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Literature summary for 1.14.11.69 extracted from

  • Couture, J.; Collazo, E.; Ortiz-Tello, P.A.; Brunzelle, J.S.; Trievel, R.C.
    Specificity and mechanism of JMJD2A, a trimethyllysine-specific histone demethylase (2007), Nat. Struct. Mol. Biol., 14, 689-695 .
    View publication on PubMed

Cloned(Commentary)

Cloned (Comment) Organism
gene KDM4A, recombinant expression of His-tagged enzyme in Escherichia coli strain Rosetta 2 (DE3) Homo sapiens

Crystallization (Commentary)

Crystallization (Comment) Organism
purified JMJD2A catalytic domain in complex with H3K9me3, H3K36me2 and H3K36me3 peptides, vapor diffusion method, from 0.2 M sodium/potassium phosphate, pH 6.5, and 20% w/v PEG 3350, at 4°C, and by microseeding from 12% w/v PEG monomethyl ether 5000 and 0.1 M HEPES, pH 7.0, X-ray diffraction structure determination and analysis at 2.05-2.30 A resolution Homo sapiens
structures of the JMJD2A catalytic domain in complex with H3K9me3, H3K36me2 and H3K36me3 peptides. The histone substrates are recognized through a network of backbone hydrogen bonds and hydrophobic interactions that deposit the trimethyllysine into the active site. The trimethylated epsilon-ammonium cation is coordinated within a methylammonium-binding pocket through carbonoxygen hydrogen bonds that position one of the theta-methyl groups adjacent to the Fe(II) center for hydroxylation and demethylation Homo sapiens

Protein Variants

Protein Variants Comment Organism
D191A site-directed mutagenesis, the mutant shows about 95%reduced activity with H3K9me3 compared to wild-type, and no activity with H3K36me3 Homo sapiens
N290A site-directed mutagenesis, the mutant shows no activity with H3K36me3 and almost no activity with H3K9me3 Homo sapiens
N290D site-directed mutagenesis, the mutant shows about 98%reduced activity with H3K9me3 compared to wild-type, and no activity with H3K36me3 Homo sapiens
S288A mutation augments activity, particularly toward H3K9me2 Homo sapiens
S288A mutations of the residues comprising the methylammonium-binding pocket abrogate demethylation by JMJD2A, with the exception of an S288A substitution, which augments activity, particularly toward H3K9me2 Homo sapiens
Y175F site-directed mutagenesis, the mutant shows about 90%reduced activity with H3K9me3 compared to wild-type, and no activity with H3K36me3 Homo sapiens
Y177F site-directed mutagenesis, the mutant shows about 90%reduced activity with H3K9me3 compared to wild-type, and no activity with H3K36me3 Homo sapiens

KM Value [mM]

KM Value [mM] KM Value Maximum [mM] Substrate Comment Organism Structure
0.32
-
[histone H3]-N6,N6,N6-trimethyllysine36 pH 7.3, 37°C Homo sapiens
0.32
-
[histone H3]-N6,N6,N6-trimethyl-L-lysine 36 pH 7.3, 37°C, recombinant enzyme Homo sapiens

Localization

Localization Comment Organism GeneOntology No. Textmining
nucleus
-
Homo sapiens 5634
-

Metals/Ions

Metals/Ions Comment Organism Structure
Fe2+ the carboxylate side chain of Glu190 chelates Fe(II) 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 36 + 2-oxoglutarate + O2 Homo sapiens
-
[histone H3]-N6,N6-dimethyl-L-lysine 36 + succinate + formaldehyde + CO2
-
?
[histone H3]-N6,N6-dimethyl-L-lysine 36 + 2-oxoglutarate + O2 Homo sapiens
-
[histone H3]-N6-methyl-L-lysine 36 + succinate + formaldehyde + CO2
-
?

