组蛋白去甲基化酶
中文名称
通路描述
组蛋白去甲基化酶（KDMs）能够逆转组蛋白的 N-甲基化，并可能作用于其他蛋白质。迄今为止，KDMs 已被证明催化 N-ε甲基化赖氨酸的去甲基化。生物化学上，存在两种具有不同催化机制的 N-ε甲基化赖氨酸去甲基化酶，两者均导致甲基基团氧化生成甲醛。KDM1A（原称 LSD1）属于黄素腺嘌呤二核苷酸（FAD）依赖性氨基酸氧化酶家族。KDM1A 反应机制需要可质子化的赖氨酸ε-氨基，而三甲基化赖氨酸不可用，因此不是 KDM1 的底物。其他 KDMs 属于 Jumonji C（JmjC）结构域家族，它们是单核 Fe(II)依赖性氧酶超家族的 Cupin 超家族成员，具有双链β-螺旋核心折叠结构。它们需要 2-氧代丁酸（2OG）和分子氧作为辅因子，除了生成甲醛外，还产生琥珀酸和二氧化碳。这种羟基化机制不需要可质子化的赖氨酸ε-氨基，因此 JmjC 包含的去甲基化酶能够去甲基化三甲基、二甲基和单甲基赖氨酸。
英文描述
HDMs demethylate histones Histone lysine demethylases (KDMs) are able to reverse N-methylations of histones and probably other proteins. To date KDMs have been demonstrated to catalyse demethylation of N-epsilon methylated lysine residues. Biochemically there are two distinct groups of N-epsilon methylated lysine demethylases with different catalytic mechanisms, both of which result in methyl group oxidation to produce formaldhyde. KDM1A, formerly known as Lysine Specific Demethylase 1 (LSD1), belongs to the flavin adenine dinucleotide (FAD)-dependent amino oxidase family. The KDM1A reaction mechanism requires a protonatable lysine epsilon-amine group, not available in trimethylated lysines, which consequently are not KDM1 substrates. Other KDMs belong to the Jumonji C (JmjC) -domain containing family. These are members of the Cupin superfamily of mononuclear Fe (II)-dependent oxygenases, which are characterised by the presence of a double-stranded beta-helix core fold. They require 2-oxoglutarate (2OG) and molecular oxygen as co-substrates, producing, in addition to formaldehyde, succinate and carbon dioxide. This hydroxylation-based mechanism does not require a protonatable lysine epsilon-amine group and consequently JmjC-containing demethylases are able to demethylate tri-, di- and monomethylated lysines.
The coordinates of post-translational modifications represented and described here follow UniProt standard practice whereby coordinates refer to the translated protein before any further processing. Histone literature typically refers to coordinates of the protein after the initiating methionine has been removed. Therefore the coordinates of post-translated residues in the Reactome database and described here are frequently +1 when compared with the literature.
In general, methylation at histone H3 lysine-5 (H3K4) and lysine-37 (H3K36), including di- and trimethylation at these sites, has been linked to actively transcribed genes (reviewed in Martin & Zhang 2005). In contrast, lysine-10 (H3K9) promoter methylation is considered a repressive mark for euchromatic genes and is also one of the landmark modifications associated with heterochromatin (Peters et al. 2002).
The first reported JmjC-containing demethylases were KDM2A/B (JHDM1A/B, FBXL11/10). These catalyse demethylation of histone H3 lysine-37 when mono- or di-methylated (H3K36Me1/2) (Tsukada et al. 2006). They were found to contain a JmjC catalytic domain, previously implicated in chromatin-dependent functions (Clissold & Ponting 2001). Subsequently, many other JmjC enzymes have been identified and discovered to have lysine demethylase activities with distinct methylation site and state specificities.
KDM3A/B (JHDM2A/B) are specific for mono or di-methylated lysine-10 on histone H3 (H3K9Me1/2) (Yamane et al. 2006, Kim et al. 2012). KDM4A-C (JMJD2A-C/JHDM3A-C) catalyse demethylation of di- or tri-methylated histone H3 at lysine-10 (H3K9Me2/3) (Cloos et al. 2006, Fodor et al. 2006), with a strong preference for Me3 (Whetstine et al. 2007). KDM4D (JMJD2D) also catalyses demethylation of H3K9Me2/3 (Whetstine et al. 2007). KDM4A-C (JHDM3A-C) can also catalyse demethylation of lysine-37 of histone H3 (H3K36Me2/3) (Klose et al. 2006). KDM5A-D (JARID1A-D) catalyses demethylation of di- or tri-methylated lysine-5 of histone H3 (H3K4Me2/3) (Christensen et al. 2007, Klose et al. 2007, Lee et al. 2007, Secombe et al. 2007, Seward et al. 2007, Iwase et al. 2007). KDM6A and KDM6B (UTX/JMJD3) catalyse demethylation of di- or tri-methylated lysine-28 of histone H3 (H3K27Me2/3) (Agger et al. 2007, Cho et al. 2007, De Santra et al. 2007, Lan et al. 2007, Lee et al. 2007).
