Ribosomal oxygenases are structurally conserved from prokaryotes to humans. by Chowdhury, R, Sekirnik, R, Brissett, N, Krojer, T, Ho, C, Ng, S, Clifton, I, Ge, W, Kershaw, N, Fox, G, Muniz, JR, Vollmar, M, Phillips, C, Pilka, E, Kavanagh, K, von Delft, F, Oppermann, U, McDonough, M, Doherty, A, Schofield, C

“…Despite differences in the residue and protein selectivities of prokaryotic and eukaryotic ROXs, comparison of the crystal structures of E. coli YcfD and Rhodothermus marinus YcfD with those of human MINA53 and NO66 reveals highly conserved folds and novel dimerization modes defining a new structural subfamily of 2OG-dependent oxygenases. ROX structures with and without their substrates support their functional assignments as hydroxylases but not demethylases, and reveal how the subfamily has evolved to catalyse the hydroxylation of different residue side chains of ribosomal proteins. …”

Ribosomal oxygenases are structurally conserved from prokaryotes to humans. by Chowdhury, R, Sekirnik, R, Brissett, N, Krojer, T, Ho, C, Ng, S, Clifton, I, Ge, W, Kershaw, N, Fox, G, Muniz, JR, Vollmar, M, Phillips, C, Pilka, E, Kavanagh, K, von Delft, F, Oppermann, U, McDonough, M, Doherty, A, Schofield, C

“…Despite differences in the residue and protein selectivities of prokaryotic and eukaryotic ROXs, comparison of the crystal structures of E. coli YcfD and Rhodothermus marinus YcfD with those of human MINA53 and NO66 reveals highly conserved folds and novel dimerization modes defining a new structural subfamily of 2OG-dependent oxygenases. ROX structures with and without their substrates support their functional assignments as hydroxylases but not demethylases, and reveal how the subfamily has evolved to catalyse the hydroxylation of different residue side chains of ribosomal proteins. …”

Inhibitor scaffolds for 2-oxoglutarate-dependent histone lysine demethylases. by Rose, N, Ng, S, Mecinović, J, Liénard, B, Bello, S, Sun, Z, McDonough, M, Oppermann, U, Schofield, C

“…Here we describe a variety of inhibitor scaffolds that inhibit the human 2-oxoglutarate-dependent JMJD2 subfamily of histone demethylases. Combined with structural data, these chemical starting points will be useful to generate small-molecule probes to analyze the physiological roles of these enzymes in epigenetic signaling.…”

Inhibitor scaffolds for 2-oxoglutarate-dependent histone lysine demethylases. by Rose, N, Ng, S, Mecinović, J, Liénard, B, Bello, S, Sun, Z, McDonough, M, Oppermann, U, Schofield, C

“…Here we describe a variety of inhibitor scaffolds that inhibit the human 2-oxoglutarate-dependent JMJD2 subfamily of histone demethylases. Combined with structural data, these chemical starting points will be useful to generate small-molecule probes to analyze the physiological roles of these enzymes in epigenetic signaling.…”

A selective inhibitor and probe of the cellular functions of Jumonji C domain-containing histone demethylases. by Luo, X, Liu, Y, Kubicek, S, Myllyharju, J, Tumber, A, Ng, S, Che, K, Podoll, J, Heightman, T, Oppermann, U, Schreiber, S, Wang, X

“…The inhibitor derives from a structure-based design and preferentially inhibits the subfamily of trimethyl lysine demethylases. Its methyl ester prodrug, methylstat, selectively inhibits Jumonji C domain-containing his-tone demethylases in cells and may be a useful small-molecule probe of chromatin and its role in epigenetics.…”

Structure-activity relationships of human AKR-type oxidoreductases involved in bile acid synthesis: AKR1D1 and AKR1C4. by Lee, W, Lukacik, P, Guo, K, Ugochukwu, E, Kavanagh, K, Marsden, B, Oppermann, U

