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Literature summary for 1.14.11.66 extracted from
- Histone modifying enzymes structures, mechanisms, and specificities (2009), Biochim. Biophys. Acta, 1789, 58-68 .
Crystallization (Commentary)
| Crystallization (Comment) | Organism |
|---|---|
| crystal structure determinations of JMJD2A in complex with histone H3 peptides bearing different methylated forms of K9 and K36 | Homo sapiens |
Protein Variants
| Protein Variants | Comment | Organism |
|---|---|---|
| additional information | mutations of the G12-G13 motif abrogating H3K9me3 demethylation by JMJD2A. Introduction of a di-glycine motif at the +3 to +4 positions of the H3K27 sequence, a site which shares sequence homology with the H3K9 sequence, enables JMJD2A to efficiently demethylate H3K27me3, cf. EC 1.14.11.68 | Homo sapiens |
| S288A | site-directed mutagenesis, the JMJD2A S2888A mutant demonstrates an approximately 12fold increase in H3K9me2 specificity compared to the native enzyme, whereas the converse A291S mutant in JMJD2D reduces H3K9me2 specificity approximately fivefold | Homo sapiens |
Inhibitors
| Inhibitors | Comment | Organism | Structure |
|---|---|---|---|
| N-oxalylglycine | NOG, a nonreactive 2-oxoglutarate analogue | Homo sapiens |  |
| Ni2+ | substitutes for Fe(II) and inhibits the hydroxylation reaction | Homo sapiens | |
Localization
| Localization | Comment | Organism | GeneOntology No. | Textmining |
|---|---|---|---|---|
| nucleus | - |
Homo sapiens | 5634 | - |
Metals/Ions
| Metals/Ions | Comment | Organism | Structure |
|---|---|---|---|
| Fe2+ | required | Homo sapiens | |
Natural Substrates/ Products (Substrates)
| Natural Substrates | Organism | Comment (Nat. Sub.) | Natural Products | Comment (Nat. Pro.) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| [histone H3]-N6,N6,N6-trimethyl-L-lysine 9 + 2-oxoglutarate + O2 | Homo sapiens | - |
[histone H3]-N6,N6-dimethyl-L-lysine 9 + succinate + formaldehyde + CO2 | - |
? | |
| [histone H3]-N6,N6-dimethyl-L-lysine 9 + 2-oxoglutarate + O2 | Homo sapiens | - |
[histone H3]-N6-methyl-L-lysine 9 + succinate + formaldehyde + CO2 | - |
? | |
Organism
| Organism | UniProt | Comment | Textmining |
|---|---|---|---|
| Homo sapiens | O75164 | - |
- |
Substrates and Products (Substrate)
| Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| additional information | human JMJD2A exhibits dual specificity for the trimethylated and, to a lesser extent, the dimethylated forms of H3K9 and H3K36, while other JMJD2 paralogues, such as JMJD2B and JMJD2D, are specific for H3K9me3/me2, with an approximately fivefold preference in specificity for the H3K9me3 substrate due to a higher KM value for the H3K36me3 peptide, suggesting that JMJD2A preferentially recognizes the H3K9me3 site | Homo sapiens | ? | - |
? | |
| [histone H3]-N6,N6,N6-trimethyl-L-lysine 9 + 2-oxoglutarate + O2 | - |
Homo sapiens | [histone H3]-N6,N6-dimethyl-L-lysine 9 + succinate + formaldehyde + CO2 | - |
? | |
| [histone H3]-N6,N6-dimethyl-L-lysine 9 + 2-oxoglutarate + O2 | - |
Homo sapiens | [histone H3]-N6-methyl-L-lysine 9 + succinate + formaldehyde + CO2 | - |
? | |
Synonyms
| Synonyms | Comment | Organism |
|---|---|---|
| histone lysine demethylase | - |
Homo sapiens |
| JMJD2A | - |
Homo sapiens |
| KDM4A | - |
Homo sapiens |
| More | see also EC 1.14.11.69 | Homo sapiens |
| trimethyllysine-specific JmjC HDM | - |
Homo sapiens |
General Information
| General Information | Comment | Organism |
|---|---|---|
| malfunction | mutations of the G12-G13 motif abrogate H3K9me3 demethylation by JMJD2A | Homo sapiens |
| metabolism | many JmjC HDMs appear to function in the context of large multimeric complexes that govern their localization, transcriptional functions, and potentially their substrate specificity. In the case of certain JmjC enzymes, these complexes appear to be critical in conferring specificity for nucleosomal substrates | Homo sapiens |
| additional information | in H3K9me3- and H3K36me3-enzyme complexes, the peptides bind in the same directionality within the substrate binding cleft of JMJD2A, depositing the trimethyllysines into the active site. The majority of the interactions between the enzyme and H3 peptides involve hydrogen bond and van der Waals interactions with the backbone atoms in the substrates. The residues N-terminal to the trimethyllysines adopt a similar beta-strand-like conformation, while the C-terminal residues in the peptides adopt distinct binding modes. Mono-, di-, and trimethyllysines bind within a methylammonium binding pocket adjacent to the Fe(II) and 2-oxoglutarate binding sites in JMJD2A. This pocket is lined with an array of oxygen atoms that participate in direct contacts with zeta-methyl groups of the trimethylated substrate. Structure-activity analysis, overview | Homo sapiens |
| physiological function | JMJD2A is implicated in transcriptional silencing and is associated with the retinoblastoma protein, class I HDACs, and the nuclear corepressor N-CoR. JMJD2A and its paralogue JMJD2D associate with the androgen receptor (AR) to upregulate the expression of AR-dependent genes. The transcriptional functions of JMJD2 enzymes appear to be context-dependent | Homo sapiens |
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