ArticleThe Journal of biological chemistry2015
Kinetic Investigations of the Role of Factor Inhibiting Hypoxia-inducible Factor (FIH) as an Oxygen Sensor.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 60 papers.
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Who cites it
60 citing papers in PubMed, 89 citations in OpenAlex.
- Impact of mitochondrial reductive stress due to respiratory chain limitation on cancer via posttranslational modifications.Redox biology · 2026Review
- A teleost-specific oxygen-immunity axis where FIH activates NF-κB via competitive IκBα binding.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- PHGDH loss promotes hypoxia tolerance through glycolytic reprogramming and enhanced HIF-1 activity.Cell death discovery · 2026Article
- Mechanistic Insights into Dioxygen Transport Routes in the PHD2 Oxygenase from Long-Time Scale Simulations.Biochemistry · 2026Article
- Prolyl hydroxylase-dependent proteolysis enables the orthogonal hypoxia responses in plants.Nature communications · 2026Article
- Metabolic Effects of Succinate Dehydrogenase Loss in Cancer.Journal of cellular physiology · 2025Review
- Review
- How oxygenation shapes immune responses: emerging roles for physioxia and pathological hypoxia.Nature reviews. Immunology · 2025Review
- Gas Tunnel Engineering of Prolyl Hydroxylase Reprograms Hypoxia Signaling in Cells.Angewandte Chemie (International ed. in English) · 2024Article
- Human prolyl hydroxylase domain 2 reacts with OScientific reports · 2024Article
- Tumor hypoxia unveiled: insights into microenvironment, detection tools and emerging therapies.Clinical and experimental medicine · 2024Review
- Substrate selectivity and inhibition of the human lysyl hydroxylase JMJD7.Protein science : a publication of the Protein Society · 2024Article
- Revisiting reactive oxygen species production in hypoxia.Pflugers Archiv : European journal of physiology · 2024Review
- Molecular characterization and function of hif1a and fih1 in response to acute thermal stress in American shad (Alosa sapidissima).Fish physiology and biochemistry · 2024Article
- N-terminal cysteine acetylation and oxidation patterns may define protein stability.Nature communications · 2024Article
- Gas tunnel engineering of prolyl hydroxylase reprograms hypoxia signaling in cells.bioRxiv : the preprint server for biology · 2024Article
- Deficiency in PHD2-mediated hydroxylation of HIF2α underlies Pacak-Zhuang syndrome.Communications biology · 2024Article
- Structure-guided optimisation ofChemical science · 2023Article
- Structural basis for binding of the renal carcinoma target hypoxia-inducible factor 2α to prolyl hydroxylase domain 2.Proteins · 2023Article
- Kinetic and inhibition studies on human Jumonji-C (JmjC) domain-containing protein 5.RSC chemical biology · 2023Article
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Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
Abstract
The hypoxia-inducible factor (HIF) hydroxylases regulate hypoxia sensing in animals. In humans, they comprise three prolyl hydroxylases (PHD1-3 or EGLN1-3) and factor inhibiting HIF (FIH). FIH is an asparaginyl hydroxylase catalyzing post-translational modification of HIF-α, resulting in reduction of HIF-mediated transcription. Like the PHDs, FIH is proposed to have a hypoxia-sensing role in cells, enabling responses to changes in cellular O2 availability. PHD2, the most important human PHD isoform, is proposed to be biochemically/kinetically suited as a hypoxia sensor due to its relatively high sensitivity to changes in O2 concentration and slow reaction with O2. To ascertain whether these parameters are conserved among the HIF hydroxylases, we compared the reactions of FIH and PHD2 with O2. Consistent with previous reports, we found lower Km(app)(O2) values for FIH than for PHD2 with all HIF-derived substrates. Under pre-steady-state conditions, the O2-initiated FIH reaction is significantly faster than that of PHD2. We then investigated the kinetics with respect to O2 of the FIH reaction with ankyrin repeat domain (ARD) substrates. FIH has lower Km(app)(O2) values for the tested ARDs than HIF-α substrates, and pre-steady-state O2-initiated reactions were faster with ARDs than with HIF-α substrates. The results correlate with cellular studies showing that FIH is active at lower O2 concentrations than the PHDs and suggest that competition between HIF-α and ARDs for FIH is likely to be biologically relevant, particularly in hypoxic conditions. The overall results are consistent with the proposal that the kinetic properties of individual oxygenases reflect their biological capacity to act as hypoxia sensors.
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