Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0FC1YX)

• DOT Name: Prolyl hydroxylase EGLN2 (EGLN2)
• Synonyms: EC 1.14.11.-; Egl nine homolog 2; EC 1.14.11.29; Estrogen-induced tag 6; EIT-6; HPH-3; Hypoxia-inducible factor prolyl hydroxylase 1; HIF-PH1; HIF-prolyl hydroxylase 1; HPH-1; Prolyl hydroxylase domain-containing protein 1; PHD1
• Gene Name: EGLN2
• UniProt ID: EGLN2_HUMAN
• PDB ID: 5V1B
• EC Number: 1.14.11.-; 1.14.11.29
• Pfam ID: PF13640
• Sequence:
  MDSPCQPQPLSQALPQLPGSSSEPLEPEPGRARMGVESYLPCPLLPSYHCPGVPSEASAG
  SGTPRATATSTTASPLRDGFGGQDGGELRPLQSEGAAALVTKGCQRLAAQGARPEAPKRK
  WAEDGGDAPSPSKRPWARQENQEAEREGGMSCSCSSGSGEASAGLMEEALPSAPERLALD
  YIVPCMRYYGICVKDSFLGAALGGRVLAEVEALKRGGRLRDGQLVSQRAIPPRSIRGDQI
  AWVEGHEPGCRSIGALMAHVDAVIRHCAGRLGSYVINGRTKAMVACYPGNGLGYVRHVDN
  PHGDGRCITCIYYLNQNWDVKVHGGLLQIFPEGRPVVANIEPLFDRLLIFWSDRRNPHEV
  KPAYATRYAITVWYFDAKERAAAKDKYQLASGQKGVQVPVSQPPTPT
• Function: Prolyl hydroxylase that mediates hydroxylation of proline residues in target proteins, such as ATF4, IKBKB, CEP192 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. 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. EGLN2 is involved in regulating hypoxia tolerance and apoptosis in cardiac and skeletal muscle. Also regulates susceptibility to normoxic oxidative neuronal death. Links oxygen sensing to cell cycle and primary cilia formation by hydroxylating the critical centrosome component CEP192 which promotes its ubiquitination and subsequent proteasomal degradation. Hydroxylates IKBKB, mediating NF-kappa-B activation in hypoxic conditions. Also mediates hydroxylation of ATF4, leading to decreased protein stability of ATF4.
• Tissue Specificity: Expressed in adult and fetal heart, brain, liver, lung, skeletal muscle, and kidney. Also expressed in testis and placenta. Highest levels in adult brain, placenta, lung, kidney, and testis. Expressed in hormone responsive tissues, including normal and cancerous mammary, ovarian and prostate epithelium.
• 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)
• BioCyc Pathway: MetaCyc:ENSG00000171570-MONOMER

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 increases the methylation of Prolyl hydroxylase EGLN2 (EGLN2).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Prolyl hydroxylase EGLN2 (EGLN2).	[7]

8 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 Prolyl hydroxylase EGLN2 (EGLN2).	[2]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Prolyl hydroxylase EGLN2 (EGLN2).	[3]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Prolyl hydroxylase EGLN2 (EGLN2).	[3]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Prolyl hydroxylase EGLN2 (EGLN2).	[4]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Prolyl hydroxylase EGLN2 (EGLN2).	[5]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Prolyl hydroxylase EGLN2 (EGLN2).	[6]
Clioquinol	DM746BZ	Withdrawn from market	Clioquinol decreases the expression of Prolyl hydroxylase EGLN2 (EGLN2).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Prolyl hydroxylase EGLN2 (EGLN2).	[9]

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] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [3] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [4] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [5] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [6] 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.
• [7] 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.
• [8] Identification of chemical compounds that induce HIF-1alpha activity. Toxicol Sci. 2009 Nov;112(1):153-63.
• [9] Epigenetic influences of low-dose bisphenol A in primary human breast epithelial cells. Toxicol Appl Pharmacol. 2010 Oct 15;248(2):111-21.