ArticleBiochemistry2013
Inverse solvent isotope effects arising from substrate triggering in the factor inhibiting hypoxia inducible factor.
Article in Biochemistry, 2013. 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, 27 citations in OpenAlex.
- Importance of Asparagine 202 in Manipulating Active Site Structure and Substrate Preference for Human CYP17A1.Biochemistry · 2022Article
- Inverse Solvent Isotope Effects in Enzyme-Catalyzed Reactions.Molecules (Basel, Switzerland) · 2020Review
- Protein Flexibility of the α-Ketoglutarate-Dependent Oxygenase Factor-Inhibiting HIF-1: Implications for Substrate Binding, Catalysis, and Regulation.Biochemistry · 2019Article
- Chloride Supports OInorganic chemistry · 2018Article
- Investigations on the role of a solvent tunnel in the α-ketoglutarate dependent oxygenase factor inhibiting HIF (FIH).Journal of inorganic biochemistry · 2018Article
- Mechanistic Insights into Dye-Decolorizing Peroxidase Revealed by Solvent Isotope and Viscosity Effects.ACS catalysis · 2017Article
- The facial triad in the α-ketoglutarate dependent oxygenase FIH: A role for sterics in linking substrate binding to OJournal of inorganic biochemistry · 2017Article
- Substrate Promotes Productive Gas Binding in the α-Ketoglutarate-Dependent Oxygenase FIH.Biochemistry · 2016Article
- Kinetic Investigations of the Role of Factor Inhibiting Hypoxia-inducible Factor (FIH) as an Oxygen Sensor.The Journal of biological chemistry · 2015Article
- Increased Turnover at Limiting O2 Concentrations by the Thr(387) → Ala Variant of HIF-Prolyl Hydroxylase PHD2.Biochemistry · 2015Article
- 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
- Solvent isotope effects on alkane formation by cyanobacterial aldehyde deformylating oxygenase and their mechanistic implications.Biochemistry · 2014Article
- A flexible glutamine regulates the catalytic activity of toluene o-xylene monooxygenase.Biochemistry · 2014Article
- Oxygen sensing strategies in mammals and bacteria.Journal of inorganic biochemistry · 2014Review
- Imposing function down a (cupin)-barrel: secondary structure and metal stereochemistry in the αKG-dependent oxygenases.Metallomics : integrated biometal science · 2013Review
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Oxygen homeostasis plays a critical role in angiogenesis, erythropoiesis, and cell metabolism. Oxygen homeostasis is set by the hypoxia inducible factor-1α (HIF-1α) pathway, which is controlled by factor inhibiting HIF-1α (FIH). FIH is a non-heme Fe(II), α-ketoglutarate (αKG)-dependent dioxygenase that inhibits HIF-1α by hydroxylating the C-terminal transactivation domain (CTAD) of HIF-1α at HIF-Asn(803). A tight coupling between CTAD binding and O2 activation is essential for hypoxia sensing, making changes in the coordination geometry of Fe(II) upon CTAD encounter a crucial feature of this enzyme. Although the consensus chemical mechanism for FIH proposes that CTAD binding triggers O2 activation by causing the Fe(II) cofactor to release an aquo ligand, experimental evidence of this has been absent. More broadly, this proposed coordination change at Fe(II) has not been observed during steady-state turnover in any αKG oxygenase to date. In this work, solvent isotope effects (SIEs) were used as a direct mechanistic probe of substrate-triggered aquo release in FIH, as inverse SIEs (SIE < 1) are signatures for pre-equilibrium aquo release from metal ions. Our mechanistic studies of FIH have revealed inverse solvent isotope effects in the steady-state rate constants at limiting concentrations of CTAD or αKG [(D2O)kcat/KM(CTAD) = 0.40 ± 0.07, and (D2O)kcat/KM(αKG) = 0.32 ± 0.08], providing direct evidence of aquo release during steady-state turnover. Furthermore, the SIE at saturating concentrations of CTAD and αKG was inverse ((D2O)kcat = 0.51 ± 0.07), indicating that aquo release occurs after CTAD binds. The inverse kinetic SIEs observed in the steady state for FIH can be explained by a strong Fe-OH2 bond. The stable Fe-OH2 bond plays an important part in FIH's regulatory role over O2 homeostasis in humans and points toward a strategy for tightly coupling O2 activation with CTAD hydroxylation that relies on substrate triggering.
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