8] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [9] Gene expression profiling in Ishikawa cells: a fingerprint for estrogen active compounds. Toxicol Appl Pharmacol. 2009 Apr 1;236(1):85-96.
• [10] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] Andrographolide inhibits hypoxia-induced HIF-1-driven endothelin 1 secretion by activating Nrf2/HO-1 and promoting the expression of prolyl hydroxylases 2/3 in human endothelial cells. Environ Toxicol. 2017 Mar;32(3):918-930. doi: 10.1002/tox.22293. Epub 2016 Jun 14.
• [13] Fluorescent tagging of endogenous Heme oxygenase-1 in human induced pluripotent stem cells for high content imaging of oxidative stress in various differentiated lineages. Arch Toxicol. 2021 Oct;95(10):3285-3302. doi: 10.1007/s00204-021-03127-8. Epub 2021 Sep 4.
• [14] 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.
• [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] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [17] Effects of nickel treatment on H3K4 trimethylation and gene expression. PLoS One. 2011 Mar 24;6(3):e17728. doi: 10.1371/journal.pone.0017728.
• [18] Whole genome mRNA transcriptomics analysis reveals different modes of action of the diarrheic shellfish poisons okadaic acid and dinophysis toxin-1 versus azaspiracid-1 in Caco-2 cells. Toxicol In Vitro. 2018 Feb;46:102-112.