title: 5-Carboxy-8-hydroxyquinoline is a Broad Spectrum 2-Oxoglutarate Oxygenase Inhibitor which Causes Iron Translocation.
abstract: 2-Oxoglutarate and iron dependent oxygenases are therapeutic targets for human diseases. Using a representative 2OG oxygenase panel, we compare the inhibitory activities of 5-carboxy-8-hydroxyquinoline (IOX1) and 4-carboxy-8-hydroxyquinoline (4C8HQ) with that of two other commonly used 2OG oxygenase inhibitors,N-oxalylglycine (NOG) and 2,4-pyridinedicarboxylic acid (2,4-PDCA). The results reveal that IOX1 has a broad spectrum of activity, as demonstrated by the inhibition of transcription factor hydroxylases, representatives of all 2OG dependent histone demethylase subfamilies, nucleic acid demethylases and γ-butyrobetaine hydroxylase. Cellular assays show that, unlike NOG and 2,4-PDCA, IOX1 is active against both cytosolic and nuclear 2OG oxygenases without ester derivatisation. Unexpectedly, crystallographic studies on these oxygenases demonstrate that IOX1, but not 4C8HQ, can cause translocation of the active site metal, revealing a rare example of protein ligand-induced metal movement.
authors.affiliation: Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA, U.K.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Hopkinson
authors.affiliation: Structural Genomics Consortium, University of Oxford, Headington, OX3 7DQ, U.K.|Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Roosevelt Drive, OX3 7FZ, UK.
authors.forename: Anthony
authors.initials: A
authors.lastname: Tumber
authors.affiliation: Structural Genomics Consortium, University of Oxford, Headington, OX3 7DQ, U.K.
authors.forename: Clarence
authors.initials: C
authors.lastname: Yapp
authors.affiliation: Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA, U.K.
authors.forename: Rasheduzzaman
authors.initials: R
authors.lastname: Chowdhury
authors.affiliation: Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA, U.K.
authors.forename: WeiShen
authors.initials: W
authors.lastname: Aik
authors.affiliation: Structural Genomics Consortium, University of Oxford, Headington, OX3 7DQ, U.K.|Botnar Research Centre, Oxford Biomedical Research Unit, Oxford OX3 7LD, U.K.
authors.forename: Ka Hing
authors.initials: KH
authors.lastname: Che
authors.affiliation: Epigenetic Regulation of Chromatin Function Group, Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, U.K.
authors.forename: Xuan Shirley
authors.initials: XS
authors.lastname: Li
authors.affiliation: Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA, U.K.|Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
authors.forename: Jan B L
authors.initials: JBL
authors.lastname: Kristensen
authors.affiliation: Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA, U.K.
authors.forename: Oliver N F
authors.initials: ONF
authors.lastname: King
authors.affiliation: Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA, U.K.|Henry Wellcome Building for Molecular Physiology, Nuffield Department of Medicine, University of Oxford, Roosevelt Drive, Oxford OX3 7LD, U.K.
authors.forename: Mun Chiang
authors.initials: MC
authors.lastname: Chan
authors.affiliation: Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA, U.K.|Henry Wellcome Building for Molecular Physiology, Nuffield Department of Medicine, University of Oxford, Roosevelt Drive, Oxford OX3 7LD, U.K.
authors.forename: Kar Kheng
authors.initials: KK
authors.lastname: Yeoh
authors.affiliation: Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA, U.K.
authors.forename: Hwanho
authors.initials: H
authors.lastname: Choi
authors.affiliation: Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA, U.K.
authors.forename: Louise J
authors.initials: LJ
authors.lastname: Walport
authors.affiliation: Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA, U.K.
authors.forename: Cyrille C
authors.initials: CC
authors.lastname: Thinnes
authors.affiliation: Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA, U.K.
authors.forename: Jacob T
authors.initials: JT
authors.lastname: Bush
authors.affiliation: Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA, U.K.
authors.forename: Clarisse
authors.initials: C
authors.lastname: Lejeune
authors.affiliation: Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA, U.K.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Rydzik
authors.affiliation: Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA, U.K.|Epigenetic Regulation of Chromatin Function Group, Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, U.K.
authors.forename: Nathan R
authors.initials: NR
authors.lastname: Rose
authors.affiliation: Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA, U.K.
authors.forename: Eleanor A
authors.initials: EA
authors.lastname: Bagg
authors.affiliation: Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA, U.K.
authors.forename: Michael A
authors.initials: MA
authors.lastname: McDonough
authors.affiliation: Structural Genomics Consortium, University of Oxford, Headington, OX3 7DQ, U.K.
authors.forename: Tobias
authors.initials: T
authors.lastname: Krojer
authors.affiliation: Structural Genomics Consortium, University of Oxford, Headington, OX3 7DQ, U.K.
authors.forename: Wyatt W
authors.initials: WW
authors.lastname: Yue
authors.affiliation: Structural Genomics Consortium, University of Oxford, Headington, OX3 7DQ, U.K.
authors.forename: Stanley S
authors.initials: SS
authors.lastname: Ng
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
authors.forename: Lars
authors.initials: L
authors.lastname: Olsen
authors.affiliation: Structural Genomics Consortium, University of Oxford, Headington, OX3 7DQ, U.K.|Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Roosevelt Drive, OX3 7FZ, UK.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Brennan
authors.affiliation: Structural Genomics Consortium, University of Oxford, Headington, OX3 7DQ, U.K.|Botnar Research Centre, Oxford Biomedical Research Unit, Oxford OX3 7LD, U.K.
authors.forename: Udo
authors.initials: U
authors.lastname: Oppermann
authors.affiliation: Structural Genomics Consortium, University of Oxford, Headington, OX3 7DQ, U.K.
authors.forename: Susanne
authors.initials: S
authors.lastname: Muller-Knapp
authors.affiliation: Epigenetic Regulation of Chromatin Function Group, Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, U.K.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Klose
authors.affiliation: Henry Wellcome Building for Molecular Physiology, Nuffield Department of Medicine, University of Oxford, Roosevelt Drive, Oxford OX3 7LD, U.K.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Ratcliffe
authors.affiliation: Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA, U.K.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Schofield
authors.affiliation: Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA, U.K.|Division of Cardiovascular Medicine, Radcliffe Department of Medicine, Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford, OX3 7LD, UK.
authors.forename: Akane
authors.initials: A
authors.lastname: Kawamura