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Lookup NU author(s): Dr Paul Brennan,
Professor Akane Kawamura
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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 proteinligand-induced metal movement.
Author(s): Hopkinson RJ, Tumber A, Yapp C, Chowdhury R, Aik W, Che KH, Li XL, Kristensen JBL, King ON, Chan MC, Yeoh KK, Choi H, Walport LJ, Thinnes CC, Bush JT, Lejeune C, Rydzik AM, Rose NR, Bagg EA, Donough MA, Yue WW, Ng SS, Olse L, Brennan P, Oppermann U, Muller-Knapp S, Klose RJ, Ratcliffe PJ, Schofield CJ, Kawamura A
Publication type: Article
Publication status: Published
Journal: Chemical Science
Online publication date: 10/06/2013
ISSN (print): 2041-6520
ISSN (electronic): 2041-6539
Publisher: Royal Society of Chemistry
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