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Information on EC 2.1.1.357 - [histone H3]-lysine36 N-dimethyltransferase and Organism(s) Homo sapiens and UniProt Accession Q53H47
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2.1.1.357 [histone H3]-lysine36 N-dimethyltransferaseIUBMB Comments
This entry describes a group of metazoan enzymes that catalyse two successive methylations of lysine36 of histone H3 (H3K36), forming mono- and dimethylated forms. These modifications influence the binding of chromatin-associated proteins. Some enzymes can catalyse three methylations, forming a trimethylated form; these enzymes are classified under EC 2.1.1.359, [histone H3]-lysine36 N-trimethyltransferase.
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Word Map
The taxonomic range for the selected organisms is: Homo sapiens
The enzyme appears in selected viruses and cellular organisms
The enzyme appears in selected viruses and cellular organisms
Synonyms
mmset, whsc1, metnase, whsc1l1, h3k36 methyltransferase, histone h3 lysine 36 methyltransferase, h3k36-specific methyltransferase, nuclear receptor-binding set domain protein 2, kmt3b, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
Ash1L
H3K36 methyltransferase
KMT3B
KMT3C
-
-
-
-
MMSET
NSD1
NSD2
SETMAR
Whsc1
KMT3B
-
-
-
-
NSD2
-
-
-
-
SETMAR
-
-
-
-
Whsc1
-
-
-
-
PATHWAY SOURCE
PATHWAYS
KEGG
SYSTEMATIC NAME
IUBMB Comments
S-adenosyl-L-methionine:[histone H3]-L-lysine36 N6-dimethyltransferase
This entry describes a group of metazoan enzymes that catalyse two successive methylations of lysine36 of histone H3 (H3K36), forming mono- and dimethylated forms. These modifications influence the binding of chromatin-associated proteins. Some enzymes can catalyse three methylations, forming a trimethylated form; these enzymes are classified under EC 2.1.1.359, [histone H3]-lysine36 N-trimethyltransferase.
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
2 S-adenosyl-L-methionine + a [histone H3]-L-lysine36
2 S-adenosyl-L-homocysteine + a [histone H3]-N6,N6-dimethyl-L-lysine36
overall reaction
-
-
?
S-adenosyl-L-methionine + a [histone H3]-L-lysine36
S-adenosyl-L-homocysteine + a [histone H3]-N6-methyl-L-lysine36
-
-
-
?
S-adenosyl-L-methionine + a [histone H3]-N6-methyl-L-lysine36
S-adenosyl-L-homocysteine + a [histone H3]-N6,N6-dimethyl-L-lysine36
-
-
-
?
2 S-adenosyl-L-methionine + a [histone H3]-L-lysine36
2 S-adenosyl-L-homocysteine + a [histone H3]-N6,N6-dimethyl-L-lysine36
2 S-adenosyl-L-methionine + [histone H3]-L-lysine36
2 S-adenosyl-L-homocysteine + [histone H3]-N6,N6-dimethyl-L-lysine36
-
-
-
?
S-adenosyl-L-homocysteine + nuclear factor-kappaB
?
NSD1 also methylates nonhistone proteins, including the p65 subunit of nuclear factor-kappaB at Lys218 and Lys221
-
-
?
S-adenosyl-L-methionine + a [histone H3]-L-lysine36
S-adenosyl-L-homocysteine + a [histone H3]-N6-methyl-L-lysine36
S-adenosyl-L-methionine + a [histone H3]-N6-methyl-L-lysine36
S-adenosyl-L-homocysteine + a [histone H3]-N6,N6-dimethyl-L-lysine36
S-adenosyl-L-methionine + chicken nucleosome
S-adenosyl-L-homocysteine + chicken nucleosome N6-methyl-L-lysine
-
-
-
?
S-adenosyl-L-methionine + histone H3(K36)
S-adenosyl-L-homocysteine + histone H3(K36) N6-methyl-L-lysine
-
-
-
?
S-adenosyl-L-methionine + recombinant nucleosome
S-adenosyl-L-homocysteine + recombinant nucleosome N6-methyl-L-lysine
-
-
-
?
2 S-adenosyl-L-methionine + a [histone H3]-L-lysine36
2 S-adenosyl-L-homocysteine + a [histone H3]-N6,N6-dimethyl-L-lysine36
overall reaction
-
-
?
2 S-adenosyl-L-methionine + a [histone H3]-L-lysine36
2 S-adenosyl-L-homocysteine + a [histone H3]-N6,N6-dimethyl-L-lysine36
-
overall reaction
-
-
?
2 S-adenosyl-L-methionine + a [histone H3]-L-lysine36
2 S-adenosyl-L-homocysteine + a [histone H3]-N6,N6-dimethyl-L-lysine36
overall reaction
-
-
?