KDM7A (KIAA1718/JHDM1D) catalyses demethylation of mono- or di-methylated lysine-10 of histone H3 (H3K9Me1/2) and mono- and di-methylated lysine-28 of histone H3 (H3K27Me1/2) (Horton et al. 2010, Huang et al. 2010). PHF8 (JHDM1E) catalyses demethylation of mono- or di-methylated lysine-10 of histone H3 (H3K9Me1/2) and mono-methylated lysine-21 of histone H4 (H4K20Me1) (Loenarz et al. 2010, Horton et al. 2010, Feng et al. 2010, Kleine-Kohlbrecher et al. 2010, Fortschegger et al. 2010, Qi et al. 2010, Liu et al. 2010). PHF2 (JHDM1E) catalyses demethylation of mono- or di-methylated lysine-10 of histone H3 (H3K9Me1/2) (Wen et al, 2010, Baba et al. 2011). JMJD6 was initially characterized as an arginine demethylase that catalyses demethylation of mono or di methylated arginine 3 of histone H3 (H3R2Me1/2) and arginine 4 of histone H4 (H4R3Me1/2) (Chang et al. 2007) although it was subsequently also characterized as a lysine hydroxylase (Webby et al. 2009). N.B. The coordinates of post-translational modifications represented and described here follow UniProt standard practice whereby coordinates refer to the translated protein before any further processing. Histone literature typically refers to coordinates of the protein after the initiating methionine has been removed. Therefore the coordinates of post-translated residues in the Reactome database and described here are frequently +1 when compared with the literature.
The coordinates of post-translational modifications represented and described here follow UniProt standard practice whereby coordinates refer to the translated protein before any further processing. Histone literature typically refers to coordinates of the protein after the initiating methionine has been removed. Therefore the coordinates of post-translated residues in the Reactome database and described here are frequently +1 when compared with the literature.
In general, methylation at histone H3 lysine-5 (H3K4) and lysine-37 (H3K36), including di- and trimethylation at these sites, has been linked to actively transcribed genes (reviewed in Martin & Zhang 2005). In contrast, lysine-10 (H3K9) promoter methylation is considered a repressive mark for euchromatic genes and is also one of the landmark modifications associated with heterochromatin (Peters et al. 2002).
The first reported JmjC-containing demethylases were KDM2A/B (JHDM1A/B, FBXL11/10). These catalyse demethylation of histone H3 lysine-37 when mono- or di-methylated (H3K36Me1/2) (Tsukada et al. 2006). They were found to contain a JmjC catalytic domain, previously implicated in chromatin-dependent functions (Clissold & Ponting 2001). Subsequently, many other JmjC enzymes have been identified and discovered to have lysine demethylase activities with distinct methylation site and state specificities.
KDM3A/B (JHDM2A/B) are specific for mono or di-methylated lysine-10 on histone H3 (H3K9Me1/2) (Yamane et al. 2006, Kim et al. 2012). KDM4A-C (JMJD2A-C/JHDM3A-C) catalyse demethylation of di- or tri-methylated histone H3 at lysine-10 (H3K9Me2/3) (Cloos et al. 2006, Fodor et al. 2006), with a strong preference for Me3 (Whetstine et al. 2007). KDM4D (JMJD2D) also catalyses demethylation of H3K9Me2/3 (Whetstine et al. 2007). KDM4A-C (JHDM3A-C) can also catalyse demethylation of lysine-37 of histone H3 (H3K36Me2/3) (Klose et al. 2006). KDM5A-D (JARID1A-D) catalyses demethylation of di- or tri-methylated lysine-5 of histone H3 (H3K4Me2/3) (Christensen et al. 2007, Klose et al. 2007, Lee et al. 2007, Secombe et al. 2007, Seward et al. 2007, Iwase et al. 2007). KDM6A and KDM6B (UTX/JMJD3) catalyse demethylation of di- or tri-methylated lysine-28 of histone H3 (H3K27Me2/3) (Agger et al. 2007, Cho et al. 2007, De Santra et al. 2007, Lan et al. 2007, Lee et al. 2007).
KDM7A (KIAA1718/JHDM1D) catalyses demethylation of mono- or di-methylated lysine-10 of histone H3 (H3K9Me1/2) and mono- and di-methylated lysine-28 of histone H3 (H3K27Me1/2) (Horton et al. 2010, Huang et al. 2010). PHF8 (JHDM1E) catalyses demethylation of mono- or di-methylated lysine-10 of histone H3 (H3K9Me1/2) and mono-methylated lysine-21 of histone H4 (H4K20Me1) (Loenarz et al. 2010, Horton et al. 2010, Feng et al. 2010, Kleine-Kohlbrecher et al. 2010, Fortschegger et al. 2010, Qi et al. 2010, Liu et al. 2010). PHF2 (JHDM1E) catalyses demethylation of mono- or di-methylated lysine-10 of histone H3 (H3K9Me1/2) (Wen et al, 2010, Baba et al. 2011). JMJD6 was initially characterized as an arginine demethylase that catalyses demethylation of mono or di methylated arginine 3 of histone H3 (H3R2Me1/2) and arginine 4 of histone H4 (H4R3Me1/2) (Chang et al. 2007) although it was subsequently also characterized as a lysine hydroxylase (Webby et al. 2009). N.B. The coordinates of post-translational modifications represented and described here follow UniProt standard practice whereby coordinates refer to the translated protein before any further processing. Histone literature typically refers to coordinates of the protein after the initiating methionine has been removed. Therefore the coordinates of post-translated residues in the Reactome database and described here are frequently +1 when compared with the literature.
所含基因
26 个基因