Information on EC 1.14.11.27 - [histone-H3]-lysine-36 demethylase and Organism(s) Homo sapiens and UniProt Accession O75164

Word Map on EC 1.14.11.27
Please wait a moment until all data is loaded. This message will disappear when all data is loaded.
Specify your search results
Select one or more organisms in this record:
This record set is specific for:
Homo sapiens
UNIPROT: O75164
Show additional data
Do not include text mining results
Include (text mining) results (more...)
Include results (AMENDA + additional results, but less precise; more...)


The taxonomic range for the selected organisms is: Homo sapiens

The enzyme appears in selected viruses and cellular organisms

EC NUMBER
COMMENTARY hide
1.14.11.27
-
RECOMMENDED NAME
GeneOntology No.
[histone-H3]-lysine-36 demethylase
SYSTEMATIC NAME
IUBMB Comments
protein-N6,N6-dimethyl-L-lysine,2-oxoglutarate:oxygen oxidoreductase
Requires iron(II). Of the seven potential methylation sites in histones H3 (K4, K9, K27, K36, K79) and H4 (K20, R3) from HeLa cells, the enzyme is specific for Lys-36. Lysine residues exist in three methylation states (mono-, di- and trimethylated). The enzyme preferentially demethylates the dimethyl form of Lys-36 (K36me2), which is its natural substrate, to form the monomethyl and unmethylated forms of Lys-36. It can also demethylate the monomethyl- but not the trimethyl form of Lys-36.
CAS REGISTRY NUMBER
COMMENTARY hide
55071-98-2
-
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
evolution
human JMJD2 (KDM4) H3K9 and H3K36 demethylases can be divided into members that act on both H3K9 and H3K36 and H3K9 alone, structural and phylogenetic analysis, overview. KDM4A/B/C act on both H3K9 and, less efficiently, on H3K36-methylated substrates, substrate selectivity of the human KDM4 histone demethylase subfamily, overview
evolution
malfunction
physiological function
additional information
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
histone H3-N6,N6,N6-trimethyl-L-lysine36 + 2-oxoglutarate + O2
histone H3-N6,N6-dimethyl-L-lysine36 + succinate + formaldehyde + CO2
show the reaction diagram
histone H3-N6,N6-dimethyl-L-lysine36 + 2-oxoglutarate + O2
histone H3-N6-methyl-L-lysine36 + succinate + formaldehyde + CO2
show the reaction diagram
[histone H3]-N6,N6,N6-trimethyl-L-lysine36 + 2-oxoglutarate + O2
[histone H3]-L-lysine36 + succinate + formaldehyde + CO2
show the reaction diagram
[histone H3]-N6,N6-dimethyl-L-lysine36 + 2-oxoglutarate + O2
[histone H3]-L-lysine36 + succinate + formaldehyde + CO2
show the reaction diagram
-
-
-
?
histone H3-N6,N6,N6-trimethyl-L-lysine36 + 2-oxoglutarate + O2
histone H3-N6,N6-dimethyl-L-lysine36 + succinate + formaldehyde + CO2
show the reaction diagram
histone H3-N6,N6-dimethyl-L-lysine36 + 2-oxoglutarate + O2
histone H3-N6-methyl-L-lysine36 + succinate + formaldehyde + CO2
show the reaction diagram
protein C/EBPalpha-N6,N6-dimethyl-L-lysine + 2-oxoglutarate + O2
protein C/EBPalpha-N6-methyl-L-lysine + succinate + formaldehyde + CO2
show the reaction diagram
protein N6,N6-dimethyl-L-lysine + 2-oxoglutarate + O2
protein N6-methyl-L-lysine + succinate + formaldehyde + CO2
show the reaction diagram
-
specifically demethylates Lys36 of histone H3
-
-
?
protein N6-methyl-L-lysine + 2-oxoglutarate + O2
protein L-lysine + succinate + formaldehyde + CO2
show the reaction diagram
-
specifically demethylates Lys36 of histone H3
-
-
?
trimethyl-histone 3 L-lysine 36 + 2-oxoglutarate + O2
dimethyl-histone 3 L-lysine 36 + ?
show the reaction diagram
-
-
-
?
[histone H3]-N6,N6-dimethyl-L-lysine36 + 2-oxoglutarate + O2
[histone H3]-L-lysine36 + succinate + formaldehyde + CO2
show the reaction diagram
-
-
-
-
?
additional information
?
