ArticleBiochemistry2011
The second coordination sphere of FIH controls hydroxylation.
Article in Biochemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 33 citations in OpenAlex.
- Ancestral Sequence Reconstruction to Accelerate Non-heme Iron-dependent Biocatalyst Engineering.ACS central science · 2025Article
- Impact of Secondary Sphere Hydrogen Bonds on OJournal of the American Chemical Society · 2025Article
- Reaction pathway engineering converts a radical hydroxylase into a halogenase.Nature chemical biology · 2022Article
- C-H Bond Cleavage by Bioinspired Nonheme Metal Complexes.Inorganic chemistry · 2021Review
- Protein Flexibility of the α-Ketoglutarate-Dependent Oxygenase Factor-Inhibiting HIF-1: Implications for Substrate Binding, Catalysis, and Regulation.Biochemistry · 2019Article
- The facial triad in the α-ketoglutarate dependent oxygenase FIH: A role for sterics in linking substrate binding to OJournal of inorganic biochemistry · 2017Article
- OBiochemistry · 2016Article
- Substrate Promotes Productive Gas Binding in the α-Ketoglutarate-Dependent Oxygenase FIH.Biochemistry · 2016Article
- The rate-limiting step of O2 activation in the α-ketoglutarate oxygenase factor inhibiting hypoxia inducible factor.Biochemistry · 2014Article
- Substrate positioning by Gln(239) stimulates turnover in factor inhibiting HIF, an αKG-dependent hydroxylase.Biochemistry · 2014Article
- Oxygen sensing strategies in mammals and bacteria.Journal of inorganic biochemistry · 2014Review
- Spectroscopic studies of the mononuclear non-heme Fe(II) enzyme FIH: second-sphere contributions to reactivity.Journal of the American Chemical Society · 2013Article
- Imposing function down a (cupin)-barrel: secondary structure and metal stereochemistry in the αKG-dependent oxygenases.Metallomics : integrated biometal science · 2013Review
- Inverse solvent isotope effects arising from substrate triggering in the factor inhibiting hypoxia inducible factor.Biochemistry · 2013Article
- Inverse solvent isotope effects demonstrate slow aquo release from hypoxia inducible factor-prolyl hydroxylase (PHD2).Biochemistry · 2012Article
- Screening chelating inhibitors of HIF-prolyl hydroxylase domain 2 (PHD2) and factor inhibiting HIF (FIH).Journal of inorganic biochemistry · 2012Article
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
The factor inhibiting HIF (FIH) is a proximate oxygen sensor for human cells, hydroxylating Asn(803) within the α-subunit of the hypoxia inducible factor (HIF). FIH is an α-ketoglutatrate (αKG)-dependent, non-heme Fe(II) dioxygenase, in which Fe(II) is coordinated by a (His(2)Asp) facial triad, αKG, and H(2)O. Hydrogen bonding among the facial triad, the HIF-Asn(803) side chain, and various second-sphere residues suggests a functional role for the second coordination sphere in tuning the chemistry of the Fe(II) center. Point mutants of FIH were prepared to test the functional role of the αKG-centered (Asn(205) and Asn(294)) or HIF-Asn(803)-centered (Arg(238) and Gln(239)) second-sphere residues. The second sphere was tested for local effects on priming Fe(II) to react with O(2), oxidative decarboxylation, and substrate positioning. Steady-sate kinetics were used to test for overall catalytic effects; autohydroxylation rates were used to test for priming and positioning, and electronic spectroscopy was used to assess the primary coordination sphere and the electrophilicity of αKG. Asn(205) → Ala and Asn(294) → Ala mutants exhibited diminished rates of steady-state turnover, while minimally affecting autohydroxylation, consistent with impaired oxidative decarboxylation. Blue-shifted metal to ligand charge transfer transitions for (Fe+αKG)FIH indicated that these point mutations destabilized the π* orbitals of αKG, further supporting a slowed rate of oxidative decarboxylation. The Arg(238) → Met mutant exhibited steady-state rates too low to measure and diminished product yields, suggesting impaired substrate positioning or priming; the Arg(238) → Met mutant was capable of O(2) activation for the autohydroxylation reaction. The Gln(239) → Asn mutant exhibited significantly slowed steady-state kinetics and diminished product yields, suggesting impaired substrate positioning or priming. As HIF binding to the Gln(239) → Asn mutant stimulated autohydroxylation, it is more likely that this point mutant simply mispositions the HIF-Asn(803) side chain. This work combines kinetics and spectroscopy to show that these second-sphere hydrogen bonds play roles in promoting oxidative decarboxylation, priming Fe(II) to bind O(2), and positioning HIF-Asn(803).
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