5-Carboxy-8-hydroxyquinoline is a Broad Spectrum 2-Oxoglutarate Oxygenase Inhibitor which Causes Iron Translocation.

Autor: Hopkinson RJ; Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA, U.K., Tumber A; 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., Yapp C; Structural Genomics Consortium, University of Oxford, Headington, OX3 7DQ, U.K., Chowdhury R; Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA, U.K., Aik W; Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA, U.K., Che KH; Structural Genomics Consortium, University of Oxford, Headington, OX3 7DQ, U.K.; Botnar Research Centre, Oxford Biomedical Research Unit, Oxford OX3 7LD, U.K., Li XS; Epigenetic Regulation of Chromatin Function Group, Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, U.K., Kristensen JBL; 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., King ONF; Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA, U.K., Chan MC; 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., Yeoh KK; 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., Choi H; Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA, U.K., Walport LJ; Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA, U.K., Thinnes CC; Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA, U.K., Bush JT; Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA, U.K., Lejeune C; Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA, U.K., Rydzik AM; Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA, U.K., Rose NR; 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., Bagg EA; Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA, U.K., McDonough MA; Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA, U.K., Krojer T; Structural Genomics Consortium, University of Oxford, Headington, OX3 7DQ, U.K., Yue WW; Structural Genomics Consortium, University of Oxford, Headington, OX3 7DQ, U.K., Ng SS; Structural Genomics Consortium, University of Oxford, Headington, OX3 7DQ, U.K., Olsen L; Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark., Brennan PE; 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., Oppermann U; Structural Genomics Consortium, University of Oxford, Headington, OX3 7DQ, U.K.; Botnar Research Centre, Oxford Biomedical Research Unit, Oxford OX3 7LD, U.K., Muller-Knapp S; Structural Genomics Consortium, University of Oxford, Headington, OX3 7DQ, U.K., Klose RJ; Epigenetic Regulation of Chromatin Function Group, Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, U.K., Ratcliffe PJ; Henry Wellcome Building for Molecular Physiology, Nuffield Department of Medicine, University of Oxford, Roosevelt Drive, Oxford OX3 7LD, U.K., Schofield CJ; Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA, U.K., Kawamura A; 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.
Jazyk: angličtina
Zdroj: Chemical science [Chem Sci] 2013 Aug 01; Vol. 4 (8), pp. 3110-3117.
DOI: 10.1039/C3SC51122G
Abstrakt: 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.
Databáze: MEDLINE