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Information on EC 1.14.99.66 - [histone H3]-N6,N6-dimethyl-L-lysine4 FAD-dependent demethylase and Organism(s) Homo sapiens and UniProt Accession O75164
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1.14.99.66 [histone H3]-N6,N6-dimethyl-L-lysine4 FAD-dependent demethylaseIUBMB Comments
The enzyme specifically removes methyl groups from mono- and dimethylated lysine4 of histone 3. During the reaction the substrate is oxidized by the FAD cofactor of the enzyme to generate the corresponding imine, which is subsequently hydrolysed in the form of formaldehyde.The enzyme is similar to flavin amine oxidases, and differs from all other known histone lysine demethylases, which are iron(II)- and 2-oxoglutarate-dependent dioxygenases. The physiological electron acceptor is not known with certainty. In vitro the enzyme can use oxygen, which is reduced to hydrogen peroxide, but generation of hydrogen peroxide in the chromatin environment is unlikely as it will result in oxidative damage of DNA.
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Word Map
- 1.14.99.66
- chromatin
-
demethylation
- corest
-
corepressors
- deacetylases
-
chromatin-modifying
- tranylcypromine
-
lsd1-mediated
- lys4
-
demethylase-1
-
di-methylated
-
swirm
-
h3k4me1
- pargyline
- diagnostics
- drug development
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
Reaction Schemes
hide(Overall reactions are displayed. Show all >>)
Synonyms
demethylase lsd1, spr-5, lsd1/kdm1a, lysine-specific histone demethylase, lysine-specific histone demethylase 1a, histone lysine-specific demethylase 1, bhc110/lsd1, lysine-specific demethylase 2, lysine demethylase 1b, h3k4me2/1 histone demethylase, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
KDM1
KDM1A
-
LSD1
lysine-specific demethylase 1
lysine-specific histone demethylase 1
lysine-specific histone demethylase 1A
additional information
KDM1
-
-
-
-
LSD1
-
-
-
-
LSD1
-
-
LSD1
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lysine-specific demethylase 1
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lysine-specific histone demethylase 1
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-
-
-
additional information
the enzyme belongs to the flavin-dependent amine oxidases
SYSTEMATIC NAME
IUBMB Comments
[histone H3]-N6,N6-dimethyl-L-lysine4:acceptor oxidoreductase (demethylating)
The enzyme specifically removes methyl groups from mono- and dimethylated lysine4 of histone 3. During the reaction the substrate is oxidized by the FAD cofactor of the enzyme to generate the corresponding imine, which is subsequently hydrolysed in the form of formaldehyde.The enzyme is similar to flavin amine oxidases, and differs from all other known histone lysine demethylases, which are iron(II)- and 2-oxoglutarate-dependent dioxygenases. The physiological electron acceptor is not known with certainty. In vitro the enzyme can use oxygen, which is reduced to hydrogen peroxide, but generation of hydrogen peroxide in the chromatin environment is unlikely as it will result in oxidative damage of DNA.
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
[histone H3]-N6,N6-dimethyl-L-lysine4 + 2 2-oxoglutarate + 2 O2
[histone H3]-L-lysine4 + 2 succinate + 2 formaldehyde + 2 CO2
[histone H3]-N6,N6-methyl-L-lysine4 + 2-oxoglutarate + O2
[histone H3]-L-lysine4 + succinate + formaldehyde + CO2
a [histone H3]-N6,N6-dimethyl-L-lysine4 + ferricenium + H2O
a [histone H3]-N6-methyl-L-lysine4 + formaldehyde + ferrocene
-
-
-
?
a [histone H3]-N6,N6-dimethyl-L-lysine4 + O2 + 2 H2O
a [histone H3]-L-lysine4 + 2 formaldehyde + 2 H2O2
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-
-
?
a [histone H3]-N6-methyl-L-lysine4 + acceptor + H2O
a [histone H3]-L-lysine4 + formaldehyde + reduced acceptor
-
-
-
?
dimethylated histone 3-Lys4 peptide + H2O
?
