| Literature DB >> 26682036 |
Richard J Hopkinson1, Anthony Tumber2,3, Clarence Yapp2, Rasheduzzaman Chowdhury1, WeiShen Aik1, Ka Hing Che2,4, Xuan Shirley Li5, Jan B L Kristensen1,6, Oliver N F King1, Mun Chiang Chan1,7, Kar Kheng Yeoh1,7, Hwanho Choi1, Louise J Walport1, Cyrille C Thinnes1, Jacob T Bush1, Clarisse Lejeune1, Anna M Rydzik1, Nathan R Rose1,5, Eleanor A Bagg1, Michael A McDonough1, Tobias Krojer2, Wyatt W Yue2, Stanley S Ng2, Lars Olsen6, Paul E Brennan2,3, Udo Oppermann2,4, Susanne Muller-Knapp2, Robert J Klose5, Peter J Ratcliffe7, Christopher J Schofield1, Akane Kawamura1,8.
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.Entities:
Year: 2013 PMID： 26682036 PMCID： PMC4678600 DOI： 10.1039/C3SC51122G
Source DB: PubMed Journal: Chem Sci ISSN： 2041-6520 Impact factor: 9.825