Pathway
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.
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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.
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). They were found to contain a JmjC catalytic domain, previously implicated in chromatin-dependent functions. 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). KDM4A-C (JMJD2A-C/JHDM3A-C) catalyse demethylation of di- or tri-methylated histone H3 at lysine-10 (H3K9Me2/3), with a strong preference for Me3. KDM4D (JMJD2D) also catalyses demethylation of H3K9Me2/3. KDM4A-C (JHDM3A-C) can also catalyse demethylation of lysine-37 of histone H3 (H3K36Me2/3). KDM5A-D (JARID1A-D) catalyses demethylation of di- or tri-methylated lysine-5 of histone H3 (H3K4Me2/3). 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). 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). PHF2 (JHDM1E) catalyses demethylation of mono- or di-methylated lysine-10 of histone H3 (H3K9Me1/2). 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) although it was subsequently also characterized as a lysine hydroxylase.
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.
What the reference databases state
Statements
26 statements
26 statements · 1 reference database · Subject: HDMs demethylate histones · Sources: Reactome
- ARID5B participates in HDMs demethylate histonesProteinReactome R-HSA-3214842Inferred only
- H3C1; H3C2; H3C3; H3C4; H3C6; H3C7; H3C8; H3C10; H3C11; H3C12 participates in HDMs demethylate histonesProteinReactome R-HSA-3214842Inferred only
- H3C15; H3C14; H3C13 participates in HDMs demethylate histonesProteinReactome R-HSA-3214842Inferred only
- H4C1; H4C2; H4C3; H4C4; H4C5; H4C6; H4C8; H4C9; H4C11; H4C12; H4C13; H4C14; H4C15; H4C16 participates in HDMs demethylate histonesProteinReactome R-HSA-3214842Inferred only
- JMJD6 participates in HDMs demethylate histonesProteinReactome R-HSA-3214842Inferred only
- KDM1A participates in HDMs demethylate histonesProteinReactome R-HSA-3214842Inferred only
- KDM1B participates in HDMs demethylate histonesProteinReactome R-HSA-3214842Inferred only
- KDM2A participates in HDMs demethylate histonesProteinReactome R-HSA-3214842Inferred only
- KDM2B participates in HDMs demethylate histonesProteinReactome R-HSA-3214842Inferred only
- KDM3A participates in HDMs demethylate histonesProteinReactome R-HSA-3214842Inferred only
- KDM3B participates in HDMs demethylate histonesProteinReactome R-HSA-3214842Inferred only
- KDM4A participates in HDMs demethylate histonesProteinReactome R-HSA-3214842Inferred only
Show the remaining 14
- KDM4B participates in HDMs demethylate histonesProteinReactome R-HSA-3214842Inferred only
- KDM4C participates in HDMs demethylate histonesProteinReactome R-HSA-3214842Inferred only
- KDM4D participates in HDMs demethylate histonesProteinReactome R-HSA-3214842Inferred only
- KDM5A participates in HDMs demethylate histonesProteinReactome R-HSA-3214842Inferred only
- KDM5B participates in HDMs demethylate histonesProteinReactome R-HSA-3214842Inferred only
- KDM5C participates in HDMs demethylate histonesProteinReactome R-HSA-3214842Inferred only
- KDM5D participates in HDMs demethylate histonesProteinReactome R-HSA-3214842Inferred only
- KDM6A participates in HDMs demethylate histonesProteinReactome R-HSA-3214842Inferred only
- KDM6B participates in HDMs demethylate histonesProteinReactome R-HSA-3214842Inferred only
- KDM7A participates in HDMs demethylate histonesProteinReactome R-HSA-3214842Inferred only
- PHF2 participates in HDMs demethylate histonesProteinReactome R-HSA-3214842Inferred only
- PHF8 participates in HDMs demethylate histonesProteinReactome R-HSA-3214842Inferred only
- RIOX2 participates in HDMs demethylate histonesProteinReactome R-HSA-3214842Inferred only
- UTY participates in HDMs demethylate histonesProteinReactome R-HSA-3214842Inferred only