Information on EC 1.14.11.27 - [histone-H3]-lysine-36 demethylase

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The expected taxonomic range for this enzyme is: Eukaryota

EC NUMBER
COMMENTARY
1.14.11.27
-
RECOMMENDED NAME
GeneOntology No.
[histone-H3]-lysine-36 demethylase
-
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
protein N6,N6-dimethyl-L-lysine + 2-oxoglutarate + O2 = protein N6-methyl-L-lysine + succinate + formaldehyde + CO2
show the reaction diagram
-
-
-
-
protein N6-methyl-L-lysine + 2-oxoglutarate + O2 = protein L-lysine + succinate + formaldehyde + CO2
show the reaction diagram
-
-
-
-
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.
SYNONYMS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
dJMJD2(1)/CG15835
-
-
dJMJD2(2)/CG33182
-
-
H3-K36-specific demethylase
-
-
H3K36 demethylase
-
-
H3K36 demethylase
-
-
H3K36 demethylase
-
H3K36 demethylase
-
-
H3K36 demethylase
Mus musculus C57BL/6J
-
-
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H3K36 histone demethylase
-
-
H3K36me2 demethylase
-
-
H3K36me2 histone demethylase
-
-
H3K36me2-specific demethylase
-
-
H3K36me2-specific demethylase
-
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H3K9/36me3 lysine demethylase
-
-
histone demethylase JmjD2A
-
-
histone H3 lysine 36 demethylase
-
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histone H3 lysine 36 demethylase
Mus musculus C57BL/6J
-
-
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histone H3 lysine 36 dimethyl–specific demethylase
-
-
histone H3K36 demethylase
-
-
histone H3K36 demethylase
Saccharomyces cerevisiae BY4742
-
-
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histone H3K9/H3K36 trimethyldemethylase
-
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histone-lysine(H3-K36) demethylase
-
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JHDM1A
Mus musculus C57BL/6J
-
-
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JHDM1A
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gene name
Jhdm1b/Kdm2b
-
-
JmjC domain histone demethylase
-
-
JmjC domain histone demethylase
Mus musculus C57BL/6
-
-
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JmjC domain-containing histone demethylase 1
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JmjC domain-containing histone demethylase 1
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JmjC domain-containing histone demethylase 1A
-
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JmjC domain-containing histone demethylation protein 3A
-
JmjC domain-containing histone demethylation protein 3b
-
JmjC protein
-
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JmjC+N histone demethylase
-
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JMJD2A
-
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JMJD2A
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JMJD5
-
-
KDM2B
-
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KDM2B
Mus musculus C57BL/6
-
-
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KDM2b/JHDM1b
-
-
KDM4A
-
-
KDM4A demethylase
-
-
KDM4A demethylase
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KDM4A/JMJD2A
-
-
Ndy1
-
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Ndy1
Mus musculus C57BL/6
-
-
-
Rph1/KDM4
Saccharomyces cerevisiae BY4742
-
-
-
[histone-H3]-lysine-36 demethylase 1
-
KDM8
-
-
additional information
-
the isozymes belongs to the JmjC+N protein family, CG33182 and CG33185 are JMJD2 proteins
additional information
the enzyme belongs to the JMJD2 family
additional information
-
the enzyme belongs to large family of Jumonji C (JmjC)-domain-containing histone lysine demethylases, JHDMs
additional information
-
JHDM1A is a member of the JHDM (JmjC-domain-containing histone demethylase) family
CAS REGISTRY NUMBER
COMMENTARY
55071-98-2
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
gene dkkdm2
UniProt
Manually annotated by BRENDA team
isoform dJMJD2(1)/CG15835
UniProt
Manually annotated by BRENDA team
isoform dJMJD2(2)/CG33182
UniProt
Manually annotated by BRENDA team
histone demethylase Jmjd2A
UniProt
Manually annotated by BRENDA team
isoform JMJD2A
UniProt
Manually annotated by BRENDA team
KDM4A; KDM4A
UniProt
Manually annotated by BRENDA team
KDM4B
-
-
Manually annotated by BRENDA team
KDM4C; KDM4C
UniProt
Manually annotated by BRENDA team
C57BL/6 mice
-
-
Manually annotated by BRENDA team
Mus musculus C57BL/6
C57BL/6 mice
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-
Manually annotated by BRENDA team
Mus musculus C57BL/6J
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-
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Manually annotated by BRENDA team
gene MAL8P1.111
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Manually annotated by BRENDA team
histone demethylases Ndy1
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Manually annotated by BRENDA team
histone demethylase Jhd1
SwissProt
Manually annotated by BRENDA team
isoform Rph1
-
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Manually annotated by BRENDA team
Saccharomyces cerevisiae BY4742
gene rph1
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Manually annotated by BRENDA team
gene JHDM1A
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Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
-
KDM4A belongs to the KDM4 family
evolution
-
JMJD5/KDM8 is a member of the JmjC family
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; 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; 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
JMJD5 JMJD5 is a Jumonji C (JmjC) protein and shares sequence and structural homology with the asparaginyl and histidinyl hydroxylase FIH-1 (factor inhibiting hypoxia-inducible factor 1 [HIF-1]), the lysyl hydroxylase JMJD6, and the RNA hydroxylase TYW5 but displays limited homology to JmjC lysine demethylases
evolution
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Rph1 is a histone demethylase containing a Jumonji C (JmjC) domain and belongs to the C2H2 zinc-finger protein family
evolution
Saccharomyces cerevisiae BY4742
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Rph1 is a histone demethylase containing a Jumonji C (JmjC) domain and belongs to the C2H2 zinc-finger protein family
-
malfunction
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depletion of Kdm2b/Jhdm1b in hematopoietic progenitors significantly impairs Hoxa9/Meis1-induced leukemic transformation. In leukemic stem cells, knockdown of Kdm2b/Jhdm1b impairs their self-renewing capability in vitro and in vivo
malfunction
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enzyme mutants show 99 misregulated genes in first instar larvae. dKDM4A overexpression results in a global decrease in H3K36me3 levels and male lethality, which might be caused by impaired dosage compensation
malfunction
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Jmjd5-/- embryos show severe growth retardation, resulting in embryonic lethality at the mid-gestation stage, Cdkn1a expression is upregulated in Jmjd5neo/neo MEFs and Jmjd5-/- embryos, which is responsible for the growth defects. phenotypes, overview. Jmjd5neo/neo hypomorphic mouse embryonic fibroblasts proliferate more slowly than wild-type
malfunction
