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C. elegans EGL-9 and Mammalian Homologs Define a Family of Dioxygenases that Regulate HIF by Prolyl Hydroxylation
TLDR
Direct modulation of recombinant enzyme activity by graded hypoxia, iron chelation, and cobaltous ions mirrors the characteristics of HIF induction in vivo, fulfilling requirements for these enzymes being oxygen sensors that regulate HIF. Expand
The Obesity-Associated FTO Gene Encodes a 2-Oxoglutarate-Dependent Nucleic Acid Demethylase
TLDR
It is found that recombinant murine Fto catalyzes the Fe(II)- and 2OG-dependent demethylation of 3-methylthymine in single-stranded DNA, with concomitant production of succinate, formaldehyde, and carbon dioxide. Expand
Hypoxia-inducible Factor (HIF) Asparagine Hydroxylase Is Identical to Factor Inhibiting HIF (FIH) and Is Related to the Cupin Structural Family*
TLDR
Assays using recombinant FIH and HIF-α fragments revealed that FIH is the enzyme that hydroxylates the CAD asparagine residue, that the activity is directly inhibited by cobalt(II) and limited by hypoxia, and that the oxygen in the alcohol of the hydroxyasparagine residues is directly derived from dioxygen. Expand
Cellular oxygen sensing: Crystal structure of hypoxia-inducible factor prolyl hydroxylase (PHD2).
TLDR
The structure of the catalytic domain of human PHD2 provides insights into the hypoxic response, helps to rationalize a clinically observed mutation leading to familial erythrocytosis, and will aid in the design of PHD selective inhibitors for the treatment of anemia and ischemic disease. Expand
Asparaginyl Hydroxylation of the Notch Ankyrin Repeat Domain by Factor Inhibiting Hypoxia-inducible Factor*
TLDR
It is proposed that ARD proteins function as natural inhibitors of FIH and that the hydroxylation status of these proteins provides another oxygen-dependent interface that modulates HIF signaling. Expand
Posttranslational hydroxylation of ankyrin repeats in IκB proteins by the hypoxia-inducible factor (HIF) asparaginyl hydroxylase, factor inhibiting HIF (FIH)
TLDR
It is shown that the human HIF asparaginyl hydroxylase, factor inhibiting HIF (FIH), also efficiently hydroxymates specific asparagsinyl (Asn)-residues within proteins of the IκB family, suggesting that FIH-dependent ARD hydroxyation is a common occurrence and potentially providing an oxygen-sensitive signal to a diverse range of processes. Expand
Structure of Factor-inhibiting Hypoxia-inducible Factor (HIF) Reveals Mechanism of Oxidative Modification of HIF-1α*
TLDR
Crystal structures of the asparagine hydroxylase (factor-inhibiting HIF, FIH) complexed with Fe(II), 2-oxoglutarate cosubstrate, and CAD fragments are reported, which reveal the structural basis of HIF modification and will assist design of hydroxyase inhibitors with proangiogenic properties. Expand
Structural and Mechanistic Studies on the Inhibition of the Hypoxia-inducible Transcription Factor Hydroxylases by Tricarboxylic Acid Cycle Intermediates*
TLDR
In vitro results suggest that the cellular inhibition of PHD2, but probably not FIH, by fumarate and succinate may play a role in the Warburg effect providing that appropriate relative concentrations of the components are achieved under physiological conditions. Expand
Disruption of dimerization and substrate phosphorylation inhibit factor inhibiting hypoxia-inducible factor (FIH) activity.
TLDR
It is shown that phosphorylation of Thr-796 prevents the hydroxylation of Asn-803 by FIH, which enhances the transcriptional response in hypoxia and implies that the homodimeric form of FIH is required for productive substrate binding. Expand
Hypoxia-inducible factor asparaginyl hydroxylase (FIH-1) catalyses hydroxylation at the beta-carbon of asparagine-803.
TLDR
NMR and other analyses of a Hydroxylated HIF fragment produced in vitro demonstrate that hydroxylation occurs at the beta-carbon of Asn-803 and imply production of the threo -isomer, in contrast with other known aspartic acid/asparagine hydroxyases that produce the erythro -isomers. Expand
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