ArticleJournal of inorganic biochemistry2012
Screening chelating inhibitors of HIF-prolyl hydroxylase domain 2 (PHD2) and factor inhibiting HIF (FIH).
Article in Journal of inorganic biochemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
20 citing papers in PubMed, 38 citations in OpenAlex.
- 2-Oxoglutarate Analog-Based Biomolecular Tools for Exploring Structure-Activity Relationships in Nonheme Iron Enzymes.Chembiochem : a European journal of chemical biology · 2025Article
- Mechanistic insights into gut microbe derived siderophores and PHD2 interactions with implications for HIF-1α stabilization.Scientific reports · 2025Article
- Stabilization of Hypoxia-Inducible Factor Promotes Antimicrobial Activity of Human Macrophages AgainstFrontiers in immunology · 2021Article
- Hypoxia Inducible Factor-1α in Osteochondral Tissue Engineering.Tissue engineering. Part B, Reviews · 2020Review
- HIF-1α is a Potential Molecular Target for Herbal Medicine to Treat Diseases.Drug design, development and therapy · 2020Review
- Noxious Iron-Calcium Connections in Neurodegeneration.Frontiers in neuroscience · 2019Review
- Investigations on the role of a solvent tunnel in the α-ketoglutarate dependent oxygenase factor inhibiting HIF (FIH).Journal of inorganic biochemistry · 2018Article
- Modulation of TRP Channel Activity by Hydroxylation and Its Therapeutic Potential.Pharmaceuticals (Basel, Switzerland) · 2017Review
- Targeting vascular and leukocyte communication in angiogenesis, inflammation and fibrosis.Nature reviews. Drug discovery · 2016Review
- Recent Advances in Developing Inhibitors for Hypoxia-Inducible Factor Prolyl Hydroxylases and Their Therapeutic Implications.Molecules (Basel, Switzerland) · 2015Review
- Increased Turnover at Limiting O2 Concentrations by the Thr(387) → Ala Variant of HIF-Prolyl Hydroxylase PHD2.Biochemistry · 2015Article
- Co-operative intermolecular kinetics of 2-oxoglutarate dependent dioxygenases may be essential for system-level regulation of plant cell physiology.Frontiers in plant science · 2015Article
- Unity in diversity, a systems approach to regulating plant cell physiology by 2-oxoglutarate-dependent dioxygenases.Frontiers in plant science · 2015Article
- Exploring the influence of the protein environment on metal-binding pharmacophores.Journal of medicinal chemistry · 2014Article
- Oxygen sensing strategies in mammals and bacteria.Journal of inorganic biochemistry · 2014Review
- Substrate preference of the HIF-prolyl hydroxylase-2 (PHD2) and substrate-induced conformational change.Journal of inorganic biochemistry · 2013Article
- Imposing function down a (cupin)-barrel: secondary structure and metal stereochemistry in the αKG-dependent oxygenases.Metallomics : integrated biometal science · 2013Review
- Reporter ligand NMR screening method for 2-oxoglutarate oxygenase inhibitors.Journal of medicinal chemistry · 2013Article
- The mitochondrial disulfide relay system: roles in oxidative protein folding and beyond.International journal of cell biology · 2013Review
- Inverse solvent isotope effects demonstrate slow aquo release from hypoxia inducible factor-prolyl hydroxylase (PHD2).Biochemistry · 2012Article
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Two primary O(2)-sensors for humans are the HIF-hydroxylases, enzymes that hydroxylate specific residues of the hypoxia inducible factor-α (HIF). These enzymes are factor inhibiting HIF (FIH) and prolyl hydroxylase-2 (PHD2), each an α-ketoglutarate (αKG) dependent, non-heme Fe(II) dioxygenase. Although the two enzymes have similar active sites, FIH hydroxylates Asn(803) of HIF-1α while PHD2 hydroxylates Pro(402) and/or Pro(564) of HIF-1α. The similar structures but unique functions of FIH and PHD2 make them prime targets for selective inhibition leading to regulatory control of diseases such as cancer and stroke. Three classes of iron chelators were tested as inhibitors for FIH and PHD2: pyridines, hydroxypyrones/hydroxypyridinones and catechols. An initial screen of the ten small molecule inhibitors at varied [αKG] revealed a non-overlapping set of inhibitors for PHD2 and FIH. Dose response curves at moderate [αKG] ([αKG]~K(M)) showed that the hydroxypyrones/hydroxypyridinones were selective inhibitors, with IC(50) in the μM range, and that the catechols were generally strong inhibitors of both FIH and PHD2, with IC(50) in the low μM range. As support for binding at the active site of each enzyme as the mode of inhibition, electron paramagnetic resonance (EPR) spectroscopy were used to demonstrate inhibitor binding to the metal center of each enzyme. This work shows some selective inhibition between FIH and PHD2, primarily through the use of simple aromatic or pseudo-aromatic chelators, and suggests that hydroxypyrones and hydroxypyridones may be promising chelates for FIH or PHD2 inhibition.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.