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histone H3K36A mutant shows increased UV sensitivity. Deletion of rph1 leads to approximately 2fold enhancement of PHR1 under normal conditions. Overexpression of Rph1 reduces the expression of PHR1 and increased UV sensitivity. The catalytically deficient mutant H235A of Rph1 diminishes the repressive transcriptional effect on PHR1 expression, which indicates that histone demethylase activity contributes to transcriptional repression; more than 75% of Rph1-regulated genes show increased expression in the rph1-deletion mutant
malfunction
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silencing of Jhdm1a promotes liver glucose synthesis, while its exogenous expression reduces blood glucose level in vivo
malfunction
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Jhdm1a knockdown mice are still able to maintain normal glycemia, but display higher glucose production upon injection of the gluconeogenic substrate pyruvate
malfunction
Mus musculus C57BL/6J
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Jhdm1a knockdown mice are still able to maintain normal glycemia, but display higher glucose production upon injection of the gluconeogenic substrate pyruvate
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malfunction
Saccharomyces cerevisiae BY4742
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histone H3K36A mutant shows increased UV sensitivity. Deletion of rph1 leads to approximately 2fold enhancement of PHR1 under normal conditions. Overexpression of Rph1 reduces the expression of PHR1 and increased UV sensitivity. The catalytically deficient mutant H235A of Rph1 diminishes the repressive transcriptional effect on PHR1 expression, which indicates that histone demethylase activity contributes to transcriptional repression; more than 75% of Rph1-regulated genes show increased expression in the rph1-deletion mutant
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physiological function
dJMJD2(1)/CG15835 is excluded from heterochromatin and localizes to multiple euchromatic sites, where it regulates H3K36 methylation and heterochromatin organization. CG15835 contributes to delimit hetero- and euchromatic territories through the regulation of H3K36 methylation in euchromatin
physiological function
in vivo, the enzyme cooperates with Polycomb but antagonizes gene activation by particular trxG methyltransferases, gene dkdm2 is an enhancer of Polycomb but a suppressor of histone methyltransferases trx and ash1
physiological function
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histone methyl-lysine marks display dynamic changes during the parasite asexual erythrocytic cycle, suggesting that they constitute an important epigenetic mechanism of gene regulation in malaria parasites
physiological function
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the enzyme protects cells against oxidative stress by inhibiting reactive oxygen species-dependent signaling, overview. Ndy1 inhibits the oxidation of deoxyguanosine and DNA damage, and the accumulation of H2O2 in both H2O2-treated and untreated cells. Ndy1 enhances the antioxidant activity of cells. The gene Serpinb1b, upregulated by Ndy1, and gene IL-19, which is downregulated by Ndy1, play indirect roles in redox homeostasis, overview
physiological function
the H3K36 demethylase Jhdm1b/Kdm2b regulates cell proliferation and senescence through p15(Ink4b), Jhdm1b targets the p15Ink4b locus and regulates its expression in an enzymatic activity-dependent manner, overview
physiological function
c-Rph1, the catalytic core of Rph1, is responsible for the demethylase activity, which is essential for the transcription elongation of some actively transcribed genes
physiological function
-
JmjD2A is specific for H3K9me3 and H3K36me3 substrates in fibroblasts. H3K9me3 and H3K36me3 occupancy regulates neural crest specifier expression in vivo. Dynamic changes in both JmjD2A and H3K9me3 occupancy of the Sox10 promoter between stages 8 and 9
physiological function
-
JHDM1A plays an central role in gene silencing, cell cycle, cell growth and cancer development through histone H3K36 demethylation modification
physiological function
-
Kdm2b/Jhdm1b functions as an oncogene and plays a critical role in leukemia development and maintenance, KDM2b/JHDM1b is required for initiation and maintenance of acute myeloid leukemia. Functions of Kdm2b/Jhdm1b are mediated by its silencing of p15Ink4b expression through active demethylation of histone H3-N6,N6-dimethyl-L-lysine. Kdm2b/Jhdm1b directly regulates p15Ink4b expression in leukemic cells
physiological function
-
H3K9me3 demethylase KDM4A/JMJD2A is able to increase accessibility and alter the replication timing at specific heterochromatic regions. KDM4A overexpression promotes copy gain of 1q12, 1q21, and Xq13.1 in cancer cells and results in site-specific copy gain of regions amplified in human tumors. These copy gains are not stably inherited but are generated transiently in each subsequent S phase and cleared by late G2. KDM4A is the only KDM4 family member that generated the gains in a catalytically dependent manner, copy gains are antagonized by coexpression of Suv39h1/KMT1A or HP1gamma, and promoted by H3K9 or H3K36 methylation interference. KDM4A associates with replication machinery and promotes rereplication of 1q12. KDM4A overexpression promotes chromatin state Changes and Recruitment of replication machinery
physiological function
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identification of dKDM4A-regulated genes, overview. Appropriate expression levels for some dKDM4A-regulated genes rely on the demethylase activity of dKDM4A, whereas others do not. Highly expressed, many demethylase-dependent and independent genes are devoid of H3K36me3 in wild-type as well as in dKDM4A mutant larvae. Some of the most strongly affected genes in dKDM4A mutant animals are not regulated by H3K36 methylation
physiological function
-
Jmjd5 is involved in the maintenance of H3K36me2 at the Cdkn1a locus
physiological function
JMJD5 participates in roles independent of histone demethylation and may function as a protein hydroxylase given its structural homology with FIH-1 and JMJD6
physiological function
-
histone H3K36 demethylase Rph1/KDM4 regulates the expression of the photoreactivation gene PHR1, the demethylation at H3K36 is linked to UV sensitivity. Overexpression of Rph1 and H3K36A mutant reduced histone acetylation at the URS, which implies a crosstalk between histone demethylation and acetylation at the PHR1 promoter. Rph1 is a repressor of the DNA repair gene PHR1. Rph1 is dissociated from the PHR1 promoter in response to DNA damage. Rad53 regulates the expression of PHR1 and dissociation of Rph1 in response to DNA damage. Activated Rad53 complex phosphorylates Rph1 and S652A-mutated Rph1 impairs the dissociation in response to DNA damage; Rph1 might be a regulatory node connecting different signal­ing pathways responding to environmental stresses. Rph1 is mainly a transcriptional repressor. Rph1-regulated genes respond to DNA damage and environmental stress. Microarray analysis, overview
physiological function
-
