title: FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor.
abstract: Mammalian cells adapt to hypoxic conditions through a transcriptional response pathway mediated by the hypoxia-inducible factor, HIF. HIF transcriptional activity is suppressed under normoxic conditions by hydroxylation of an asparagine residue within its C-terminal transactivation domain, blocking association with coactivators. Here we show that the protein FIH-1, previously shown to interact with HIF, is an asparaginyl hydroxylase. Like known hydroxylase enzymes, FIH-1 is an Fe(II)-dependent enzyme that uses molecular O(2) to modify its substrate. Together with the recently discovered prolyl hydroxylases that regulate HIF stability, this class of oxygen-dependent enzymes comprises critical regulatory components of the hypoxic response pathway.
authors.affiliation: Department of Molecular BioSciences (Biochemistry) and the Centre for the Molecular Genetics of Development, Adelaide University SA 5005, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Lando
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Peet
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Gorman
authors.forename: Dean A
authors.initials: DA
authors.lastname: Whelan
authors.forename: Murray L
authors.initials: ML
authors.lastname: Whitelaw
authors.forename: Richard K
authors.initials: RK
authors.lastname: Bruick
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001216:Asparagine / Q000737:chemistry*; D051792:Basic Helix-Loop-Helix Proteins; D002460:Cell Line; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D006900:Hydroxylation; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007501:Iron / Q000378:metabolism; D007656:Ketoglutaric Acids / Q000378:metabolism; D013058:Mass Spectrometry; D051379:Mice; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D008969:Molecular Sequence Data; D010100:Oxygen / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism* / Q000502:physiology*; D017386:Sequence Homology, Amino Acid; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D001216:Asparagine; D051792:Basic Helix-Loop-Helix Proteins; D005982:Glutathione Transferase; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007501:Iron; D007656:Ketoglutaric Acids; D006899:Mixed Function Oxygenases; D010100:Oxygen; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human; C439790:HIF1AN protein, human; C058291:aspartic acid 2-oxoglutarate-dependent dioxygenase