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Literature summary extracted from

  • Marmorstein, R.; Trievel, R.C.
    Histone modifying enzymes structures, mechanisms, and specificities (2009), Biochim. Biophys. Acta, 1789, 58-68 .
    View publication on PubMedView publication on EuropePMC

Crystallization (Commentary)

EC Number Crystallization (Comment) Organism
1.14.11.66 crystal structure determinations of JMJD2A in complex with histone H3 peptides bearing different methylated forms of K9 and K36 Homo sapiens
1.14.11.69 crystal structure determinations of JMJD2A in complex with histone H3 peptides bearing different methylated forms of K9 and K36 Homo sapiens
1.14.99.66 crystal structure determination of LSD1/CoREST complex bound to histone H3 peptides, and of LSD1 complexed with a suicide inhibitor consisting of a 21-residue histone H3 peptide in which K4 is modified by an N-methylpropargyl group Homo sapiens

Protein Variants

EC Number Protein Variants Comment Organism
1.14.11.66 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
1.14.11.66 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
1.14.11.69 additional information 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

Inhibitors

EC Number Inhibitors Comment Organism Structure
1.14.11.66 N-oxalylglycine NOG, a nonreactive 2-oxoglutarate analogue Homo sapiens
1.14.11.66 Ni2+ substitutes for Fe(II) and inhibits the hydroxylation reaction Homo sapiens
1.14.11.69 N-oxalylglycine NOG, a nonreactive 2-OG analogue Homo sapiens
1.14.11.69 Ni2+ substitutes for Fe(II) and inhibits the hydroxylation reaction Homo sapiens
1.14.99.66 additional information a suicide inhibitor consisting of a 21-residue histone H3 peptide, in which K4 is modified by an N-methylpropargyl group, forms a covalent adduct with the reactive N5 atom of the flavin isoalloxazine ring via the N-methylpropargyl group, permitting the visualization of the first seven residues in the histone H3 peptide in the crystal structure. The residues adopt three successive gamma-turns, resulting in an approximately W-shaped conformation of the H3 peptide backbone. The inhibitor and LSD1 interact through a series of main and side chain hydrogen bonds and van der Waals contacts, further stabilizing the compact conformation of the H3 peptide. Notable interactions with the inhibitor include hydrogen bonds to its R2 and Q5 side chains and a salt bridge interaction between the alpha-amine of A1 and Asp555 in LSD. The addition of acetyl or glycyl blocking groups to the N-terminus of the H3K4me2 peptide or the substitution of the epsilon-amine of A1 with a methyl group disrupts the ionic interaction between Asp555 in LSD1 and the H3 peptide alpha-amine, diminishing specificity over 20fold. And analysis of the LSD1/CoREST-C complex co-crystallized with a 20-residue histone H3 peptide inhibitor in which Lys4 is mutated to a methionine (H3K4M). The overall conformation of the H3K4M peptide is roughly U-shaped, a binding mode that is strikingly different than the gamma-turn geometry adopted by the suicide inhibitor. The peptide's binding is stabilized by a complex network of intramolecular hydrogen bonds and intermolecular hydrogen bonds and van der Waals contacts with residues comprising the substrate binding cleft of LSD1. In particular, multiple hydrogen bonds and salt bridge interactions with the guanidinium groups of R2 and R8 in H3K4M appear to be important in maintaining the peptide's conformation and interactions with LSD1. This binding mode positions M4, which functions as a methyllysine mimic, into the pocket adjacent to the flavin moiety of FAD. Modeling of K4me2 based on the coordinates of the M4 side chain indicates that the dimethyl epsilon-amine group is at an appropriate distance for hydride transfer to the N5 atom in the FAD isoalloxazine ring Homo sapiens

Localization

EC Number Localization Comment Organism GeneOntology No. Textmining
1.14.11.66 nucleus
-
Homo sapiens 5634
-
1.14.99.66 nucleus
-
Homo sapiens 5634
-

Metals/Ions

EC Number Metals/Ions Comment Organism Structure
1.14.11.66 Fe2+ required Homo sapiens
1.14.11.69 Fe2+ required Homo sapiens

Natural Substrates/ Products (Substrates)

EC Number Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
1.14.11.66 [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
-
?
1.14.11.66 [histone H3]-N6,N6-dimethyl-L-lysine 9 + 2-oxoglutarate + O2 Homo sapiens
-
[histone H3]-N6-methyl-L-lysine 9 + succinate + formaldehyde + CO2
-
?
1.14.11.69 [histone H3]-N6,N6,N6-trimethyl-L-lysine 36 + 2-oxoglutarate + O2 Homo sapiens
-
[histone H3]-N6,N6-dimethyl-L-lysine 36 + succinate + formaldehyde + CO2
-
?
1.14.11.69 [histone H3]-N6,N6-dimethyl-L-lysine 36 + 2-oxoglutarate + O2 Homo sapiens
-
[histone H3]-N6-methyl-L-lysine 36 + succinate + formaldehyde + CO2
-
?
1.14.99.66 [histone H3]-N6,N6-dimethyl-L-lysine 4 + acceptor + H2O Homo sapiens
-
[histone H3]-N6-methyl-L-lysine 4 + formaldehyde + reduced acceptor
-
?
1.14.99.66 [histone H3]-N6,N6-methyl-L-lysine 4 + acceptor + H2O Homo sapiens
-
[histone H3]-L-lysine 4 + formaldehyde + reduced acceptor
-
?