histone demethylase Jhdm1a regulates hepatic gluconeogenesis, regulation of gluconeogenesis by Jhdm1a requires its demethylation activity. Jhdm1a is a key negative regulator of gluconeogenic gene expression. Jhdm1a regulates the expression of a major gluconeogenic regulator, C/EBPalpha, by its USF1-dependent association with the C/EBPa promoter and its subsequent demethylation of dimethylated H3K36 on the C/EBPa lpha locus
physiological function
-
Jhdm1a has a physiological role in hepatic gluconeogenesis in vivo, and this role is mediated by its histone demethylation activity
physiological function
-
dKDM4A demethylase activity regulates eu- and heterochromatic genes
physiological function
-
demethylation of H3K36 reduces DSB repair. Expression of JHDM1a decreases the association of early NHEJ repair components with an induced DSB and decreased DSB repair
physiological function
Mus musculus C57BL/6J
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Jhdm1a has a physiological role in hepatic gluconeogenesis in vivo, and this role is mediated by its histone demethylation activity
-
physiological function
Mus musculus C57BL/6
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the enzyme protects cells against oxidative stress by inhibiting reactive oxygen species-dependent signaling, overview. Ndy1 inhibits the oxidation of deoxyguanosine and DNA damage, and the accumulation of H2O2 in both H2O2-treated and untreated cells. Ndy1 enhances the antioxidant activity of cells. The gene Serpinb1b, upregulated by Ndy1, and gene IL-19, which is downregulated by Ndy1, play indirect roles in redox homeostasis, overview
-
physiological function
Saccharomyces cerevisiae BY4742
-
histone H3K36 demethylase Rph1/KDM4 regulates the expression of the photoreactivation gene PHR1, the demethylation at H3K36 is linked to UV sensitivity. Overexpression of Rph1 and H3K36A mutant reduced histone acetylation at the URS, which implies a crosstalk between histone demethylation and acetylation at the PHR1 promoter. Rph1 is a repressor of the DNA repair gene PHR1. Rph1 is dissociated from the PHR1 promoter in response to DNA damage. Rad53 regulates the expression of PHR1 and dissociation of Rph1 in response to DNA damage. Activated Rad53 complex phosphorylates Rph1 and S652A-mutated Rph1 impairs the dissociation in response to DNA damage; Rph1 might be a regulatory node connecting different signal­ing pathways responding to environmental stresses. Rph1 is mainly a transcriptional repressor. Rph1-regulated genes respond to DNA damage and environmental stress. Microarray analysis, overview
-
metabolism
dKDM2 couples histone H2A ubiquitylation to histone H3 demethylation during Polycomb group gene silencing as a mode of histone crosstalk, the enzyme acts as part of the dRING-associated factor, dRAF, a Polycomb group silencing complex harboring also the histone H2A ubiquitin ligase dRING, Posterior sex combs and the F-box protein, overview. dRAF and PCR1 are separtate Polycomb group complexes, dKDM2 and PRC1 control overlapping transcriptomes, mechanisms, overview
additional information
-
loss of JmjD2A leads to depletion of neural crest specifier genes, but causes no significant changes in the expression of several neural tube, ectodermal, neural plate, and border genes, or in markers of proliferation and apoptosis, overview
additional information
-
ectopic expression of Kdm2b/Jhdm1b is sufficient to transform hematopoietic progenitors
additional information
-
a modest increase in global H3K36me3 levels is compatible with viability, fertility, and the expression of most genes, whereas decreased H3K36me3 levels are detrimental in males
additional information
-
nuclear protein Jmjd5 or Kdm8 is a histone lysine demethylase that contains a JmjC domain in the C-terminal region
additional information
substrate selectivity is determined by multiple interactions within the catalytic domain but outside the active site, structural basis of sequence celectivity between KDM4 members, overview; substrate selectivity is determined by multiple interactions within the catalytic domain but outside the active site, structural basis of sequence celectivity between KDM4 members, overview; substrate selectivity is determined by multiple interactions within the catalytic domain but outside the active site, structural basis of sequence celectivity between KDM4 members, overview
additional information
enzyme structure reveals a beta-barrel fold that is conserved in the JmjC family and a long shallow cleft that opens into the enzyme's active site
additional information
-
Rph1 is a labile protein, and Rad53 negatively modulates Rph1 protein level. The JmjN domain is important in maintaining protein stability and the repressive effect of Rph1. Binding motif 5'-CCCCTWA-3', which resembles the stress re­sponse element, is overrepresented in the promoters of Rph1-repressed genes. JmjN and ZF domains of Rph1 are required for its function. Rph1 binds to gene promoters and is dissociated with DNA damage
additional information
-
expression of the wild-type Jhdm1a, but not the H212A point mutant, decreased the expression of PEPCK and G6Pase in diabetic ob/ob mice
additional information
Mus musculus C57BL/6J
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expression of the wild-type Jhdm1a, but not the H212A point mutant, decreased the expression of PEPCK and G6Pase in diabetic ob/ob mice
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SUBSTRATE
PRODUCT                      
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
LITERATURE
(Substrate)
COMMENTARY
(Product)
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
dimethyl-histone 3 L-lysine 36 + 2-oxoglutarate + O2
methyl-histone 3 L-lysine 36 + succinate + formaldehyde + CO2
show the reaction diagram
-
-
?
dimethyl-histone 3 L-lysine 36 + 2-oxoglutarate + O2
methyl-histone 3 L-lysine 36 + succinate + formaldehyde + CO2
show the reaction diagram
-
enzyme Rph1 is specific for di- and trimethyl-histone 3 L-lysine36
-
?
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,N6-trimethyl-L-lysine36 + 2-oxoglutarate + O2
histone H3 N6,N6-dimethyl-L-lysine36 + succinate + formaldehyde + CO2
show the reaction diagram
calf thymus type II-A histones
-
?
histone H3 N6,N6-dimethyl-L-lysine36 + 2-oxoglutarate + O2
histone H3 N6-methyl-L-lysine36 + succinate + formaldehyde + CO2
show the reaction diagram
calf thymus type II-A histones
-
?
histone H3 N6-methyl-L-lysine36 + 2-oxoglutarate + O2
histone H3 L-lysine36 + succinate + formaldehyde + CO2
show the reaction diagram
calf thymus type II-A histones
-
?
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,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,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,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,N6-trimethyl-L-lysine36 + 2-oxoglutarate + O2
histone H3-N6,N6-dimethyl-L-lysine36 + succinate + formaldehyde + CO2
show the reaction diagram
-
KDM4A demethylates H3K36me3, a modification enriched in the 3' end of active genes
-
?
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
substrate is preferred compared to histone H3-N6,N6-dimethyl-L-lysine36
-
?
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
Saccharomyces cerevisiae BY4742
-
-
-
?
