Egl nine homolog 1

Function

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 HIF1B. 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. EGLN1 is the most important isozyme under normoxia and, through regulating the stability of HIF1, involved in various hypoxia-influenced processes such as angiogenesis in retinal and cardiac functionality. Target proteins are preferentially recognized via a LXXLAP motif.

Classification

Family (Pfam)

PF13640 2OG-FeII_Oxy_3, PF01753 zf-MYND

InterPro

HIF_prolyl_hydroxylases, Oxoglu/Fe-dep_dioxygenase_dom, Pro_4_hyd_alph, Pro_4_hyd_alph_FE2OG_OXY, Znf_MYND

Functional cluster

Serine/Threonine Protein Kinases

Experimental structures · PDB · 64

• 2G19 X-ray 1.70A
• 2G1M X-ray 2.20A
• 2HBT X-ray 1.60A
• 2HBU X-ray 1.85A
• 2Y33 X-ray 2.00A
• 2Y34 X-ray 2.01A
• 3HQR X-ray 2.00A
• 3HQU X-ray 2.30A
• 3OUH X-ray 2.51A
• 3OUI X-ray 1.70A
• 3OUJ X-ray 2.30A
• 4BQW X-ray 1.79A
• … and 52 more

A predicted model is available from AlphaFold.

Gene Ontology · 25

• GO:0005737 cytoplasm
• GO:0005829 cytosol
• GO:0098978 glutamatergic synapse
• GO:0005634 nucleus
• GO:0014069 postsynaptic density
• GO:0016706 2-oxoglutarate-dependent dioxygenase activity
• GO:0019899 enzyme binding
• GO:0004857 enzyme inhibitor activity
• GO:0008198 ferrous iron binding
• GO:0160082 hypoxia-inducible factor-proline dioxygenase activity
• GO:0031418 L-ascorbic acid binding
• GO:0031545 peptidyl-proline 4-dioxygenase activity
• GO:0031543 peptidyl-proline dioxygenase activity
• GO:0008270 zinc ion binding
• GO:0071456 cellular response to hypoxia
• GO:0006879 intracellular iron ion homeostasis
• GO:0032364 intracellular oxygen homeostasis
• GO:1902072 negative regulation of hypoxia-inducible factor-1alpha signaling pathway
• GO:0045944 positive regulation of transcription by RNA polymerase II
• GO:0045765 regulation of angiogenesis
• GO:0099159 regulation of modification of postsynaptic structure
• GO:0043523 regulation of neuron apoptotic process
• GO:0140252 regulation protein catabolic process at postsynapse
• GO:0001666 response to hypoxia
• GO:0071731 response to nitric oxide

Disease associations

• erythrocytosis, familial, 3 MONDO:0012353

Drugs targeting this protein · 5

• ROXADUSTAT inhibitor
• DAPRODUSTAT inhibitor
• MOLIDUSTAT inhibitor
• VADADUSTAT inhibitor
• ENARODUSTAT inhibitor

Related proteins · sequence + function similarity

• Egl nine homolog 1 0.91
• Egl nine homolog 1 0.87
• Prolyl hydroxylase EGLN2 0.80
• Prolyl hydroxylase EGLN2 0.79
• Prolyl hydroxylase EGLN2 0.77
• Prolyl hydroxylase EGLN3 0.63
• Prolyl hydroxylase EGLN3 0.62
• Prolyl hydroxylase EGLN3 0.59
• Probable trehalose-phosphate phosphatase 6 0.59
• Serine/threonine-protein kinase PAK 4 0.56
• 5-methylcytosine-modifying enzyme 1 0.55
• Rhoptry apical surface protein 2 0.55

Co-cited proteins · studied together in the literature

• Prolyl hydroxylase EGLN2 11 shared papers
• Prolyl hydroxylase EGLN3 10 shared papers
• Putative SCAN domain-containing protein SCAND2P 1 shared papers
• Protein OPG005 1 shared papers
• Inhibitor of growth protein 4 1 shared papers
• Hypoxia-inducible factor 1-alpha 4 shared papers
• Transmembrane prolyl 4-hydroxylase 1 shared papers
• Prostaglandin E synthase 3 1 shared papers
• Endothelial PAS domain-containing protein 1 1 shared papers
• von Hippel-Lindau disease tumor suppressor 2 shared papers
• Transcriptional corepressor CBFA2T3 1 shared papers
• Egl nine homolog 1 1 shared papers

Literature · 39 cited papers

• 1,2,4-Triazolo-[1,5-a]pyridine HIF Prolylhydroxylase Domain-1 (PHD-1) Inhibitors With a Novel Monodentate Binding Interaction. J. Med. Chem. · 2017
• Myeloid translocation gene-16 co-repressor promotes degradation of hypoxia-inducible factor 1. PLoS ONE · 2015
• A genetic mechanism for Tibetan high-altitude adaptation. Nat. Genet. · 2014
• Defective Tibetan PHD2 binding to p23 links high altitude adaption to altered oxygen sensing. J. Biol. Chem. · 2014
• SIRT2 regulates tumour hypoxia response by promoting HIF-1alpha hydroxylation. Oncogene · 2015
• A mechanism for induction of a hypoxic response by vaccinia virus. Proc. Natl. Acad. Sci. U.S.A. · 2013
• Toward a comprehensive characterization of a human cancer cell phosphoproteome. J. Proteome Res. · 2013
• N-terminal acetylome analyses and functional insights of the N-terminal acetyltransferase NatB. Proc. Natl. Acad. Sci. U.S.A. · 2012
• The LIMD1 protein bridges an association between the prolyl hydroxylases and VHL to repress HIF-1 activity. Nat. Cell Biol. · 2012
• Prolyl hydroxylase-2 (PHD2) exerts tumor-suppressive activity in pancreatic cancer. Cancer · 2012
• Studies on the reaction of nitric oxide with the hypoxia-inducible factor prolyl hydroxylase domain 2 (EGLN1). J. Mol. Biol. · 2011
• Initial characterization of the human central proteome. BMC Syst. Biol. · 2011
• … and 27 more in the literature graph