2 S-adenosyl-L-methionine + a [histone H3]-L-lysine36
2 S-adenosyl-L-homocysteine + a [histone H3]-N6,N6-dimethyl-L-lysine36
overall reaction
-
-
?
S-adenosyl-L-methionine + a [histone H3]-L-lysine36
S-adenosyl-L-homocysteine + a [histone H3]-N6-methyl-L-lysine36
-
-
-
?
S-adenosyl-L-methionine + a [histone H3]-L-lysine36
S-adenosyl-L-homocysteine + a [histone H3]-N6-methyl-L-lysine36
-
-
-
-
?
S-adenosyl-L-methionine + a [histone H3]-L-lysine36
S-adenosyl-L-homocysteine + a [histone H3]-N6-methyl-L-lysine36
-
-
-
?
S-adenosyl-L-methionine + a [histone H3]-L-lysine36
S-adenosyl-L-homocysteine + a [histone H3]-N6-methyl-L-lysine36
-
-
-
?
S-adenosyl-L-methionine + a [histone H3]-N6-methyl-L-lysine36
S-adenosyl-L-homocysteine + a [histone H3]-N6,N6-dimethyl-L-lysine36
-
-
-
?
S-adenosyl-L-methionine + a [histone H3]-N6-methyl-L-lysine36
S-adenosyl-L-homocysteine + a [histone H3]-N6,N6-dimethyl-L-lysine36
-
-
-
-
?
S-adenosyl-L-methionine + a [histone H3]-N6-methyl-L-lysine36
S-adenosyl-L-homocysteine + a [histone H3]-N6,N6-dimethyl-L-lysine36
-
-
-
?
S-adenosyl-L-methionine + a [histone H3]-N6-methyl-L-lysine36
S-adenosyl-L-homocysteine + a [histone H3]-N6,N6-dimethyl-L-lysine36
preferred reaction
-
-
?
additional information
?
-
enzyme mono- and dimethylates H3K36 and is inactive with H3K4 as substrate. Nucleosome containing histone H3 mutant K36A or histone H3 peptide 18-44 are not substrates. Isoform SETD2 is able to trimethylate H3K36 in vitro
-
-
?
additional information
?
-
the catalytic domain does not methylate recombinant nucleosomes containing histone H3 K36A mutants
-
-
?
additional information
?
-
enzyme shows versatilitiy in substrate recognition. In a pan-methylation assay of histone H3, H3K4me3 and H3K27me3 species are preferably detected rather than me1 and me2 species, while H3K9-me1 and -me2 and H3K79-me1 and -me2 species are favored against me3 species. H3K36 appears to be the preferable in vitro substrate for NSD1-C-terminal domain. NSD1 shows mono-/tri-methylation of histone H4K20
-
-
-
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
2 S-adenosyl-L-methionine + a [histone H3]-L-lysine36
2 S-adenosyl-L-homocysteine + a [histone H3]-N6,N6-dimethyl-L-lysine36
overall reaction
-
-
?
S-adenosyl-L-methionine + a [histone H3]-L-lysine36
S-adenosyl-L-homocysteine + a [histone H3]-N6-methyl-L-lysine36
-
-
-
?
S-adenosyl-L-methionine + a [histone H3]-N6-methyl-L-lysine36
S-adenosyl-L-homocysteine + a [histone H3]-N6,N6-dimethyl-L-lysine36
-
-
-
?
2 S-adenosyl-L-methionine + a [histone H3]-L-lysine36
2 S-adenosyl-L-homocysteine + a [histone H3]-N6,N6-dimethyl-L-lysine36
2 S-adenosyl-L-methionine + [histone H3]-L-lysine36
2 S-adenosyl-L-homocysteine + [histone H3]-N6,N6-dimethyl-L-lysine36
-
-
-
?
S-adenosyl-L-homocysteine + nuclear factor-kappaB
?
NSD1 also methylates nonhistone proteins, including the p65 subunit of nuclear factor-kappaB at Lys218 and Lys221
-
-
?
S-adenosyl-L-methionine + a [histone H3]-L-lysine36
S-adenosyl-L-homocysteine + a [histone H3]-N6-methyl-L-lysine36
S-adenosyl-L-methionine + a [histone H3]-N6-methyl-L-lysine36
S-adenosyl-L-homocysteine + a [histone H3]-N6,N6-dimethyl-L-lysine36
2 S-adenosyl-L-methionine + a [histone H3]-L-lysine36
2 S-adenosyl-L-homocysteine + a [histone H3]-N6,N6-dimethyl-L-lysine36
overall reaction
-
-
?