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-dimethyl-L-lysine36 + 2-oxoglutarate + O2
histone H3-N6-methyl-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-dimethyl-L-lysine36 + 2-oxoglutarate + O2
histone H3-N6-methyl-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-dimethyl-L-lysine36 + 2-oxoglutarate + O2
histone H3-N6-methyl-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-dimethyl-L-lysine36 + 2-oxoglutarate + O2
histone H3-N6-methyl-L-lysine36 + succinate + formaldehyde + CO2
show the reaction diagram
low activity
-
?
histone H3-N6,N6-dimethyl-L-lysine36 + 2-oxoglutarate + O2
histone H3-N6-methyl-L-lysine36 + succinate + formaldehyde + CO2
show the reaction diagram
-
Jhdm1a is a histone demethylase that specifically demethylates dimethylated H3K36
-
?
histone H3-N6,N6-dimethyl-L-lysine36 + 2-oxoglutarate + O2
histone H3-N6-methyl-L-lysine36 + succinate + formaldehyde + CO2
show the reaction diagram
-
KDM2b/JHDM1b is an H3K36me2-specific demethylase
-
?
histone H3-N6,N6-dimethyl-L-lysine36 + 2-oxoglutarate + O2
histone H3-N6-methyl-L-lysine36 + succinate + formaldehyde + CO2
show the reaction diagram
Saccharomyces cerevisiae BY4742
-
-
-
?
protein 6-N,6-N-dimethyl-L-lysine + 2-oxoglutarate + O2
protein 6-N-methyl-L-lysine + succinate + formaldehyde + CO2
show the reaction diagram
-
specifically demethylates Lys36 of histone H3
-
?
protein 6-N-methyl-L-lysine + 2-oxoglutarate + O2
protein L-lysine + succinate + formaldehyde + CO2
show the reaction diagram
-
specifically demethylates Lys36 of histone H3
-
?
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 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
-
?
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
Mus musculus C57BL/6J
-
-
-
?
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 + succinate + formaldehyde + CO2
show the reaction diagram
-
enzyme Rph1 is specific for di- and trimethyl-histone 3 L-lysine36
-
?
trimethyl-histone 3 L-lysine 36 + 2-oxoglutarate + O2
dimethyl-histone 3 L-lysine 36 + ?
show the reaction diagram
-
-
?
trimethyl-histone 3 L-lysine 36 + alpha-ketoglutarate + O2
dimethyl-histone 3 L-lysine 36 + ?
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
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
-
-
?
[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-dimethyl-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-dimethyl-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-dimethyl-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
-
H3K36 demethylation activity of the fly dKDM4A is dramatically stimulated upon HP1a association
-
?
[histone H3]-N6,N6-dimethyl-L-lysine36 + 2-oxoglutarate + O2
[histone H3]-L-lysine36 + succinate + formaldehyde + CO2
show the reaction diagram
histone H3K36 methylation is enriched in coding regions of actively transcribed genes. dKDM4A is a JmjC domain-containing protein specifically demethylates H3K36me2 and H3K36me3 both in vitro and in vivo. H3K36 methylation is also subject to dynamic regulation. HP1a regulates histone H3K36 methylation in Drosophila larvae
-
?
[histone H3]-N6,N6-dimethyl-L-lysine36 + 2-oxoglutarate + O2
[histone H3]-L-lysine36 + succinate + formaldehyde + CO2
show the reaction diagram
-
JmjC domain-containing protein dKDM4A is a histone H3K36 demethylase. Histone H3 methylation is one of the consistent marks distinguishing alternative chromatin packaging states
-
?
[histone H3]-N6,N6-dimethyl-L-lysine36 + 2-oxoglutarate + O2
[histone H3]-L-lysine36 + succinate + formaldehyde + CO2
show the reaction diagram
-
predicted site-specificity from phylogenetic analysis
-
?
[histone H3]-N6,N6-dimethyl-L-lysine36 + 2-oxoglutarate + O2
[histone H3]-L-lysine36 + succinate + formaldehyde + CO2
show the reaction diagram
removal of histone H3 Lys36 dimethylation is coupled to histone H2A monoubiquitinylation, overview
-
?
[histone H3]-N6,N6-dimethyl-L-lysine36 + 2-oxoglutarate + O2
[histone H3]-L-lysine36 + succinate + formaldehyde + CO2
show the reaction diagram
the effect of Jhdm1b on cell proliferation and cellular senescence is mediated through de-repression of p15Ink4b as loss of p15Ink4b function rescues cell proliferation defects in Jhdm1b knockdown cells
-
?
[histone H3]-N6,N6-dimethyl-L-lysine36 + 2-oxoglutarate + O2
[histone H3]-L-lysine36 + succinate + formaldehyde + CO2
show the reaction diagram
dJMJD2(1)/CG15835 and dJMJD2(2)/CG33182 demethylate both H3K9me3 and H3K36me3
-
?
[histone H3]-N6,N6-dimethyl-L-lysine36 + 2-oxoglutarate + O2
[histone H3]-L-lysine36 + succinate + formaldehyde + CO2
show the reaction diagram
with HeLa cell core histone 3. dKDM4A is a JmjC domain-containing protein specifically demethylates H3K36me2 and H3K36me3 both in vitro and in vivo. The demethylation reaction mediated by dKDM4A requires Fe2+, 2-oxoglutarate, and ascorbate as cofactors
-
?
[histone H3]-N6,N6-dimethyl-L-lysine9 + 2-oxoglutarate + O2
[histone H3]-L-lysine9 + succinate + formaldehyde + CO2
show the reaction diagram
-
-
?
[histone H3]-N6,N6-dimethyl-L-lysine9 + 2-oxoglutarate + O2
[histone H3]-L-lysine9 + succinate + formaldehyde + CO2
show the reaction diagram
dJMJD2(1)/CG15835 and dJMJD2(2)/CG33182 demethylate both H3K9me3 and H3K36me3
-
?
histone H3-N6,N6-dimethyl-L-lysine36 + 2-oxoglutarate + O2
histone H3-N6-methyl-L-lysine36 + succinate + formaldehyde + CO2
show the reaction diagram
Mus musculus C57BL/6J
-
Jhdm1a is a histone demethylase that specifically demethylates dimethylated H3K36
-
?
additional information
?
-
-
general function of histone demethylase for histone 3 L-lysine 36 is to promote transcription elongation by antagonizing repressive L-lysine 36 methylation by Set2 methyltransferase
-
-
-
additional information
?
-
isoform dJMJD2(1)/CG15835 regulates heterochromatin organization. It is excluded from heterochromatin and localizes to multiple euchromatic sites, where it regulates trimethylated histone 3 lysine 36 methylation
-
-
-
additional information
?
-
-
Ndy1 is a physiological inhibitor of senescence in dividing cells and inhibition of senescence depends on histone H3 demethylation
-
-
-
additional information
?
-
no substrate: methyl-histone 3 L-lysine 4, histone 3 L-lysine 79
-
-
-
additional information
?
-
-
dynamic nature of histone methylation regulation on four of the main lysine sites of methylation on histone H3 and H4 tails, i.e. H3K4, H3K9, H3K27 and H3K36, overview. Methylation of non-histone proteins may be a general means to regulate epigenetic information
-
-
-
additional information
?