Organism

EC Number Organism UniProt Comment Textmining
1.14.11.66 Homo sapiens O75164
-
-
1.14.11.69 Homo sapiens O75164
-
-
1.14.99.66 Homo sapiens O60341
-
-

Substrates and Products (Substrate)

EC Number Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
1.14.11.66 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 ?
-
?
1.14.11.66 [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
-
?
1.14.11.66 [histone H3]-N6,N6-dimethyl-L-lysine 9 + 2-oxoglutarate + O2
-
Homo sapiens [histone H3]-N6-methyl-L-lysine 9 + succinate + formaldehyde + CO2
-
?
1.14.11.69 additional information human JMJD2A exhibits dual specificity for the trimethylated and, to a lesser extent, the dimethylated forms of H3K9 and H3K36, 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 ?
-
?
1.14.11.69 [histone H3]-N6,N6,N6-trimethyl-L-lysine 36 + 2-oxoglutarate + O2
-
Homo sapiens [histone H3]-N6,N6-dimethyl-L-lysine 36 + succinate + formaldehyde + CO2
-
?
1.14.11.69 [histone H3]-N6,N6-dimethyl-L-lysine 36 + 2-oxoglutarate + O2
-
Homo sapiens [histone H3]-N6-methyl-L-lysine 36 + succinate + formaldehyde + CO2
-
?
1.14.99.66 additional information the enzyme is specific for mono- and dimethylated Lys4 in histone H3 (H3K4me1/2). LSD1 prefers an unmodified alpha-amine three residues preceding the methyllysine in the protein substrate, consistent with its specificity for H3K4me1/2 in vitro. To catalyze efficient demethylation, the enzyme requires H3 peptides at least 16 residues in length. In addition, LSD1 exhibits a strong preference toward H3K4me2 substrates lacking other covalent modifications, including R2me, R8me, S10ph, K9ac, and K14ac. In addition, LSD1 might also by active with mono- and dimethylated Lys9 in histone H3 (H3K9me1/2), cf. EC 3.4.11.66 Homo sapiens ?
-
?
1.14.99.66 [histone H3]-N6,N6-dimethyl-L-lysine 4 + acceptor + H2O
-
Homo sapiens [histone H3]-N6-methyl-L-lysine 4 + formaldehyde + reduced acceptor
-
?
1.14.99.66 [histone H3]-N6,N6-methyl-L-lysine 4 + acceptor + H2O
-
Homo sapiens [histone H3]-L-lysine 4 + formaldehyde + reduced acceptor
-
?

Synonyms

EC Number Synonyms Comment Organism
1.14.11.66 histone lysine demethylase
-
Homo sapiens
1.14.11.66 JMJD2A
-
Homo sapiens
1.14.11.66 KDM4A
-
Homo sapiens
1.14.11.66 More see also EC 1.14.11.69 Homo sapiens
1.14.11.66 trimethyllysine-specific JmjC HDM
-
Homo sapiens
1.14.11.69 histone lysine demethylase
-
Homo sapiens
1.14.11.69 JMJD2A
-
Homo sapiens
1.14.11.69 KDM4A
-
Homo sapiens
1.14.11.69 More see also EC 1.14.11.66 Homo sapiens
1.14.11.69 trimethyllysine-specific JmjC HDM
-
Homo sapiens
1.14.99.66 BHC110
-
Homo sapiens
1.14.99.66 KDM1
-
Homo sapiens
1.14.99.66 KDM1A
-
Homo sapiens
1.14.99.66 KIAA0601
-
Homo sapiens
1.14.99.66 LSD1
-
Homo sapiens
1.14.99.66 lysine specific demethylase 1
-
Homo sapiens

Cofactor

EC Number Cofactor Comment Organism Structure
1.14.99.66 FAD dependent on Homo sapiens

General Information

EC Number General Information Comment Organism
1.14.11.66 malfunction mutations of the G12-G13 motif abrogate H3K9me3 demethylation by JMJD2A Homo sapiens
1.14.11.66 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
1.14.11.66 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
1.14.11.66 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
1.14.11.69 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
1.14.11.69 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
1.14.11.69 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
1.14.99.66 evolution LSD1 belongs to the flavin adenine dinucleotide (FAD)-dependent amino oxidase family and is conserved in Schizosaccharomyces pombe through humans Homo sapiens
1.14.99.66 additional information demethylation by LSD1 is consistent with an amine oxidase-based mechanism in which the methyllysine Nepsilon-CH3 bond is oxidized to an imine intermediate. The reducing equivalents are concomitantly transferred to FAD yielding FADH2, which is recycled to its oxidized state through reduction of molecular oxygen to hydrogen peroxide. The methyllysine imine intermediate subsequently undergoes hydrolysis, resulting in the demethylation of the lysine epsilon-amine group and the release of the byproduct formaldehyde. The reaction mechanism of LSD1 requires a protonatable lysine epsilon-amine for amine oxidation Homo sapiens
1.14.99.66 physiological function LSD1 can repress gene expression through the demethylation H3K4me1/2, this methylation site is associated with transcriptionally poised or active genes. But LSD1 also associates with the androgen receptor (AR) to enhance the expression of AR target genes. LSD1 is implicated in AR-dependent demethylation of H3K9me1/2, a methylation site enriched in silent chromatin. Enzyme Lsd1 demethylate mono- and dimethylated Lys370 in the regulatory domain of the tumor suppressor p53, precluding the binding of the transcriptional coactivator 53BP1. The complexes in which LSD1 resides tightly coordinate its gene regulatory functions and also influence its specificity for histone and non-histone substrates. LSD1 possesses coactivator functions Homo sapiens