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Pubmed ID :29078149
Publication Date : //

Investigations on the role of a solvent tunnel in the α-ketoglutarate dependent oxygenase factor inhibiting HIF (FIH).


Non-heme Fe(II)/α-ketoglutarate (αKG)-dependent oxygenases catalyze a wide array of reactions through coupling oxidative decarboxylation of αKG to substrate oxygenation. This class of enzymes follows a sequential mechanism in which O reacts only after binding primary substrate, raising questions over how protein structure tailors molecular access to the Fe(II) cofactor. The enzyme "factor inhibiting hypoxia inducible factor" (FIH) senses pO in human cells by hydroxylating the C-terminal transactivation domain (CTAD), suggesting that structural elements limiting molecular access to the active site may limit the pO response. In this study, we tested the impact of a solvent-accessible tunnel in FIH on molecular access to the active site in FIH. The size of the tunnel was increased through alanine point mutagenesis (Y93A, E105A, and Q147A), followed by a suite of mechanistic and spectroscopic probes. Steady-state kinetics varying O or CTAD indicated that O passage through the tunnel was not affected by Ala substitutions, allowing us to conclude that this narrow tunnel did not impact pO sensing by FIH. Steady-state kinetics with varied αKG concentrations revealed increased substrate inhibition for the Ala variants, suggesting that a second αKG molecule may bind near the active site of FIH. If this solvent-accessible tunnel is the O entry tunnel, it may be narrow in order to permit O access while preventing metabolic intermediates, such as αKG, from inhibiting FIH under physiological conditions.

Authors : Chaplin Vanessa D , Valliere Meaghan A , Hangasky John A , Knapp Michael J ,

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