-
the enzyme specifically removes methyl groups from Lys4 of histone 3. The enzyme exhibits oxidase activity (with production of H2O2) but it can function also with a synthetic mono-electronic acceptor
-
-
?
H3(1-20) K4-dimethylated peptide + 2-oxoglutarate + O2
H3(1-20) K4-monomethylated peptide + succinate + formaldehyde + CO2
-
-
-
?
H3K4me2 (1-21 aa) peptide + 2-oxoglutarate + O2
H3K4me1 (1-21 aa) peptide + succinate + formaldehyde + CO2
H3K4me2 1-21 peptide + 2-oxoglutarate + O2
H3K4me1 1-21 peptide + succinate + formaldehyde + CO2
-
-
-
?
H3K4me2 peptide 3-21 + 2-oxoglutarate + O2
H3K4me1 peptide 3-21 + succinate + formaldehyde + CO2
-
-
-
?
histone H3 N6,N6-dimethyl-L-lysine4 + 2-oxoglutarate + O2
histone H3 N6-methyl-L-lysine4 + succinate + formaldehyde + CO2
histone H3 N6-methyl-L-lysine4 + 2-oxoglutarate + O2
histone H3 L-lysine4 + succinate + formaldehyde + CO2
[histone H3]-N6,N6-dimethyl-L-lysine 4 + 2-oxoglutarate + O2
[histone H3]-N6-methyl-L-lysine 4 + succinate + formaldehyde + CO2
[histone H3]-N6,N6-dimethyl-L-lysine 4 + acceptor + H2O
[histone H3]-N6-methyl-L-lysine 4 + formaldehyde + reduced acceptor
-
-
-
?
[histone H3]-N6,N6-dimethyl-L-lysine 9 + 2-oxoglutarate + O2
[histone H3]-N6-methyl-L-lysine 9 + succinate + formaldehyde + CO2
-
-
-
?
[histone H3]-N6,N6-dimethyl-L-lysine4 + 2 2-oxoglutarate + 2 O2
[histone H3]-L-lysine4 + 2 succinate + 2 formaldehyde + 2 CO2
[histone H3]-N6,N6-L-dimethyllysine21 + O2 + 2 H2O
[histone H3]-L-lysine + 2 formaldehyde + 2 H2O2
diMeK4H3-21 i.e. a dimethyl K4-containing histone H3 peptide
-
-
?
[histone H3]-N6,N6-L-dimethyllysine4 + O2 + 2 H2O
[histone H3]-N6,N6-L-dimethyllysine4 + 2 formaldehyde + 2 H2O2
-
-
-
?
[histone H3]-N6,N6-L-dimethyllysine4-1-21 + O2 + 2 H2O
[histone H3]-L-lysine4-1-21 + 2 formaldehyde + 2 H2O2
substrate is a dimethylated peptide corresponding to the first 21 amino acids of the N-terminal tail of histone H3
-
-
?
[histone H3]-N6,N6-methyl-L-lysine 4 + acceptor + H2O
[histone H3]-L-lysine 4 + formaldehyde + reduced acceptor
-
-
-
?
[histone H3]-N6-methyl-L-lysine 4 + 2-oxoglutarate + O2
[histone H3]-L-lysine 4 + succinate + formaldehyde + CO2
[histone H3]-N6-methyl-L-lysine 9 + 2-oxoglutarate + O2
[histone H3]-L-lysine 9 + succinate + formaldehyde + CO2
-
-
-
?
[histone H3]-N6-methyl-L-lysine4 + 2-oxoglutarate + O2
[histone H3]-L-lysine4 + succinate + formaldehyde + CO2
-
-
-
-
?
[histone H4]-N6-methyl-L-lysine 20 + 2-oxoglutarate + O2
[histone H4]-L-lysine 20 + succinate + formaldehyde + CO2
-
-
-
?