-
-
histone methyl-lysine marks display dynamic changes during the parasite asexual erythrocytic cycle, suggesting that they constitute an important epigenetic mechanism of gene regulation in malaria parasites
-
-
-
additional information
?
-
HP1a and dKDM4A interact with each other and loss of HP1a leads to an increased level of histone H3K36me3
-
-
-
additional information
?
-
JMJD2A associates with the androgen receptor to upregulate the expression of androgen receptor-dependent genes. JMJD2A exhibits dual specificity for the trimethylated and, to a lesser extent, the dimethylated forms of H3K9 and H3K36, while other JMJD2 paralogs, such as JMJD2B and JMJD2D, are specific for H3K9me2/3, analysis of the molecular basis of JMJD2A substrate specificity, overview
-
-
-
additional information
?
-
substrate specificity of Jhdm1b in vivo using HEK293 cells overexpressing the enzyme, overview
-
-
-
additional information
?
-
demethylase activity of dJMJD2(1)/CG15835 depends on the JmjC domain. No activity with H3K4me3 and H3K27me3 by dJMJD2(1)/CG15835 and dJMJD2(2)/CG33182
-
-
-
additional information
?
-
Jhdm1b, like its paralogue, JHDM1A, can specifically demethylate H3K36me2 and H3K36me1 histone substrates, but they are not active on methylated Lys4
-
-
-
additional information
?
-
-
JMJD2A also catalyzes the reaction of the [histone H3]-lysine-9 demethylase. JMJD2A exclusively catalyzes the demethylation of H3K9me3 and H3K36me3, converting H3K9/36me3 to H3K9/36me2 but it cannot convert H3K9/36me1 or unmethylated H3K9/K36, overview
-
-
-
additional information
?
-
JMJD2A is unable to demethylate other sites, notably H3K4 or H4K20, and JMJD2 enzymes are unable to recognize H3K36me3. Analysis of the substrate binding structure at the active site, the Ser/Ala position in the methylammonium binding pocket modulates the methylation state specificities of JMJD2 enzymes by altering the propensity of dimethyllysines to assume different conformations within the pocket that either promote or preclude demethylation
-
-
-
additional information
?
-
-
the enzymealso demethylates [histone H3]-N6,N6-dimethyl-L-lysine9
-
-
-
additional information
?
-
-
JmjD2A is specific for H3K9me3 and H3K36me3 substrates in fibroblasts, and does not affect H3K27me3 methylation marks
-
-
-
additional information
?
-
Rph1 is a histone demethylase that can specifically demethylate tri- and dimethylated Lys36 of histone H3. 2-Oxoglutarate forms hydrogen-bonding interactions with the side chains of conserved residues. The substrate-binding cleft of Rph1 is formed with several structural elements of the JmjC domain, the long beta-hairpin and the mixed structural motif, and the methylated Lys36 of H3 is recognized by several conserved residues of the JmjC domain. Molecular basis for the substrate specificity of Rph1, overview
-
-
-
additional information
?
-
-
bifunctional H3K9/36me3 lysine demethylase KDM4A/JMJD2A acting on Lys 9 and Lys36 of histone 3
-
-
-
additional information
?
-
JMJD5 does not display demethylase activity toward methylated H3K36 nor toward the other methyllysines in the N-terminal tails of histones H3 and H4
-
-
-
additional information
?
-
KDM4D and -E only act on H3K9, with no evidence for demethylation of H3K36, while KDM4A/B/C act on both H3K9 and, less efficiently, on H3K36-methylated substrates. No activity by all isozymes with H3K4me3, H3K9me1, and H3K27me3
-
-
-
additional information
?
-
Saccharomyces cerevisiae, Saccharomyces cerevisiae BY4742
-
Rph1 is a histone demethylase specific to tri-methylated-H3K36. Rph1 binds to the URS of PHR1 through ZF domains and modulates chromatin modifications in specific regions of the PHR1 promoter
-
-
-
NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
LITERATURE
(Substrate)
COMMENTARY
(Product)
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
dimethyl-histone 3 L-lysine 36 + 2-oxoglutarate + O2
methyl-histone 3 L-lysine 36 + succinate + formaldehyde + CO2
show the reaction diagram
-
enzyme Rph1 is specific for di- and trimethyl-histone 3 L-lysine36
-
?
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,N6-trimethyl-L-lysine36 + 2-oxoglutarate + O2
histone H3 N6,N6-dimethyl-L-lysine36 + succinate + formaldehyde + CO2
show the reaction diagram
P39956
-
-
?
histone H3 N6,N6-dimethyl-L-lysine36 + 2-oxoglutarate + O2
histone H3 N6-methyl-L-lysine36 + succinate + formaldehyde + CO2
show the reaction diagram
P39956
-
-
?
histone H3 N6-methyl-L-lysine36 + 2-oxoglutarate + O2
histone H3 L-lysine36 + succinate + formaldehyde + CO2
show the reaction diagram
P39956
-
-
?
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,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,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,N6-trimethyl-L-lysine36 + 2-oxoglutarate + O2
histone H3-N6,N6-dimethyl-L-lysine36 + succinate + formaldehyde + CO2
show the reaction diagram
-
KDM4A demethylates H3K36me3, a modification enriched in the 3' end of active genes
-
?
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
Saccharomyces cerevisiae BY4742
-
-
-
?
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-dimethyl-L-lysine36 + 2-oxoglutarate + O2
histone H3-N6-methyl-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-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-dimethyl-L-lysine36 + 2-oxoglutarate + O2
histone H3-N6-methyl-L-lysine36 + succinate + formaldehyde + CO2
show the reaction diagram
-
Jhdm1a is a histone demethylase that specifically demethylates dimethylated H3K36
-
?
histone H3-N6,N6-dimethyl-L-lysine36 + 2-oxoglutarate + O2
histone H3-N6-methyl-L-lysine36 + succinate + formaldehyde + CO2
show the reaction diagram
-
KDM2b/JHDM1b is an H3K36me2-specific demethylase
-
?
histone H3-N6,N6-dimethyl-L-lysine36 + 2-oxoglutarate + O2
histone H3-N6-methyl-L-lysine36 + succinate + formaldehyde + CO2
show the reaction diagram
Saccharomyces cerevisiae BY4742
-
-
-
?
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 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
-
?
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
Mus musculus C57BL/6J
-
-
-
?
trimethyl-histone 3 L-lysine 36 + 2-oxoglutarate + O2
dimethyl-histone 3 L-lysine 36 + succinate + formaldehyde + CO2
show the reaction diagram
-
enzyme Rph1 is specific for di- and trimethyl-histone 3 L-lysine36
-
?
[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
Q9V333, Q9V6L0
-
-
?
