Tclin EGLN3 Egl nine homolog 3

Protein Summary

Description

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. EGLN3 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. Target proteins are preferentially recognized via a LXXLAP motif.

Uniprot Accession IDs

• Q9H6Z9
• Q2TA79
• Q3B8N4
• Q6P1R2

Gene Name

• EGLN3

Ensembl ID

• ENST00000250457
• ENSP00000250457
• ENSG00000129521

Symbol

• PHD3
• HIFPH3
• HIFP4H3

Knowledge Table

Most Knowledge About	Knowledge Value (0 to 1 scale)
gene perturbation	0.96
PubMedID	0.95
kinase perturbation	0.91
microRNA	0.83
biological process	0.79

IDG Development Level Summary

Tdark

These are targets about which virtually nothing is known. They do not have known drug or small molecule activities
- AND - satisfy two or more of the following criteria:

Pubmed score: 126.64   (req: < 5)

Gene RIFs: 68   (req: <= 3)

Antibodies: 440   (req: <= 50)

Tbio

These targets do not have known drug or small molecule activities
- AND - satisfy two or more of the following criteria:

Pubmed score: 126.64   (req: >= 5)

Gene RIFs: 68   (req: > 3)

Antibodies: 440   (req: > 50)

- OR - satisfy the following criterion:

Gene Ontology Terms: 13

Tchem

Target has at least one ChEMBL compound with an activity cutoff of < 30 nM - AND - satisfies the preceding conditions

Active Ligands: 82

Tclin

Target has at least one approved drug - AND - satisfies the preceding conditions

Active Drug: 1

Approved Drugs (1)

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1 – 1 of 1

roxadustat

EGLN3Tclin

INHIBITOR IC50: 5.18

Active Ligands (82)

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1 – 10 of 82

CHEMBL3646215

EGLN3Tclin

IC50: 6.75

CHEMBL3646221

EGLN3Tclin

IC50: 6.41

CHEMBL3646220

EGLN3Tclin

IC50: 7.08

CHEMBL2043327,CHEMBL2043004

EGLN3Tclin

IC50: 7.96

CHEMBL3646118,CHEMBL3931782

EGLN3Tclin

IC50: 6.35

CHEMBL2041169

EGLN3Tclin

IC50: 8.46000004

CHEMBL3646219

EGLN3Tclin

IC50: 6.25

CHEMBL2041193

EGLN3Tclin

IC50: 8.8

CHEMBL2041181

EGLN3Tclin

IC50: 7.44

CHEMBL2041185

EGLN3Tclin

IC50: 8.7

Pathways (31)

Reactome (4)

KEGG (3)

PathwayCommons (4)

WikiPathways (20)

Cellular response to hypoxia (R-HSA-1234174)

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Items per page:

5

1 – 4 of 4

Data Source	Name	Explore in Pharos	Explore in Source
Reactome	Cellular response to hypoxia	76 targets	R-HSA-1234174
Reactome	Cellular responses to external stimuli	487 targets	R-HSA-8953897
Reactome	Cellular responses to stress	392 targets	R-HSA-2262752
Reactome	Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha	67 targets	R-HSA-1234176

Name	Explore in Pharos	Explore in Source
Cellular response to hypoxia	76 targets	R-HSA-1234174
Cellular responses to external stimuli	487 targets	R-HSA-8953897
Cellular responses to stress	392 targets	R-HSA-2262752
Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha	67 targets	R-HSA-1234176

Gene Ontology Terms (17)

Functions (4)

Components (4)

Processes (9)

Items per page:

10

1 – 4 of 4

GO Term	Evidence	Assigned by
oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, 2-oxoglutarate as one donor, and incorporation of one atom each of oxygen into both donors	Inferred from Direct Assay (IDA)	MGI
peptidyl-proline 4-dioxygenase activity	Inferred from Direct Assay (IDA)	FlyBase
iron ion binding	Inferred from Electronic Annotation (IEA)	InterPro
L-ascorbic acid binding	Inferred from Electronic Annotation (IEA)	UniProtKB-KW

Protein-Protein Interactions (158)

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1 – 10 of 158

• See Interactions on String-DB

SBDS

Tbio

Novelty: 0.00526647

p_int: 0.999984597

p_ni: 0.000015403

Data Source: BioPlex

CCT6B

Tdark

Novelty: 0.35608309

p_int: 0.993218455

p_ni: 0.006781544

p_wrong: 1e-9

Data Source: BioPlex

ACACA

Tchem

Family: Enzyme

Novelty: 0.00198949

p_int: 0.984992108

p_ni: 0.015007892

Data Source: BioPlex

HIF1A

Tchem

Family: TF

Novelty: 0.00031917

Score: 0.991

Data Source: Reactome,STRINGDB

EPAS1

Tchem

Novelty: 0.00460751

Score: 0.983

Data Source: Reactome,STRINGDB

VHL

Tchem

Family: Enzyme

Novelty: 0.00323188

Score: 0.982

Data Source: Reactome,STRINGDB

HIF3A

Tbio

Novelty: 0.00260684

Score: 0.976

Data Source: Reactome,STRINGDB

ELOC

Tbio

Novelty: 0.0146568

Score: 0.954

Data Source: Reactome,STRINGDB

OS9

Tbio

Novelty: 0.01598375

Score: 0.952

Data Source: STRINGDB

CUL2

Tbio

Novelty: 0.00892549

Score: 0.946

Data Source: Reactome,STRINGDB

Publication Statistics

PubMed Score  126.64

PubMed score by year

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PubTator Score  110.98

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Amino Acid Sequence

Residue Counts

Sequence

MPLGHIMRLDLEKIALEYIVPCLHEVGFCYLDNFLGEVVGDCVLERVKQLHCTGALRDGQLAGPRAGVSK

1-70

RHLRGDQITWIGGNEEGCEAISFLLSLIDRLVLYCGSRLGKYYVKERSKAMVACYPGNGTGYVRHVDNPN

70-140

GDGRCITCIYYLNKNWDAKLHGGILRIFPEGKSFIADVEPIFDRLLFFWSDRRNPHEVQPSYATRYAMTV

140-210

WYFDAEERAEAKKKFRNLTRKTESALTED

210-239

MPLGHIMRLDLEKIALEYIVPCLHEVGFCYLDNFLGEVVGDCVLERVKQLHCTGALRDGQLAGPRAGVSKRHLRGDQITWIGGNEEGCEAISFLLSLIDRLVLYCGSRLGKYYVKERSKAMVACYPGNGTGYVRHVDNPNGDGRCITCIYYLNKNWDAKLHGGILRIFPEGKSFIADVEPIFDRLLFFWSDRRNPHEVQPSYATRYAMTVWYFDAEERAEAKKKFRNLTRKTESALTED

Find similar targets by:

Uniprot Keyword

Apoptosis
Complete proteome
Cytoplasm
Dioxygenase
DNA damage
Iron
Metal-binding
Nucleus
Oxidoreductase
Polymorphism