[histone H3]-N6,N6-dimethyl-L-lysine4 + 2 2-oxoglutarate + 2 O2
[histone H3]-L-lysine4 + 2 succinate + 2 formaldehyde + 2 CO2
dimethyl-H3K4 is an activation markers for gene expression
-
-
?
[histone H3]-N6,N6-dimethyl-L-lysine4 + 2 2-oxoglutarate + 2 O2
[histone H3]-L-lysine4 + 2 succinate + 2 formaldehyde + 2 CO2
specific pockets in the substrate-binding site of LSD1 that interact with several H3 side chains, Thr6, Arg8, Lys9 and Thr11, and also with the N-terminal amino group of Ala1, N-term pocket, overview
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-
?
[histone H3]-N6,N6-methyl-L-lysine4 + 2-oxoglutarate + O2
[histone H3]-L-lysine4 + succinate + formaldehyde + CO2
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-
-
?
[histone H3]-N6,N6-methyl-L-lysine4 + 2-oxoglutarate + O2
[histone H3]-L-lysine4 + succinate + formaldehyde + CO2
specific pockets in the substrate-binding site of LSD1 that interact with several H3 side chains, Thr6, Arg8, Lys9 and Thr11, and also with the N-terminal amino group of Ala1, N-term pocket
-
-
?
H3K4me2 (1-21 aa) peptide + 2-oxoglutarate + O2
H3K4me1 (1-21 aa) peptide + succinate + formaldehyde + CO2
-
-
-
?
H3K4me2 (1-21 aa) peptide + 2-oxoglutarate + O2
H3K4me1 (1-21 aa) peptide + succinate + formaldehyde + CO2
a peptide corresponding to the first 21 amino acids of histone H3 with a dimethylated lysine at the fourth residue [ARTK(diMe)QTARKSTGGKAPRKQLA]
-
-
?
histone H3 N6,N6-dimethyl-L-lysine4 + 2-oxoglutarate + O2
histone H3 N6-methyl-L-lysine4 + succinate + formaldehyde + CO2
-
-
-
-
?
histone H3 N6,N6-dimethyl-L-lysine4 + 2-oxoglutarate + O2
histone H3 N6-methyl-L-lysine4 + succinate + formaldehyde + CO2
-
-
-
?
histone H3 N6-methyl-L-lysine4 + 2-oxoglutarate + O2
histone H3 L-lysine4 + succinate + formaldehyde + CO2
-
-
-
-
?
histone H3 N6-methyl-L-lysine4 + 2-oxoglutarate + O2
histone H3 L-lysine4 + succinate + formaldehyde + CO2
-
-
-
?
[histone H3]-N6,N6-dimethyl-L-lysine 4 + 2-oxoglutarate + O2
[histone H3]-N6-methyl-L-lysine 4 + succinate + formaldehyde + CO2
-
-
-
?
[histone H3]-N6,N6-dimethyl-L-lysine 4 + 2-oxoglutarate + O2
[histone H3]-N6-methyl-L-lysine 4 + succinate + formaldehyde + CO2
-
-
-
-
?
[histone H3]-N6,N6-dimethyl-L-lysine 4 + 2-oxoglutarate + O2
[histone H3]-N6-methyl-L-lysine 4 + succinate + formaldehyde + CO2
-
-
-
?
[histone H3]-N6,N6-dimethyl-L-lysine4 + 2 2-oxoglutarate + 2 O2
[histone H3]-L-lysine4 + 2 succinate + 2 formaldehyde + 2 CO2
-
-
-
-
?
[histone H3]-N6,N6-dimethyl-L-lysine4 + 2 2-oxoglutarate + 2 O2
[histone H3]-L-lysine4 + 2 succinate + 2 formaldehyde + 2 CO2
-
lack of H3K4diMe is possibly due to complex epigenetic regulation involving Ash2 and LSD1
-
-
?
[histone H3]-N6-methyl-L-lysine 4 + 2-oxoglutarate + O2
[histone H3]-L-lysine 4 + succinate + formaldehyde + CO2
-
-
-
?