[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-dimethyl-L-lysine36 + 2-oxoglutarate + O2
[histone H3]-L-lysine36 + succinate + formaldehyde + CO2
show the reaction diagram
O75164
-
-
?
[histone H3]-N6,N6-dimethyl-L-lysine36 + 2-oxoglutarate + O2
[histone H3]-L-lysine36 + succinate + formaldehyde + CO2
show the reaction diagram
-
H3K36 demethylation activity of the fly dKDM4A is dramatically stimulated upon HP1a association
-
?
[histone H3]-N6,N6-dimethyl-L-lysine36 + 2-oxoglutarate + O2
[histone H3]-L-lysine36 + succinate + formaldehyde + CO2
show the reaction diagram
Q9V333
histone H3K36 methylation is enriched in coding regions of actively transcribed genes. dKDM4A is a JmjC domain-containing protein specifically demethylates H3K36me2 and H3K36me3 both in vitro and in vivo. H3K36 methylation is also subject to dynamic regulation. HP1a regulates histone H3K36 methylation in Drosophila larvae
-
?
[histone H3]-N6,N6-dimethyl-L-lysine36 + 2-oxoglutarate + O2
[histone H3]-L-lysine36 + succinate + formaldehyde + CO2
show the reaction diagram
-
JmjC domain-containing protein dKDM4A is a histone H3K36 demethylase. Histone H3 methylation is one of the consistent marks distinguishing alternative chromatin packaging states
-
?
[histone H3]-N6,N6-dimethyl-L-lysine36 + 2-oxoglutarate + O2
[histone H3]-L-lysine36 + succinate + formaldehyde + CO2
show the reaction diagram
-
predicted site-specificity from phylogenetic analysis
-
?
[histone H3]-N6,N6-dimethyl-L-lysine36 + 2-oxoglutarate + O2
[histone H3]-L-lysine36 + succinate + formaldehyde + CO2
show the reaction diagram
Q9VHH9
removal of histone H3 Lys36 dimethylation is coupled to histone H2A monoubiquitinylation, overview
-
?
[histone H3]-N6,N6-dimethyl-L-lysine36 + 2-oxoglutarate + O2
[histone H3]-L-lysine36 + succinate + formaldehyde + CO2
show the reaction diagram
Q6P1G2
the effect of Jhdm1b on cell proliferation and cellular senescence is mediated through de-repression of p15Ink4b as loss of p15Ink4b function rescues cell proliferation defects in Jhdm1b knockdown cells
-
?
[histone H3]-N6,N6-dimethyl-L-lysine9 + 2-oxoglutarate + O2
[histone H3]-L-lysine9 + succinate + formaldehyde + CO2
show the reaction diagram
Q9V333, Q9V6L0
-
-
?
histone H3-N6,N6-dimethyl-L-lysine36 + 2-oxoglutarate + O2
histone H3-N6-methyl-L-lysine36 + succinate + formaldehyde + CO2
show the reaction diagram
Mus musculus C57BL/6J
-
Jhdm1a is a histone demethylase that specifically demethylates dimethylated H3K36
-
?
additional information
?
-
-
general function of histone demethylase for histone 3 L-lysine 36 is to promote transcription elongation by antagonizing repressive L-lysine 36 methylation by Set2 methyltransferase
-
-
-
additional information
?
-
Q9V333, Q9V6L0
isoform dJMJD2(1)/CG15835 regulates heterochromatin organization. It is excluded from heterochromatin and localizes to multiple euchromatic sites, where it regulates trimethylated histone 3 lysine 36 methylation
-
-
-
additional information
?
-
-
Ndy1 is a physiological inhibitor of senescence in dividing cells and inhibition of senescence depends on histone H3 demethylation
-
-
-
additional information
?
-
-
dynamic nature of histone methylation regulation on four of the main lysine sites of methylation on histone H3 and H4 tails, i.e. H3K4, H3K9, H3K27 and H3K36, overview. Methylation of non-histone proteins may be a general means to regulate epigenetic information
-
-
-
additional information
?
-
-
histone methyl-lysine marks display dynamic changes during the parasite asexual erythrocytic cycle, suggesting that they constitute an important epigenetic mechanism of gene regulation in malaria parasites
-
-
-
additional information
?
-
Q9V333
HP1a and dKDM4A interact with each other and loss of HP1a leads to an increased level of histone H3K36me3
-
-
-
additional information
?
-
O75164
JMJD2A associates with the androgen receptor to upregulate the expression of androgen receptor-dependent genes. JMJD2A exhibits dual specificity for the trimethylated and, to a lesser extent, the dimethylated forms of H3K9 and H3K36, while other JMJD2 paralogs, such as JMJD2B and JMJD2D, are specific for H3K9me2/3, analysis of the molecular basis of JMJD2A substrate specificity, overview
-
-
-
additional information
?
-
Q6P1G2
substrate specificity of Jhdm1b in vivo using HEK293 cells overexpressing the enzyme, overview
-
-
-
additional information
?
-
-
JmjD2A is specific for H3K9me3 and H3K36me3 substrates in fibroblasts, and does not affect H3K27me3 methylation marks
-
-
-
additional information
?
-
P39956
Rph1 is a histone demethylase that can specifically demethylate tri- and dimethylated Lys36 of histone H3. 2-Oxoglutarate forms hydrogen-bonding interactions with the side chains of conserved residues. The substrate-binding cleft of Rph1 is formed with several structural elements of the JmjC domain, the long beta-hairpin and the mixed structural motif, and the methylated Lys36 of H3 is recognized by several conserved residues of the JmjC domain. Molecular basis for the substrate specificity of Rph1, overview
-
-
-
additional information
?
-
-
bifunctional H3K9/36me3 lysine demethylase KDM4A/JMJD2A acting on Lys 9 and Lys36 of histone 3
-
-
-
additional information
?
-
Q8N371
JMJD5 does not display demethylase activity toward methylated H3K36 nor toward the other methyllysines in the N-terminal tails of histones H3 and H4
-
-
-
additional information
?
