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

RJ Hopkinson; A Tumber; C Yapp; R Chowdhury; W Aik; KH Che; XS Li; JBL Kristensen; ONF King; MC Chan; KK Yeoh; H Choi; LJ Walport; CC Thinnes; JT Bush; C Lejeune; AM Rydzik; NR Rose; EA Bagg; MA McDonough; TJ Krojer; WW Yue; SS Ng; Lars Olsen; PE Brennan; U Oppermann; S Muller; RJ Klose; PJ Ratcliffe; CJ Schofield; A Kawamura

doi:10.1039/C3SC51122G

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

RJ Hopkinson, A Tumber, C Yapp, R Chowdhury, W Aik, KH Che, XS Li, JBL Kristensen, ONF King, MC Chan, KK Yeoh, H Choi, LJ Walport, CC Thinnes, JT Bush, C Lejeune, AM Rydzik, NR Rose, EA Bagg, MA McDonoughTJ Krojer, WW Yue, SS Ng, Lars Olsen, PE Brennan, U Oppermann, S Muller, RJ Klose, PJ Ratcliffe, CJ Schofield, A Kawamura

97 Citations (Scopus)

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.

Original language	English
Journal	Chemical Science
Volume	4
Issue number	8
Pages (from-to)	3110-3117
ISSN	2041-6520
DOIs	https://doi.org/10.1039/C3SC51122G
Publication status	Published - 1 Jul 2013

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Hopkinson, RJ., Tumber, A., Yapp, C., Chowdhury, R., Aik, W., Che, KH., Li, XS., Kristensen, JBL., King, ONF., Chan, MC., Yeoh, KK., Choi, H., Walport, LJ., Thinnes, CC., Bush, JT., Lejeune, C., Rydzik, AM., Rose, NR., Bagg, EA., ... Kawamura, A. (2013). 5-Carboxy-8-hydroxyquinoline is a broad spectrum 2-oxoglutarate oxygenase inhibitor which causes iron translocation. Chemical Science, 4(8), 3110-3117. https://doi.org/10.1039/C3SC51122G

Hopkinson, RJ, Tumber, A, Yapp, C, Chowdhury, R, Aik, W, Che, KH, Li, XS, Kristensen, JBL, King, ONF, Chan, MC, Yeoh, KK, Choi, H, Walport, LJ, Thinnes, CC, Bush, JT, Lejeune, C, Rydzik, AM, Rose, NR, Bagg, EA, McDonough, MA, Krojer, TJ, Yue, WW, Ng, SS, Olsen, L, Brennan, PE, Oppermann, U, Muller, S, Klose, RJ, Ratcliffe, PJ, Schofield, CJ & Kawamura, A 2013, '5-Carboxy-8-hydroxyquinoline is a broad spectrum 2-oxoglutarate oxygenase inhibitor which causes iron translocation', Chemical Science, vol. 4, no. 8, pp. 3110-3117. https://doi.org/10.1039/C3SC51122G

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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.",

author = "RJ Hopkinson and A Tumber and C Yapp and R Chowdhury and W Aik and KH Che and XS Li and JBL Kristensen and ONF King and MC Chan and KK Yeoh and H Choi and LJ Walport and CC Thinnes and JT Bush and C Lejeune and AM Rydzik and NR Rose and EA Bagg and MA McDonough and TJ Krojer and WW Yue and SS Ng and Lars Olsen and PE Brennan and U Oppermann and S Muller and RJ Klose and PJ Ratcliffe and CJ Schofield and A Kawamura",

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T1 - 5-Carboxy-8-hydroxyquinoline is a broad spectrum 2-oxoglutarate oxygenase inhibitor which causes iron translocation

AU - Hopkinson, RJ

AU - Tumber, A

AU - Yapp, C

AU - Chowdhury, R

AU - Aik, W

AU - Che, KH

AU - Li, XS

AU - Kristensen, JBL

AU - King, ONF

AU - Chan, MC

AU - Yeoh, KK

AU - Choi, H

AU - Walport, LJ

AU - Thinnes, CC

AU - Bush, JT

AU - Lejeune, C

AU - Rydzik, AM

AU - Rose, NR

AU - Bagg, EA

AU - McDonough, MA

AU - Krojer, TJ

AU - Yue, WW

AU - Ng, SS

AU - Olsen, Lars

AU - Brennan, PE

AU - Oppermann, U

AU - Muller, S

AU - Klose, RJ

AU - Ratcliffe, PJ

AU - Schofield, CJ

AU - Kawamura, A

PY - 2013/7/1

Y1 - 2013/7/1

N2 - 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.

AB - 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.

U2 - 10.1039/C3SC51122G

DO - 10.1039/C3SC51122G

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SN - 2041-6520

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JO - Chemical Science

JF - Chemical Science

IS - 8

ER -

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

Abstract

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