[histone H3]-N6-methyl-L-lysine 4 + 2-oxoglutarate + O2
[histone H3]-L-lysine 4 + succinate + formaldehyde + CO2
-
-
-
-
?
[histone H3]-N6-methyl-L-lysine 4 + 2-oxoglutarate + O2
[histone H3]-L-lysine 4 + succinate + formaldehyde + CO2
-
-
-
?
additional information
?
-
LSD1 interacts with several interaction partners and transcription factors for performing its role in gene regulation, overview. LSD1 forms a complex with CoREST, structure with bound histone H3 peptide substrate, overview. LSD1 tightly associates with the CoREST C-terminal SANT domain. This intermolecular association is mediated by the LSD1 tower domain, whose alpha-helices are embraced by a helical segment of CoREST, generating an intermolecular helical coil. The histone H3 N-terminal peptide binds deeply in the LSD1 amine oxidase domain in proximity to the flavin cofactor
-
-
?
additional information
?
-
LSD1 catalyzes the demethylation of Lys4 of histone H3 through a flavin-dependent oxidative reaction via an imine intermediate. LSD1 can act both on mono- and dimethylated H3K4. The reaction involves several steps, overview
-
-
?
additional information
?
-
functional interplay between histone demethylase and histone deacetylase
-
-
?
additional information
?
-
-
LSD1 forms a complex with CoREST and histone deacetylase 1. LSD1 mediates the transrepressive function of TLX, an orphan nuclear receptor, also called NR2E1, that regulates the expression of target genes by functioning as a constitutive transrepressor, through direct interaction via its SWIRM and amine oxidase domains. Physiological significance of TLX in the cytodifferentiation of neural cells in the brain
-
-
?
additional information
?
-
-
LSD1 forms a stable complex with Rb, but with E2F1, cell cycle regulatory proteins. LSD1 binds to Epstein-Barr virus C promoter Cp in a cell cycle-dependent manner, as do the the cell cycle regulatory proteins E2F1 and Rb. Rb and LSD1 binding to Cp increase after the S phase, corresponding to a decrease in histone H3 K4 methylation and Cp transcription, overview
-
-
?
additional information
?
-
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LSD1 interacts with CoREST, a co-repressor protein that binds REST and recruits other histone-modifying enzymes such as histone deacetylases 1 ? 2. The function of the LSD1CoRESThistone deacetylase subcomplex in transcriptional repression events is not limited to REST-regulated neuronal genes, but can be extended to other contexts such as hematopoietic differentiation and the telomerase reverse transcriptase genes
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?
additional information
?
-
-
LSD1 is specific for Lys4 of both mono- and dimethylated histone H3 using a highly specific recognition mechanism, LSD1-catalyzed reaction produces an imine intermediate that is hydrolyzed to the demethylated product and formaldehyde, Reduced flavin is reoxidized by molecular oxygen with the concomitant production of hydrogen peroxide, overview
-
-
?
additional information
?
-
LSD1 specificity and mechanism of action are complex-dependent
-
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?
additional information
?
-
-
LSD1 removes the methyl groups from lysines 4 and 9 of histone 3 with the generation of formaldehyde from the methyl group
-
-
?
additional information
?
-
LSD1 directly binds to the promoter of P21 where it catalyzes H3K4me2 demethylation. FEZF1-AS1, a 2564 bp RNA overexpressed in gastric cancer, epigenetically represses the expression of P21 via binding with LSD1
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?
additional information
?
-
lysine-specific demethylase 1(LSD1) demethylates mono- and dimethylated residues of lysine-4 on histone H3 (H3K4me1 and H3K4me2) and lysine-9 on histone H3 (H3K9me1 and H3K9me2)
-
-
?
additional information
?
-
histone demethylase LSD1 demethylates Lys4 or Lys9 of histone H3 using FAD as cofactor
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?
additional information
?
-
no substrates: dimethylated histone H3 K9 residues
-
-
?
additional information
?