“…Based on the evidence gathered from our docking experiments and experimental structures, this tryptophan residue emerges as a major determinant governing substrate specificity of a subset of enzymes belonging to the AKR1 subfamily.…”

Investigations on small molecule inhibitors targeting the histone H3K4 tri-methyllysine binding PHD-finger of JmjC histone demethylases by Bhushan, B, Erdmann, A, Zhang, Y, Belle, R, Johannson, C, Oppermann, U, Hopkinson, R, Schofield, C, Kawamura, A

“…Amiodarone derivatives also bind to H3K4me3-binding PHD-fingers from the KDM7 subfamily. Further work is required to develop potent and selective PHD finger inhibitors.…”

Selective inhibitors of the JMJD2 histone demethylases: combined nondenaturing mass spectrometric screening and crystallographic approaches. by Rose, N, Woon, E, Kingham, G, King, O, Mecinović, J, Clifton, I, Ng, S, Talib-Hardy, J, Oppermann, U, McDonough, M, Schofield, C

“…Here we report studies on the inhibition of the JMJD2 subfamily of histone demethylases, employing binding analyses by nondenaturing mass spectrometry (MS), dynamic combinatorial chemistry coupled to MS, turnover assays, and crystallography. …”

Identification of the 2-benzoxazol-2-yl-phenol scaffold as new hit for JMJD3 inhibition by Giordano, A, Forte, G, Terracciano, S, Russo, A, Sala, M, Scala, M, Johansson, C, Oppermann, U, Riccio, R, Bruno, I, Di Micco, S

“…JMJD3 is a member of the KDM6 subfamily and catalyzes the demethylation of lysine 27 on histone H3 (H3K27). …”

Structural and mechanistic studies on γ-butyrobetaine hydroxylase. by Leung, I, Krojer, T, Kochan, G, Henry, L, von Delft, F, Claridge, T, Oppermann, U, McDonough, M, Schofield, C

“…Crystallographic and sequence analyses reveal that BBOX and trimethyllysine hydroxylase form a subfamily of 2OG oxygenases that dimerize using an N-terminal domain. …”

Structural and mechanistic studies on γ-butyrobetaine hydroxylase. by Leung, I, Krojer, T, Kochan, G, Henry, L, von Delft, F, Claridge, T, Oppermann, U, McDonough, M, Schofield, C

“…Crystallographic and sequence analyses reveal that BBOX and trimethyllysine hydroxylase form a subfamily of 2OG oxygenases that dimerize using an N-terminal domain. …”

Human UTY(KDM6C) is a male-specific Nϵ-methyl lysyl demethylase. by Walport, L, Hopkinson, R, Vollmar, M, Madden, S, Gileadi, C, Oppermann, U, Schofield, C, Johansson, C

“…KDM6A (UTX) and KDM6B (JMJD3) are KDM6 subfamily members that catalyze demethylation of N(ϵ)-methylated histone 3 lysine 27 (H3K27), a mark important for transcriptional repression. …”

Structure-activity relationships of human AKR-type oxidoreductases involved in bile acid synthesis: AKR1D1 and AKR1C4. by Lee, W, Lukacik, P, Guo, K, Ugochukwu, E, Kavanagh, K, Marsden, B, Oppermann, U

“…Based on the evidence gathered from our docking experiments and experimental structures, this tryptophan residue emerges as a major determinant governing substrate specificity of a subset of enzymes belonging to the AKR1 subfamily.…”

Selective inhibitors of the JMJD2 histone demethylases: combined nondenaturing mass spectrometric screening and crystallographic approaches. by Rose, N, Woon, E, Kingham, G, King, O, Mecinović, J, Clifton, I, Ng, S, Talib-Hardy, J, Oppermann, U, McDonough, M, Schofield, C

“…Here we report studies on the inhibition of the JMJD2 subfamily of histone demethylases, employing binding analyses by nondenaturing mass spectrometry (MS), dynamic combinatorial chemistry coupled to MS, turnover assays, and crystallography. …”