-
NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
histone H3-N6,N6,N6-trimethyl-L-lysine36 + 2-oxoglutarate + O2
histone H3-N6,N6-dimethyl-L-lysine36 + succinate + formaldehyde + CO2
show the reaction diagram
O75164, Q9H3R0
-
-
-
?
histone H3-N6,N6-dimethyl-L-lysine36 + 2-oxoglutarate + O2
histone H3-N6-methyl-L-lysine36 + succinate + formaldehyde + CO2
show the reaction diagram
O75164, Q9H3R0
-
-
-
?
[histone H3]-N6,N6,N6-trimethyl-L-lysine36 + 2-oxoglutarate + O2
[histone H3]-L-lysine36 + succinate + formaldehyde + CO2
show the reaction diagram
O75164
JMJD2A is a trimethyllysine-specific JmjC HDM
-
-
?
[histone H3]-N6,N6-dimethyl-L-lysine36 + 2-oxoglutarate + O2
[histone H3]-L-lysine36 + succinate + formaldehyde + CO2
show the reaction diagram
O75164
-
-
-
?
histone H3-N6,N6,N6-trimethyl-L-lysine36 + 2-oxoglutarate + O2
histone H3-N6,N6-dimethyl-L-lysine36 + succinate + formaldehyde + CO2
show the reaction diagram
O75164, Q9H3R0
-
-
-
?
histone H3-N6,N6-dimethyl-L-lysine36 + 2-oxoglutarate + O2
histone H3-N6-methyl-L-lysine36 + succinate + formaldehyde + CO2
show the reaction diagram
protein C/EBPalpha-N6,N6-dimethyl-L-lysine + 2-oxoglutarate + O2
protein C/EBPalpha-N6-methyl-L-lysine + succinate + formaldehyde + CO2
show the reaction diagram
-
Jhdm1a actively demethylates dimethylated H3K36 on the C/EBPalpha locus
-
-
?
[histone H3]-N6,N6-dimethyl-L-lysine36 + 2-oxoglutarate + O2
[histone H3]-L-lysine36 + succinate + formaldehyde + CO2
show the reaction diagram
-
-
-
-
?
additional information
?
-
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Fe2+
required for activity
Iron
-
the mechansim for achieving methylation state selectivity involves the orientation of the substrate methyl groups towards a ferryl intermediate
Zn2+
structure of Zn2+ binding sites of the isozymes, overview
Fe2+
-
required
Iron
-
Fe(II) center
Zn2+
structure of Zn2+ binding sites of the isozymes, overview
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
N-oxalylglycine
i.e. NOG, a non-reactive 2-oxoglutarate analogue
Ni2+
substitutes Fe2+ and inhibits the hydroxylation reaction
Co2+
-
cobalt ions increase H3K9me3 and H3K36me3 by inhibiting histone demethylation process. Cobalt ions do not affect JMJD2A protein level but directly inhibit its demethylase activity. Exposure of both lung carcinoma A-549 cells and bronchial epithelial Beas-2B cells, to CoCl2 at 0.2 mM for 24 h increases methylation of histone H3 lysine residues 4, 9, 27 and 36, i.e. H3K4me3, H3K9me2, H3K9me3, H3K27me3, H3K36me3, as well as ubiquitination of histone H2A and H2B, while it decreases acetylation at histone H4, overview
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
ascorbate
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.32
trimethyl-histone 3 L-lysine 36
-
pH 7.3, 37°C
-
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.00022
trimethyl-histone 3 L-lysine 36
Homo sapiens
-
pH 7.3, 37°C
-
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
7.5
assay at
8
-
assay at
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
-
high expression level of KDM2b/JHDM1b
Manually annotated by BRENDA team
additional information
-
KDM4A is amplified and overexpressed in several tumor types
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
PDB
SCOP
CATH
ORGANISM
UNIPROT
-
-
-
-
-
Crystallization/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
crystallization of JMJD2A in complex with histone H3 peptides bearing different methylated forms of K9 and K36, cocrystallization of inactivated substrate with either N-oxalylglycine, a non-reactive 2-OG analog, or with Ni(II), which substitutes for Fe(II) and inhibits the hydroxylation reaction. Structures analysis, overview