-
the bifunctional enzyme catalyzes the demethylation of H3K4me2/me1 and H3K9me2/me1 (EC 1.14.11.65)
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?
additional information
?
-
the bifunctional enzyme catalyzes the demethylation of H3K4me2/me1 and H3K9me2/me1 (EC 1.14.11.65)
-
-
?
additional information
?
-
the bifunctional enzyme catalyzes the demethylation of H3K4me2/me1 and H3K9me2/me1 (EC 1.14.11.65), as well as non-histone substrates. Tight-binding nature of the H3/KDM1A interaction, kinetics, overview. No other core histones exhibits inhibition of KDM1A demethylation activity, which is consistent with H3 being the preferred histone substrate of KDM1A versus H2A, H2B, and H4. Kinetic analysis of full-length histone products against KDM1A. KDM1A requires a minimal substrate corresponding to the first 21 residues of the N-terminal histone H3 tail for efficient demethylation activity. Recombinant KDM1A/LSD11 forms a complex in vitro with recombinant transcription factor CoREST
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?
additional information
?
-
the bifunctional enzyme catalyzes the demethylation of H3K4me2/me1 and H3K9me2/me1 (EC 1.14.11.65). Functional interplay between histone demethylase and histone deacetylase. The enzymatic activities of the histone demethylase and the deacetylase are intimately linked. The cross talk between the two enzymes is seen only when nucleosomal substrates are used and is mediated through different domains of the CoREST protein (FLAG-tagged CoREST and mutants are recombinantly expressed in HEK-293 cells and Escherichia coli strain BL21). LSD1-HDAC1 complexes display enhanced acetylation activity in presence of CoREST
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-
?
additional information
?
-
the bifunctional enzyme catalyzes the demethylation of H3K4me2/me1 and H3K9me2/me1 (EC 1.14.11.65). LSD1 is specific for Lys-4 of histone H3 and can oxidatively demethylate the dimethyl or monomethyl Lys-containing substrates
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?
additional information
?
-
the bifunctional enzyme catalyzes the demethylation of H3K9me2/me1 (EC 1.14.11.65) and H3K4me2/me1
-
-
?
additional information
?
-
the bifunctional enzyme catalyzes the demethylation of H3K9me2/me1 (EC 1.14.11.65) and H3K4me2/me1
-
-
?
additional information
?
-
the bifunctional enzyme catalyzes the demethylation of H3K9me2/me1 (EC 1.14.11.65) and H3K4me2/me1
-
-
?
additional information
?
-
the bifunctional enzyme catalyzes the demethylation of H3K9me2/me1 (EC 1.14.11.65) and H3K4me2/me1
-
-
?
additional information
?
-
the bifunctional enzyme catalyzes the demethylation of H3K9me2/me1 (EC 1.14.11.65) and H3K4me2/me1
-
-
?
additional information
?
-
the bifunctional enzyme catalyzes the demethylation of H3K9me2/me1 (EC 1.14.11.65) and H3K4me2/me1
-
-
?
additional information
?
-
-
the bifunctional enzyme catalyzes the demethylation of H3K9me2/me1 (EC 1.14.11.65) and H3K4me2/me1
-
-
?
additional information
?
-
the bifunctional enzyme catalyzes the demethylation of H3K9me2/me1 (EC 1.14.11.65) and H3K4me2/me1
-
-
?
additional information
?
-
the bifunctional enzyme catalyzes the demethylation of H3K9me2/me1 (EC 1.14.11.65) and H3K4me2/me1. As LSD1 can demethylate both H3K4 and H3K9, the coupling of this protein in the HCF-1 Set1 or MLL methyltransferase complex may enhance H3K9 demethylation or preferentially target it to this substrate, although additional histone modifications and modification activities may also contribute to the H3K4 or H3K9 recognition and specificity
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-
?
additional information
?