Organism

Organism UniProt Comment Textmining
Homo sapiens O75164
-
-

Purification (Commentary)

Purification (Comment) Organism
recombinant His-tagged enzyme from Escherichia coli strain Rosetta 2 (DE3) by nickel affinity chromatography and gel filtration Homo sapiens

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
additional information enzyme additionally demethylates H3K9me3, reaction of EC 1.14.11.66 Homo sapiens ?
-
?
additional information JMJD2A is a JmjC histone demethylase (HDM) that catalyzes the demethylation of di- and trimethylated Lys9 and Lys36 in histone H3 (H3K9me2/3 and H3K36me2/3). Trimethylated Lys9 is the best substrate. JMJD2A preferentially demethylates trimethylated substrates. Histone substrates are recognized through a network of backbone hydrogen bonds and hydrophobic interactions that deposit the trimethyllysine into the active site. The trimethylated epsilon-ammonium cation is coordinated within a methylammonium-binding pocket through carbon-oxygen hydrogen bonds that position one of the zeta-methyl groups adjacent to the Fe(II) center for hydroxylation and demethylation. Analysis of the H3K9me3 or H3K36me3 peptide binding structure to the enzyme, overview Homo sapiens ?
-
?
[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
-
?
[histone H3]-N6,N6,N6-trimethyllysine36 + 2 2-oxoglutarate + 2 O2
-
Homo sapiens [histone H3]-N6-methyllysine36 + 2 succinate + 2 formaldehyde + 2 CO2
-
?
[histone H3]-N6,N6,N6-trimethyllysine36 + 2-oxoglutarate + O2
-
Homo sapiens [histone H3]-N6,N6-dimethyllysine36 + succinate + formaldehyde + CO2
-
?
[histone H3]-N6,N6-dimethyl-L-lysine 36 + 2-oxoglutarate + O2
-
Homo sapiens [histone H3]-N6-methyl-L-lysine 36 + succinate + formaldehyde + CO2
-
?
[histone H3]-N6,N6-dimethyllysine36 + 2-oxoglutarate + O2
-
Homo sapiens [histone H3]-N6-methyllysine36 + succinate + formaldehyde + CO2
-
?

Synonyms

Synonyms Comment Organism
JMJD2A
-
Homo sapiens
KDM4A
-
Homo sapiens
More see also EC 1.14.11.66 Homo sapiens
trimethyllysine-specific histone demethylase
-
Homo sapiens

Temperature Optimum [°C]

Temperature Optimum [°C] Temperature Optimum Maximum [°C] Comment Organism
37
-
assay at Homo sapiens

Turnover Number [1/s]

Turnover Number Minimum [1/s] Turnover Number Maximum [1/s] Substrate Comment Organism Structure
0.000217
-
[histone H3]-N6,N6,N6-trimethyl-L-lysine 36 pH 7.3, 37°C, recombinant enzyme Homo sapiens
0.00022
-
[histone H3]-N6,N6,N6-trimethyllysine36 pH 7.3, 37°C Homo sapiens

pH Optimum

pH Optimum Minimum pH Optimum Maximum Comment Organism
7.3
-
assay at Homo sapiens

General Information

General Information Comment Organism
evolution JMJD2A is a JmjC histone demethylase (HDM) Homo sapiens
malfunction mutations of the residues comprising the methylammonium-binding pocket abrogate demethylation by JMJD2A, with the exception of an S288A substitution, which augments activity, particularly toward H3K9me2 Homo sapiens
additional information residue S288 modulates the methylation-state specificities of JMJD2 enzymes and other trimethyllysine-specific JmjC HDMs. The mechanisms by which JMJD2A discriminates against the demethylation of H3K4me and H4K20me. An alignment of the H3K4, H3K9, H3K36 and H4K20 methylation sites reveals substantial sequence diversity among the methylation motifs. The methylammonium-binding pocket is composed of the carbonyl oxygen of Gly170, the hydroxyl groups of Tyr177 and Ser288, and the carboxylate side chain of Glu190. Active site site structure with bound substrate, overview Homo sapiens

kcat/KM [mM/s]

kcat/KM Value [1/mMs-1] kcat/KM Value Maximum [1/mMs-1] Substrate Comment Organism Structure
0.00068
-
[histone H3]-N6,N6,N6-trimethyl-L-lysine 36 pH 7.3, 37°C, recombinant enzyme Homo sapiens
0.0069
-
[histone H3]-N6,N6,N6-trimethyllysine36 pH 7.3, 37°C Homo sapiens