Is JmjC oxygenase catalysis limited to demethylation?
Is JmjC oxygenase catalysis limited to demethylation?
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DOI：
10.1002/anie.201303282
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发表时间：
2013-07-22
影响因子：
16.6
通讯作者：
Schofield, Christopher J.
中科院分区：
文献类型：
--
作者：
Hopkinson, Richard J.;Walport, Louise J.;Muenzel, Martin;Rose, Nathan R.;Smart, Tristan J.;Kawamura, Akane;Claridge, Timothy D. W.;Schofield, Christopher J.
组蛋白修饰在转录调控中具有核心重要性。[1，2]虽然组蛋白乙酰化通常是转录激活的，但组蛋白赖氨酸甲基化可以是激活的或抑制的，这取决于包括修饰位点和类型在内的因素。因此，正在寻求组蛋白甲基化的调节以用于基因表达的治疗性调节。[3-6] Nε-甲基赖氨酸组蛋白脱甲基酶的JmjC家族是亚铁和2-酮戊二酸（2 OG）加氧酶，可能存在于所有动物中。[7-9]与黄素依赖性赖氨酸特异性脱甲基酶不同，较大的JmjC脱甲基酶家族接受所有3个Nε-赖氨酸甲基化状态。建议通过羟基化进行JmjC催化，得到半缩醛胺中间体，其片段得到脱甲基产物和甲醛（图1）;然而，迄今为止尚未观察到半缩醛胺。[10虽然已经对JmjC酶的序列和甲基化状态选择性进行了研究[12-15]，但目前还没有关于它们是否可以氧化除甲基以外的N-烷基或它们对赖氨酸侧链的选择性的报道。在这里，我们报告了具有代表性的人类JmjC脱甲基酶的底物选择性研究，揭示了它们对甲基以外的N-烷基基团起作用的潜力，并催化N-甲基以外的基团的羟基化。
Histone modifications are of central importance in the regulation of transcription.[1, 2] Whilst histone acetylation is in general transcriptionally activating, histone lysine methylation can be activating or inhibitory depending on factors including the site and type of modification. Therefore, modulation of histone methylation is being pursued for the therapeutic regulation of gene expression.[3–6]The JmjC family of Nε-methyllysine histone demethylases are ferrous iron and 2-oxoglutarate (2OG) oxygenases that are likely present in all animals.[7–9] Unlike the flavin-dependent lysinespecific demethylases, the larger JmjC demethylase family accepts all 3 Nε-lysine methylation states. JmjC catalysis is proposed to proceed by means of hydroxylation to give a hemiaminal intermediate, which fragments to give the demethylated product and formaldehyde (Figure1); however, to date the hemiaminal has not been observed.[10, 11] Although there have been studies on the sequence and methylation-state selectivities of JmjC enzymes,[12–15] currently there are no reports on whether they can oxidize N-alkyl groups other than methyl or on their selectivity for the lysine side chain. Here we report substrate–selectivity studies with representative human JmjC demethylases, which reveal their potential to act on N-alkyl groups other than methyl, and to catalyze hydroxylation of groups other than N-methyl.
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影响因子：
2.3
作者：
Brooks, PJ;Theruvathu, JA
通讯作者：
Theruvathu, JA
影响因子：
14.8
作者：
Vedadi, Masoud;Barsyte-Lovejoy, Dalia;Liu, Feng;Rival-Gervier, Sylvie;Allali-Hassani, Abdellah;Labrie, Viviane;Wigle, Tim J.;DiMaggio, Peter A.;Wasney, Gregory A.;Siarheyeva, Alena;Dong, Aiping;Tempel, Wolfram;Wang, Sun-Chong;Chen, Xin;Chau, Irene;Mangano, Thomas J.;Huang, Xi-ping;Simpson, Catherine D.;Pattenden, Samantha G.;Norris, Jacqueline L.;Kireev, Dmitri B.;Tripathy, Ashutosh;Edwards, Aled;Roth, Bryan L.;Janzen, William P.;Garcia, Benjamin A.;Petronis, Arturas;Ellis, James;Brown, Peter J.;Frye, Stephen V.;Arrowsmith, Cheryl H.;Jin, Jian
通讯作者：
Jin, Jian
影响因子：
16.8
作者：
Couture, Jean-Francois;Collazo, Evys;Trievel, Raymond C.
通讯作者：
Trievel, Raymond C.
影响因子：
2.9
作者：
Kawamura A;Tumber A;Rose NR;King ON;Daniel M;Oppermann U;Heightman TD;Schofield C
通讯作者：
Schofield C
影响因子：
7.3
作者：
Rose NR;Woon EC;Tumber A;Walport LJ;Chowdhury R;Li XS;King ON;Lejeune C;Ng SS;Krojer T;Chan MC;Rydzik AM;Hopkinson RJ;Che KH;Daniel M;Strain-Damerell C;Gileadi C;Kochan G;Leung IK;Dunford J;Yeoh KK;Ratcliffe PJ;Burgess-Brown N;von Delft F;Muller S;Marsden B;Brennan PE;McDonough MA;Oppermann U;Klose RJ;Schofield CJ;Kawamura A
通讯作者：
Kawamura A