-
Saccharomyces cerevisiae, Saccharomyces cerevisiae BY4742
-
Rph1 is a histone demethylase specific to tri-methylated-H3K36. Rph1 binds to the URS of PHR1 through ZF domains and modulates chromatin modifications in specific regions of the PHR1 promoter
-
-
-
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Fe2+
activates, required
Fe2+
required for activity
Fe2+
-
required
Fe2+
required for the catalytic activity
Iron
Fe2+ is required
Iron
-
Fe(II) center
Iron
-
the mechansim for achieving methylation state selectivity involves the orientation of the substrate methyl groups towards a ferryl intermediate
Ni2+
the Ni2+ ion at the active site is chelated by conserved residues and the cofactor 2-oxoglutarate
Zn2+
structure of Zn2+ binding sites of the isozymes, overview; structure of Zn2+ binding sites of the isozymes, overview; structure of Zn2+ binding sites of the isozymes, overview
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY
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
additional information
-
expression of GTT1, UGX2, CTT1, and HSP26 is highly induced by H2O2 treatment and causes the dissociation of Rph1 from the promoters of these genes
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
ascorbate
-
required for optimal activity
ascorbate
stimulation
ascorbate
-
required
heterochromatin protein 1
-
predominant localization to centric heterochromatin. HP1a, when resident near centromeres, plays a role in the gene silencing associated with heterochromatin packaging. HP1a binding, two molecules HP1a per enzyme molecule, stimulates demethylation of H3K36me2 and H3K36me3 by dKDM4a, mechanism, overview. HP1a mutant V26M is inactive
-
HP1 a protein
HP1a, encoded by the Su(var)2-5 gene and involved in the establishment and maintenance of higher-order structure of heterochromatin, stimulates the histone H3K36 demethylation activity of dKDM4A, and this stimulation depends on the H3K9me-binding motif of HP1a. HP1a and dKDM4A interact with each other, and loss of HP1a leads to an increased level of histone H3K36me3. The CSD of HP1a and a consensus HP1-interacting PxVxL motif in dKDM4A are responsible for the HP1a-dKDM4A interaction
-
HP1a
-
H3K36 demethylation activity of the fly dKDM4A is dramatically stimulated upon HP1a association
-
HP1a
-
HP1a targets the H3K36 demethylase dKDM4A to heterochromatic genes, it is required for dKDM4A-mediated H3K36me3 demethylation at a subset of heterochromatic genes. Demethylation activity of dKDM4A at euchromatin is independent of HP1a targeting
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.32
trimethyl-histone 3 L-lysine 36
-
pH 7.3, 37°C
-
additional information
additional information
binding affinities of c-Rph1 with H3K36 and H3K9 peptides, overview
-
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.00022
trimethyl-histone 3 L-lysine 36
Homo sapiens
-
pH 7.3, 37°C
-
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
7.5
assay at
8
-
assay at
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
37
-
assay at
37
assay at
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
Mus musculus C57BL/6J
-
primary
-
Manually annotated by BRENDA team
-
quantitative RT-PCRof dKDM4A expression analysis of wild-type and mutant enzymes in larvae
Manually annotated by BRENDA team
-
high expression level of KDM2b/JHDM1b
Manually annotated by BRENDA team
Mus musculus C57BL/6J
-
-
-
Manually annotated by BRENDA team
additional information
-
the mRNA expression of porcine JHDM1A is significantly higher in the middle at 65 days and later at 90 days period's embryo skeletal muscle than that of 33 days, and showed a ubiquitously expression but with the highest abundance in kidney, lung and liver of an adult pig
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
GeneOntology No.
LITERATURE
SOURCE
-
Rph1 is associated with a specific chromatin locus. Release of Rph1 from chromatin also required the phosphorylation at S652
Manually annotated by BRENDA team
Saccharomyces cerevisiae BY4742
-
Rph1 is associated with a specific chromatin locus. Release of Rph1 from chromatin also required the phosphorylation at S652
-
Manually annotated by BRENDA team
Saccharomyces cerevisiae BY4742
-
-
-
Manually annotated by BRENDA team
PDB
SCOP
CATH
ORGANISM
UNIPROT
Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
250000
gel filtration
688966
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
oligomer
x * 56500, calculated
additional information
domain organization and sequence homology analysis of JmjC+N proteins, overview
additional information
the structure of c-Rph1 is composed of a JmjN, Jumonji N, domain, a long beta-hairpin, a mixed structural motif and a JmjC domain
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
phosphoprotein
-
Rph1 is phosphorylated under oxidative stress, which leads to Rph1 dissociation and transcriptional activation. Rad53 may be the key kinase essential for Rph1 phosphorylation on oxidative stress with H2O2 treatment; the crucial checkpoint protein Rad53 acts as an upstream regulator of Rph1 and dominates the phosphorylation of Rph1 that is required for efficient PHR1 expression and the dissociation of Rph1. Release of Rph1 from chromatin also required the phosphorylation at S652
phosphoprotein
Saccharomyces cerevisiae BY4742
-
Rph1 is phosphorylated under oxidative stress, which leads to Rph1 dissociation and transcriptional activation. Rad53 may be the key kinase essential for Rph1 phosphorylation on oxidative stress with H2O2 treatment; the crucial checkpoint protein Rad53 acts as an upstream regulator of Rph1 and dominates the phosphorylation of Rph1 that is required for efficient PHR1 expression and the dissociation of Rph1. Release of Rph1 from chromatin also required the phosphorylation at S652
-
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
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
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
catalytic core of Rph1, hanging drop vapour diffusion method, X-ray diffraction structure determination and analysis at 2.5 A resolution
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
the JmjN domain is important in maintaining protein stability and the repressive effect of Rph1
-
Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
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 KDM4A from Escherichia coli by nickel affinity chromatography; 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
characterization of dKDM4A alleles, and the dKDM4A genomic locus, the dKDM4A locus contains four exons, overview. Quantitative RT-PCR of dKDM4A expression analysis of wild-type and mutant enzymes in larvae
-
expression of wild-type and mutant dKDM4A in Spodoptera frugiperda Sf21 cells using baculovirus transfection
gene dkdm4a, expression of FLAG-tagged wild-type and V423A mutant enzymes
-
overexpression of FLAG-tagged CG15835 in S2 cells
expression of GFP-tagged JmjD2A under the control beta-actin promoter in chicken fibroblasts
-
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 KDM4A in Escherichia coli; expression of N-terminally His-tagged KDM4B in Escherichia coli; expression of N-terminally His-tagged KDM4C in Escherichia coli
ectopic expression of either wild-type Jhdm1a or H212A point mutant in the liver of diabetic ob/ob mice
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expression analysis by quantitative reverse transcriptase PCR, overexpression of wild-type Jhdm1b in HeLa and HEK293 cells
