Aik W

Bagg EA

Brennan P

Bush JT

Chan MC

Che KH

Choi H

Chowdhury R

Donough MA

Hopkinson RJ

Kawamura A

King ON

Klose RJ

Kristensen JBL

Lejeune C

Li XL

Muller-Knapp S

Ng SS

Olse L

Oppermann U

Ratcliffe PJ

Rose NR

Rydzik AM

Schofield CJ

Thinnes CC

Tumber A

Walport LJ

Yapp C

Yeoh KK

Yue WW

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

Newcastle University E-Prints

5-Carboxy-8-hydroxyquinoline is a broad spectrum 2-oxoglutarate oxygenase inhibitor which causes iron translocation

5-Carboxy-8-hydroxyquinoline is a broad spectrum 2-oxoglutarate oxygenase inhibitor which causes iron translocation

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