PHD2 / prolyl hydroxylase

Domain

The beta(2)beta(3) 'finger-like' loop domain is important for substrate (HIFs' CODD/NODD) selectivity.

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.

Involvement in disease

Erythrocytosis, familial, 3

ECYT3

An autosomal dominant disorder characterized by elevated serum hemoglobin and hematocrit, and normal serum erythropoietin levels.

None

The disease is caused by variants affecting the gene represented in this entry.

Post-translational modifications

S-nitrosylation inhibits the enzyme activity up to 60% under aerobic conditions. Chelation of Fe(2+) has no effect on the S-nitrosylation. It is uncertain whether nitrosylation occurs on Cys-323 or Cys-326.

Tissue specificity

According to PubMed:11056053, widely expressed with highest levels in skeletal muscle and heart, moderate levels in pancreas, brain (dopaminergic neurons of adult and fetal substantia nigra) and kidney, and lower levels in lung and liver. According to PubMed:12351678 widely expressed with highest levels in brain, kidney and adrenal gland. Expressed in cardiac myocytes, aortic endothelial cells and coronary artery smooth muscle. According to PubMed:12788921; expressed in adult and fetal heart, brain, liver, lung, skeletal muscle and kidney. Also expressed in placenta. Highest levels in adult heart, brain, lung and liver and fetal brain, heart spleen and skeletal muscle.

Cellular localization

• Cytoplasm
• Nucleus
• Mainly cytoplasmic. Shuttles between the nucleus and cytoplasm (PubMed:19631610). Nuclear export requires functional XPO1.

Alternative names

• Egl nine homolog 1
• Hypoxia-inducible factor prolyl hydroxylase 2
• Prolyl hydroxylase domain-containing protein 2
• SM-20
• HIF-PH2
• HIF-prolyl hydroxylase 2
• HPH-2
• PHD2
• PNAS-118
• EGLN1
• C1orf12
• PNAS-137

Database links

• entrezGene:54583
• omim:606425
• swissprot:Q9GZT9

Target type

Proteins

Primary research area

Oncology

Molecular weight

46021Da