gene Jmjd5, FLAG-His6 tagged mutant H319A is cloned into the pDON-5 Neo plasmid to produce retroviruses, shRNA-expressing retroviruses are used for silencing of the enzyme, expression of C-terminally His-tagged JMJD5 in Escherichia coli, quantitative reverse transcription PCR expression analysis
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Ndy1 overexpression in mouse embryonic fibroblasts, quantitative real-time reverse transcriptase PCR expression analysis
-
gene MAL8P1.111, located on chromosome 8, DNA and amino acid sequence determination and analysis, detailed phylogenetic analysis, overview
-
expression in mouse embryo fibroblast
-
expression of Flag-tagged protein
DNA and amino acid sequence determination and analysis, chromosomal location and association analysis , the porcine JHDM1A gene encodes 1,162 amino acids and contains JmjC, F-box, and CXXC zinc-finger domains, which coding sequence and deduced protein shares 91 and 99% similarity with human JHDM1A, respectively
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EXPRESSION
ORGANISM
UNIPROT
LITERATURE
CG15835 overexpression induces spreading of HP1, out of heterochromatin, into euchromatin, without affecting the actual pattern of histone modifications of heterochromatin. Overexpression of dJMJD2(1)/CG15835 results in a strong decrease on the levels of H3K9me3 and H3K36me3, but it does not show any significant effect on the extent of H3K9me3 and H3K9me2 at the chromocentre
knockdown of Jhdm1b in primary mouse embryonic fibroblasts inhibits cell proliferation and induces cellular senescence in a pRb and p53 pathway-dependent manner. The effect of Jhdm1b on cell proliferation and cellular senescence is mediated through de-repression of p15Ink4b as loss of p15Ink4b function rescues cell proliferation defects in Jhdm1b knockdown cells
checkpoint kinase Rad53 negatively modulates Rph1 protein level; the crucial checkpoint protein Rad53 acts as an upstream regulator of Rph1 and dominates the phosphorylation of Rph1 that is required for efficient PHR1 expression and the dissociation of Rph1
-
Rph1 is phosphorylated under oxidative stress, which leads to Rph1 dissociation and transcriptional activation. Rad53 may be the key kinase essential for Rph1 phosphorylation on oxidative stress with H2O2 treatment
-
checkpoint kinase Rad53 negatively modulates Rph1 protein level; the crucial checkpoint protein Rad53 acts as an upstream regulator of Rph1 and dominates the phosphorylation of Rph1 that is required for efficient PHR1 expression and the dissociation of Rph1
Saccharomyces cerevisiae BY4742
-
-
Rph1 is phosphorylated under oxidative stress, which leads to Rph1 dissociation and transcriptional activation. Rad53 may be the key kinase essential for Rph1 phosphorylation on oxidative stress with H2O2 treatment
Saccharomyces cerevisiae BY4742
-
-
ENGINEERING
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
H195A
construction of a mutant dKDM4A in which a conserved amino acid in the iron-binding site is mutated to alanine, the mutant dKDM4A has no demethylation activity on histones H3K36me3 and H3K36me2
H188A
-
inactive mutant
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
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
H211A
inactive mutant
H212A
-
inactive mutant
H235A
-
catalytically deficient mutant
H305A
-
mutation completely abolishes the enzymatic activity
T302A
more than 90% loss of activity
Y315A
more than 90% loss of activity
H235A
Saccharomyces cerevisiae BY4742
-
catalytically deficient mutant
-
H195A
-
site-directed mutagenesis
additional information
construction of a P-element insertion mutant of dKDMA4, the mutant is homozygous viable, the P element insertion elevates the bulk level of histone H3K36me3 in mutant embryos. Overexpression of dKDM4A seems to only lead to demethylation of histone H3K36, since the level of histone H3K9me3 and H3K4me2 remains unchanged
additional information
-
generation of JmjC protein dKDM4A mutant allele, DELTAdKDM4A, with a deletion spanning from 47 nucleotides downstream of the ATG to the end of the gene by means of imprecise excision of the P-element P{GawB}NP0618
additional information
-
generation of dkdm4a mutant embryos, the dkdm4a allele contains a P-element inserted within the first exon of the gene and abrogates dKDM4A transcription
V423A
-
site-directed mutagenesis, the point mutation at the central valine of PxVxL motif disrupts the interaction between dKDM4A and HP1a in vitro
additional information
-
overexpression of JmjD2A in fibroblasts specifically depletes H3K9me3 and H3K36me3. Loss of JmjD2A by knockdown leads to depletion of neural crest specifier genes, but causes no significant changes in the expression of several neural tube, ectodermal, neural plate, and border genes, or in markers of proliferation and apoptosis, overview
H212A
-
mutation completely abolishes the enzymatic activity
additional information
-
Kdm2b/Jhmd1b is required for Hoxa9/Meis1-induced leukemic transformation in vitro
additional information
-
KDM4A/JMJD2A overexpression leads to localized copy gain of 1q12, 1q21, and Xq13.1 without global chromosome instability
additional information
-
shRNA knockdown of Jhdm1a in Hep-G2 cells elevating gluconeogenic gene expression
H319A
-
a catalytically inactive mutant
additional information
-
Ndy1 knockdown by siRNA enhances sensitivity to oxidative stress, downregulation of Ndy1 activates the phosphorylation of AMPK, JNK, and p38MAPK and the cleavage of caspase-3 both before and after treatment with H2O2, Ndy1 overexpression protects cells against oxidative stress,overexpression of Ndy1 inhibits the phosphorylation of AMPK, JNK, and p38MAPK and the cleavage of caspase-3 both before and after treatment with H2O2
additional information
-
generation of Jmjd5-deficient mice
additional information
-
Jhdm1a knockdown or scramble adenoviruses are transduced into the liver of wild-type male C57BL/6J mice
additional information
Mus musculus C57BL/6
-
Ndy1 knockdown by siRNA enhances sensitivity to oxidative stress, downregulation of Ndy1 activates the phosphorylation of AMPK, JNK, and p38MAPK and the cleavage of caspase-3 both before and after treatment with H2O2, Ndy1 overexpression protects cells against oxidative stress,overexpression of Ndy1 inhibits the phosphorylation of AMPK, JNK, and p38MAPK and the cleavage of caspase-3 both before and after treatment with H2O2
-
H212A
Mus musculus C57BL/6J
-
inactive mutant
-
additional information
Mus musculus C57BL/6J
-
Jhdm1a knockdown or scramble adenoviruses are transduced into the liver of wild-type male C57BL/6J mice
-
additional information
-
expression of histone demthylase Ndy1 in mouse embryo fibroblast results in immortalization in absence of replicative senescence via a JmjC domain-dependent process that targets the Rb and p53 pathways. Knockdown of endogenous Ndy1 or expression of JmjC domain mutants of Ndy1 promote senescence, suggesting that Ndy1 is a physiological inhibitor of senescence in dividing cells and that inhibition of senescence depends on histone H3 demethylation
H305A
more than 90% loss of activity
additional information
-
overexpression bypasses the requirement for the positive elongation factor gene BUR1
additional information
overexpression results in moderate decrease in dimethyl-histone 3 L-lysine 36 and a slight decrease in trimethyl-histone 3 L-lysine 36 along with unaltered methyl-histone 3 L-lysine 36 levels. Deletion of the N-terminal PHD domain leads to about 50% decrease in activity. Deletion of C-terminal 125, 193, or 244 amino acids results in more than 90% loss of activity