structures of JMJD2A–Ni(II)–Zn(II) inhibitor complexes bound to tri-, di- and monomethyl forms of histone 3 lysine 9 andthe trimethyl form of histone 3 lysine 36. The structures reveal a lysyl-binding pocket in which substrates are bound in distinct bent conformations involving the Zn-binding site. The mechansim for achieving methylation state selectivity involves the orientation of the substrate methyl groups towards a ferryl intermediate
-
structures of the catalytic core complexed with methylated histone 3 L-lysine36 peptide substrates in the presence of Fe(II) and N-oxalylglycine. The interaction between enzyme and peptides largely involves the main chains of the enzyme and the peptide. The peptide-binding specificity is primarily determined by the primary structure of the peptide
in complex with trimethyl-histone 3 L-lysine 9, dimethyl-histone 3 L-lysine 36, and trimethyl-histone 3 L-lysine 36, and N-oxalylglycine, 2-oxoglutarate, and succinate, respectively. 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 methyl groups adjacent to the Fe(II) center for hydroxylation and demethylation
-
purified recombinant fusion protein, JMJD5 catalytic domain in complex with substrate 2-oxoglutarate and inhibitor N-oxalylglycine, hanging drop vapor diffusion, mixing of 12 mg/ml protein in for the inhibitor complex 15 mM bis-Tris, pH 7.2, 25 mM NaCl, 1.0 mM dithiothreitol, 1.0 mM N--oxalylglycine, and 0.5 mM CoCl2, or for te substrate complex in 15mM Tris, pH 8.5, 25 mM NaCl, 1.5 mM 2-oxoglutarate, 1.5 mM dithiothreitol, and 4 mM H3K36me2-L peptide, ,with an equal volume of mother liquor containing 4.5% w/v PEG 3000, 0.1M bis-Tris, pH 5.5, and 50 mM MgCl2, 20°C, X-ray diffraction structure determination and analysis at 1.05-1.15 A resolution
purified recombinant KDM4C, sitting drop vapor diffusion method, mixing of 7 mg/ml protein with 2 mM N-oxalylglycine with well solution, containing 25% v/v PEG 3350, 0.2 M sodium nitrate, 0.1 M Bis tris propane, pH 6.5, 5% v/v ethylene glycol, 0.01 M NiCl2, in a 2:1 ratio, 4°C, X-ray diffraction structure determination and analysis at 2.55 A resolution
Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
recombinant N-terminally His-tagged KDM4A from Escherichia coli by nickel affinity chromatography
recombinant enzyme purified from baculovirus-infected Sf9 cells
-
recombinant fusion proteins His6-Smt3-JMJD5183–416 and His6-Smt3-JMJD52–416 from Escherichia coli strain BL21 Rosetta2 DE3 by nickel affinity chromatography and gel filtration
recombinant N-terminally His-tagged KDM4B from Escherichia coli by nickel affinity chromatography
recombinant N-terminally His-tagged KDM4C from Escherichia coli by nickel affinity chromatography
Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
expression of N-terminally His-tagged KDM4A in Escherichia coli
ectopic expression of Jhdm1a in HeLa and wild-type and enzyme-deficient Hep-G2 cells via lentivirus transfection
-
enzyme overexpression in HEK-293T cells, phenotype,, overview
-
expression in Escherichia coli, His-tagged
-
expression of FLAG-tagged JMJD2A in Spodoptera frugiperda Sf9 cells
-
expression of fusion proteins His6-Smt3-JMJD5183–416 and His6-Smt3-JMJD52–416 in Escherichia coli strain BL21 Rosetta2 DE3
expression of N-terminally His-tagged KDM4B in Escherichia coli
expression of N-terminally His-tagged KDM4C in Escherichia coli
ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
S288A
the mutant displays enhanced specificity for H3K9me2 and H3K36me2 without altering activity toward trimethyllysines, consistent with the H3K9me2/3 specificity of JMJD2D which possesses an alanine, Ala29, in this position. Kinetic analysis of S288A mutant shows a 12fold increase in H3K9me2 specificity versus the native enzyme, whereas the converse A291S mutant in JMJD2D reduces H3K9me2 specificity approximately fivefold
H188A
-
inactive mutant
H212A
-
mutation completely abolishes the enzymatic activity
S288A
-
demethylation of substrates of EC 1.14.11.B1, trimethyl-histone 3 L-lysine 9 and dimethyl-histone 3 L-lysine 9 with 2-fold and 12-fold greater efficiency, respectively
additional information