hypoxia-inducible factor-proline dioxygenase activity

Definition

Target type: molecularfunction

Catalysis of the reaction: 2-oxoglutarate + L-prolyl-[hypoxia-inducible factor alpha subunit] + O2 = CO2 + succinate + trans-4-hydroxy-L-prolyl-[hypoxia-inducible factor alpha subunit]. [PMID:11595184, PMID:11598268]

Hypoxia-inducible factor-proline dioxygenase (HIF-P4H) activity is a critical regulatory mechanism involved in cellular responses to oxygen deprivation (hypoxia). It is a vital component of the HIF pathway, which orchestrates transcriptional adaptations to low oxygen levels. HIF-P4Hs are dioxygenases that catalyze the hydroxylation of specific proline residues within the alpha subunit of the hypoxia-inducible factor (HIF). This hydroxylation event is essential for the subsequent ubiquitination and proteasomal degradation of HIF-alpha, ultimately leading to the regulation of target gene expression.

HIF-P4Hs are active only in the presence of oxygen. They utilize molecular oxygen (O2) as a substrate, along with ferrous iron (Fe2+), 2-oxoglutarate (2-OG), and ascorbate as cofactors. The catalytic mechanism involves the coordination of Fe2+ within the enzyme active site, followed by the binding of 2-OG and the proline residue of HIF-alpha. This complex then undergoes a series of steps involving O2 activation and the transfer of an oxygen atom to the proline residue, leading to its hydroxylation.

The hydroxylation of proline residues within HIF-alpha destabilizes the protein, rendering it susceptible to ubiquitination by the von Hippel-Lindau (VHL) E3 ubiquitin ligase complex. This ubiquitination event targets HIF-alpha for proteasomal degradation, effectively shutting down the HIF pathway under normoxic conditions.

Under hypoxic conditions, the activity of HIF-P4Hs is significantly reduced due to the limited availability of oxygen. This decrease in HIF-P4H activity allows HIF-alpha to accumulate, translocate to the nucleus, and activate the transcription of target genes involved in angiogenesis, erythropoiesis, glucose metabolism, and other cellular processes that promote survival and adaptation to hypoxia.

In summary, HIF-P4H activity acts as a key oxygen sensor and regulator of the HIF pathway. Its ability to hydroxylate specific proline residues within HIF-alpha ultimately controls the stability and activity of HIF, orchestrating cellular responses to changes in oxygen availability.'
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Proteins (4)

Compounds (25)