2 S-adenosyl-L-methionine + a [histone H3]-L-lysine36
2 S-adenosyl-L-homocysteine + a [histone H3]-N6,N6-dimethyl-L-lysine36
-
overall reaction
-
-
?
2 S-adenosyl-L-methionine + a [histone H3]-L-lysine36
2 S-adenosyl-L-homocysteine + a [histone H3]-N6,N6-dimethyl-L-lysine36
overall reaction
-
-
?
2 S-adenosyl-L-methionine + a [histone H3]-L-lysine36
2 S-adenosyl-L-homocysteine + a [histone H3]-N6,N6-dimethyl-L-lysine36
overall reaction
-
-
?
S-adenosyl-L-methionine + a [histone H3]-L-lysine36
S-adenosyl-L-homocysteine + a [histone H3]-N6-methyl-L-lysine36
-
-
-
?
S-adenosyl-L-methionine + a [histone H3]-L-lysine36
S-adenosyl-L-homocysteine + a [histone H3]-N6-methyl-L-lysine36
-
-
-
-
?
S-adenosyl-L-methionine + a [histone H3]-L-lysine36
S-adenosyl-L-homocysteine + a [histone H3]-N6-methyl-L-lysine36
-
-
-
?
S-adenosyl-L-methionine + a [histone H3]-L-lysine36
S-adenosyl-L-homocysteine + a [histone H3]-N6-methyl-L-lysine36
-
-
-
?
S-adenosyl-L-methionine + a [histone H3]-N6-methyl-L-lysine36
S-adenosyl-L-homocysteine + a [histone H3]-N6,N6-dimethyl-L-lysine36
-
-
-
?
S-adenosyl-L-methionine + a [histone H3]-N6-methyl-L-lysine36
S-adenosyl-L-homocysteine + a [histone H3]-N6,N6-dimethyl-L-lysine36
-
-
-
-
?
S-adenosyl-L-methionine + a [histone H3]-N6-methyl-L-lysine36
S-adenosyl-L-homocysteine + a [histone H3]-N6,N6-dimethyl-L-lysine36
-
-
-
?
S-adenosyl-L-methionine + a [histone H3]-N6-methyl-L-lysine36
S-adenosyl-L-homocysteine + a [histone H3]-N6,N6-dimethyl-L-lysine36
preferred reaction
-
-
?
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
histone H3.3 K36M mutant protein
-
inhibits the H3K36 methyltransferases MMSET and SETD2
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0028
S-adenosyl-L-methionine
cosubstrate recombinant nucleosome, pH 9.0, 23°C
0.0038
S-adenosyl-L-methionine
cosubstrate chicken nucleosome, pH 9.0, 23°C
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0000028
A-893
Homo sapiens
pH and temperature not specified in the publication
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
physiological function
the enzyme enhances nonhomologous end-joining repair of, and survival after, DNA double-strand breaks
malfunction
physiological function
malfunction
germline deletion of NSD2 causes Wolf-Hirschhorn syndrome, a developmental disorder characterized by craniofacial defects, growth retardation and microcephaly
malfunction
mutations in NSD1 cause Sotos syndrome, a condition of childhood overgrowth and intellectual disability
malfunction
-
NSD1 enzyme mutants are associated with Sotos syndrome, myelodysplastic syndrome and cancer. NSD2 enzyme mutants are associated with Wolf-Hirschhorn syndrome and multiple myeloma
physiological function
ASH1L is a HOX gene activator and important transcriptional regulator during development
physiological function
NSD2 is an important developmental regulator and oncogene. ASH1L is a HOX gene activator and important transcriptional regulator during development. SMYD2 promotes cancer cell proliferation in head and neck squamous cell carcinoma and esophageal squamous-cell carcinoma. SETMAR protein is linked to cancer via its role in DNA repair. The tumor suppressor SETD3 is implicated in DNA replication and repair due to its interaction with proliferating cell nuclear antigen
physiological function
NSD2 is an important developmental regulator and oncogene. SMYD2 promotes cancer cell proliferation in head and neck squamous cell carcinoma and esophageal squamous-cell carcinoma. SETMAR protein is linked to cancer via its role in DNA repair. The tumor suppressor SETD3 is implicated in DNA replication and repair due to its interaction with proliferating cell nuclear antigen
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). SETMR_HUMAN
684
0
78034
Swiss-Prot
other Location (Reliability: 1)
PDB
SCOP
CATH
UNIPROT
ORGANISM
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
catalytic domain, in 0.2 M lithium sulfate, 0.1 M HEPES, pH 7.5, and 25% (w/v) PEG 3350 at 20°C
molecular modelling of the open-and-closed conformation of the catalytic domain
