title: Selective inhibition of factor inhibiting hypoxia-inducible factor.
abstract: A set of four non-heme iron(II) and 2-oxoglutarate-dependent enzymes catalyze the post-translational modification of a transcription factor, hypoxia inducible factor (HIF), that mediates the hypoxic response in animals. Hydroxylation of HIF both causes its degradation and limits its activity. We describe how the use of structural data coupled to solid-phase synthesis led to the discovery of a selective inhibitor of one of the HIF hydroxylases. The inhibitor N-oxalyl-d-phenylalanine was shown to inhibit the HIF asparaginyl hydroxylase (FIH) but not a HIF prolyl hydroxylase. A crystal structure of the inhibitor complexed to FIH reveals that it binds in the 2OG and, likely, in the dioxygen binding site. The results will help to enable the modulation of the hypoxic response for the up-regulation of specific genes of biomedical importance, such as erythropoietin and vascular endothelial growth factor.
authors.affiliation: The Department of Chemistry and The Oxford Centre for Molecular Sciences, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA, United Kingdom.
authors.forename: Michael A
authors.initials: MA
authors.lastname: McDonough
authors.forename: Luke A
authors.initials: LA
authors.lastname: McNeill
authors.forename: Melanie
authors.initials: M
authors.lastname: Tilliet
authors.forename: Cyril A
authors.initials: CA
authors.lastname: Papamicaël
authors.forename: Qiu-Yun
authors.initials: QY
authors.lastname: Chen
authors.forename: Biswadip
authors.initials: B
authors.lastname: Banerji
authors.forename: Kirsty S
authors.initials: KS
authors.lastname: Hewitson
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Schofield
mesh_terms: D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007700:Kinetics; D006899:Mixed Function Oxygenases; D008958:Models, Molecular; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000378:metabolism; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D017433:Protein Structure, Secondary; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D010649:Phenylalanine; D006899:Mixed Function Oxygenases; C439790:HIF1AN protein, human; D011393:Procollagen-Proline Dioxygenase; C030606:proline, 2-oxoglutarate 3-dioxygenase