8-substituted pyrido[3,4-d]pyrimidin-4(3H)-one derivatives as potent, cell permeable, KDM4 (JMJD2) and KDM5 (JARID1) histone lysine demethylase inhibitors by Bavetsias, V, Lanigan, R, Ruda, G, Atrash, B, McLaughlin, M, Tumber, A, Mok, N, Le Bihan, Y, Dempster, S, Boxall, K, Jeganathan, F, Hatch, S, Savitsky, P, Velupillai, S, Krojer, T, England, K, Sejberg, J, Thai, C, Donovan, A, Pal, A, Scozzafava, G, Bennett, J, Kawamura, A, Johansson, C, Szykowska, A, Gileadi, C, Burgess-Brown, N, von Delft, F, Oppermann, U, Walters, Z, Shipley, J, Raynaud, F, Westaway, S, Prinjha, R, Fedorov, O, Burke, R, Schofield, C, Westwood, I, Bountra, C, Müller, S, van Montfort, R, Brennan, P, Blagg, J

“…Substitution from C4 of the pyrazole moiety allows access to the histone peptide substrate binding site; incorporation of a conformationally constrained 4-phenylpiperidine linker gives derivatives such as 54j and 54k which demonstrate equipotent activity versus the KDM4 (JMJD2) and KDM5 (JARID1) subfamily demethylases, selectivity over representative exemplars of the KDM2, KDM3, and KDM6 subfamilies, cellular permeability in the Caco-2 assay, and, for 54k, inhibition of H3K9Me3 and H3K4Me3 demethylation in a cell-based assay.…”

Structure of human phytanoyl-CoA 2-hydroxylase identifies molecular mechanisms of Refsum disease. by McDonough, M, Kavanagh, K, Butler, D, Searls, T, Oppermann, U, Schofield, C

“…PAHX may be the first of a new subfamily of coenzyme A-binding 2OG oxygenases.…”

Studies on the interaction of the histone demethylase KDM5B with tricarboxylic acid cycle intermediates by Tarhonskaya, H, Nowak, RP, Johansson, C, Szykowska, A, Tumber, A, Hancock, RL, Lang, P, Flashman, E, Oppermann, U, Schofield, CJ, Kawamura, A

“…Removal of the transcriptionally activating H3K4 methylation is catalyzed by histone demethylases, including the Jumonji C (JmjC) KDM5 subfamily. The JmjC KDMs are Fe(II) and 2-oxoglutarate (2OG)-dependent oxygenases, some of which are associated with cancer. …”

Assessing histone demethylase inhibitors in cells: lessons learned by Hatch, S, Yapp, C, Montenegro, R, Savitsky, P, Gamble, V, Tumber, A, Ruda, G, Bavetsias, V, Fedorov, O, Atrash, B, Raynaud, F, Lanigan, R, Carmichael, L, Tomlin, K, Burke, R, Westway, S, Brown, J, Prinjha, R, Martinez, E, Oppermann, U, Schofield, C, Bountra, C, Kawamura, A, Blagg, J, Brennan, P, Rossanese, O, Müller, S

“…<br/><br/> Results<br/> A panel of assays for the Jumonji C subfamily of KDMs was developed to encompass all major branches of the JmjC phylogenetic tree. …”

Development of biochemical tools to characterise human H3K27 histone demethylase JmjD3 by Che, KH

“…JmjD3 is a JumonjiC domain containing histone demethylase, belongs to the KDM6 subfamily, and catalyses the removal of methyl groups on methylated lysine 27 on histone 3 (H3K27), a critical mark to promote polycomb mediated repression and gene silencing. …”

Coenzyme-based functional assignments of short-chain dehydrogenases/reductases (SDRs). by Persson, B, Kallberg, Y, Oppermann, U, Jörnvall, H

“…Only two of these were known before, called 'Classical' and 'Extended', but are now distinguished at a further level based on patterns of charged residues in the coenzyme-binding region, giving seven subfamilies of classical SDRs and three subfamilies of extended SDRs. …”