the SET domain is composed of three groups of canonical beta-sheets arranged in a triangular fashion with a group of two beta-sheets closely neighboring a conserved alpha-helix defining a cleft for the binding to the histone-tail ligand. The cofactor AdoMet and substrate bind at two adjacent sites to the SET domain. The histone-tail ligand binds into a groove formed by both the SET and postSET domains. The cofactor AdoMet binds into a distinct pocket located on the other side of the SET domain and acts as a methyl group donor. Both AdoMet and the L-lysine-histone are connected through a narrow tunnel where the methyl group is channeled. In the structure of the peptide-less NSDx02SET domain, the postSET domain loop is extended on top of the histone binding site, which sterically prevents the binding of either H3K36 or H4K20 substrates. In the presence of ligand, a network of residues stabilizes the H4-peptide tail on the binding site
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
glutathione Sepharose column chromatography, Mono S cation exchange column chromatography, and Superdex S200 gel filtration
glutathione-Sepharose column chromatography and Superdex 75 gel filtration
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
synthesis
expression of NSDs via tagging with a human influenza hemagglutinin tag greatly improves the quality of the recombinant NSDs, resulting in more than 95% pure, stable, and active NSD-hemagglutinins, with an increase in production yield up to 22.4fold and up to 6.25 mg/l from LB Eschewrichia coli culture, and without further purification
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Eram, M.S.; Kuznetsova, E.; Li, F.; Lima-Fernandes, E.; Kennedy, S.; Chau, I.; Arrowsmith, C.H.; Schapira, M.; Vedadi, M.
Kinetic characterization of human histone H3 lysine 36 methyltransferases, ASH1L and SETD2
Biochim. Biophys. Acta
1850
1842-1848
2015
Homo sapiens (Q9NR48)
Rogawski, D.; Grembecka, J.; Cierpicki, T.
H3K36 methyltransferases as cancer drug targets Rationale and perspectives for inhibitor development
Future Med. Chem.
8
1589-1607
2016
Homo sapiens, Homo sapiens (Q96L73), Homo sapiens (Q9NR48)
-
Poulin, M.; Schneck, J.; Matico, R.; Hou, W.; McDevitt, P.; Holbert, M.; Schramm, V.
Nucleosome binding alters the substrate bonding environment of histone H3 lysine 36 methyltransferase NSD2
J. Am. Chem. Soc.
138
6699-6702
2016
Homo sapiens (Q96028)
Qiao, Q.; Li, Y.; Chen, Z.; Wang, M.; Reinberg, D.; Xu, R.
The structure of NSD1 reveals an autoregulatory mechanism underlying histone H3K36 methylation
J. Biol. Chem.
286
8361-8368
2011
Homo sapiens (Q96L73)
Wagner, E.; Carpenter, P.
Understanding the language of Lys36 methylation at histone H3
Nat. Rev. Mol. Cell Biol.
13
115-126
2012
Homo sapiens
Fnu, S.; Williamson, E.; De Haro, L.; Brenneman, M.; Wray, J.; Shaheen, M.; Radhakrishnan, K.; Lee, S.; Nickoloff, J.; Hromasa, R.
Methylation of histone H3 lysine 36 enhances DNA repair by nonhomologous end-joining
Proc. Natl. Acad. Sci. USA
108
551-556
2011
Homo sapiens (Q53H47), Homo sapiens
Poulin, M.; Schneck, J.; Matico, R.; McDevitt, P.; Huddleston, M.; Hou, W.; Johnson, N.; Thrall, S.; Meek, T.; Schramm, V.
Transition state for the NSD2-catalyzed methylation of histone H3 lysine 36
Proc. Natl. Acad. Sci. USA
113
1197-1201
2016
Homo sapiens (O96028)
Fang, D.; Gan, H.; Lee, J.; Han, J.; Wang, Z.; Riester, S.; Jin, L.; Chen, J.; Zhou, H.; Wang, J.; Zhang, H.; Yang, N.; Bradley, E.; Ho, T.; Rubin, B.; Bridge, J.; Thibodeau, S.; Ordog, T.; Chen, Y.; Van Wijnen, A.; Oliveira, A.; Xu, R.; Westendorf, J.
The histone H3.3K36M mutation reprograms the epigenome of chondroblastomas
Science
352
1344-1348
2016
Homo sapiens
Morishita, M.; Di Luccio, E.
Structural insights into the regulation and the recognition of histone marks by the SET domain of NSD1
Biochem. Biophys. Res. Commun.
412
214-219
2011
Homo sapiens (Q96L73)
Morishita, M.; Mevius, D.; Di Luccio, E.
In vitro histone lysine methylation by NSD1, NSD2/MMSET/WHSC1 and NSD3/WHSC1L
BMC Struct. Biol.
14
25
2014
Homo sapiens (Q96L73)
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