-
the enzyme is specific for mono- and dimethylated Lys4 in histone H3 (H3K4me1/2). LSD1 prefers an unmodified alpha-amine three residues preceding the methyllysine in the protein substrate, consistent with its specificity for H3K4me1/2 in vitro. To catalyze efficient demethylation, the enzyme requires H3 peptides at least 16 residues in length. In addition, LSD1 exhibits a strong preference toward H3K4me2 substrates lacking other covalent modifications, including R2me, R8me, S10ph, K9ac, and K14ac. In addition, LSD1 might also by active with mono- and dimethylated Lys9 in histone H3 (H3K9me1/2), cf. EC 3.4.11.66
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-
?
additional information
?
-
the rate-limiting reductive half-reaction of LSD1 employs a direct hydride transfer mechanism. Conserved residue Tyr761 and the lysine-water-flavin motif help properly orienting FAD with respect to substrate, thereby stabilizing the catalytic environment and facilitating the demethylation reaction
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-
?
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
[histone H3]-N6,N6-dimethyl-L-lysine4 + 2 2-oxoglutarate + 2 O2
[histone H3]-L-lysine4 + 2 succinate + 2 formaldehyde + 2 CO2
dimethyl-H3K4 is an activation markers for gene expression
-
-
?
[histone H3]-N6,N6-methyl-L-lysine4 + 2-oxoglutarate + O2
[histone H3]-L-lysine4 + succinate + formaldehyde + CO2
-
-
-
?
a [histone H3]-N6,N6-dimethyl-L-lysine4 + O2 + 2 H2O
a [histone H3]-L-lysine4 + 2 formaldehyde + 2 H2O2
-
-
-
?
histone H3 N6,N6-dimethyl-L-lysine4 + 2-oxoglutarate + O2
histone H3 N6-methyl-L-lysine4 + succinate + formaldehyde + CO2
histone H3 N6-methyl-L-lysine4 + 2-oxoglutarate + O2
histone H3 L-lysine4 + succinate + formaldehyde + CO2
[histone H3]-N6,N6-dimethyl-L-lysine 4 + 2-oxoglutarate + O2
[histone H3]-N6-methyl-L-lysine 4 + succinate + formaldehyde + CO2
[histone H3]-N6,N6-dimethyl-L-lysine 4 + acceptor + H2O
[histone H3]-N6-methyl-L-lysine 4 + formaldehyde + reduced acceptor
-
-
-
?
[histone H3]-N6,N6-dimethyl-L-lysine 9 + 2-oxoglutarate + O2
[histone H3]-N6-methyl-L-lysine 9 + succinate + formaldehyde + CO2
-
-
-
?
[histone H3]-N6,N6-dimethyl-L-lysine4 + 2 2-oxoglutarate + 2 O2
[histone H3]-L-lysine4 + 2 succinate + 2 formaldehyde + 2 CO2
[histone H3]-N6,N6-methyl-L-lysine 4 + acceptor + H2O
[histone H3]-L-lysine 4 + formaldehyde + reduced acceptor
-
-
-
?
[histone H3]-N6-methyl-L-lysine 4 + 2-oxoglutarate + O2
[histone H3]-L-lysine 4 + succinate + formaldehyde + CO2
[histone H3]-N6-methyl-L-lysine 9 + 2-oxoglutarate + O2
[histone H3]-L-lysine 9 + succinate + formaldehyde + CO2
-
-
-
?
[histone H3]-N6-methyl-L-lysine4 + 2-oxoglutarate + O2
[histone H3]-L-lysine4 + succinate + formaldehyde + CO2
-
-
-
-
?
histone H3 N6,N6-dimethyl-L-lysine4 + 2-oxoglutarate + O2
histone H3 N6-methyl-L-lysine4 + succinate + formaldehyde + CO2
-
-
-
-
?
histone H3 N6,N6-dimethyl-L-lysine4 + 2-oxoglutarate + O2
histone H3 N6-methyl-L-lysine4 + succinate + formaldehyde + CO2
-
-
-
?
histone H3 N6-methyl-L-lysine4 + 2-oxoglutarate + O2
histone H3 L-lysine4 + succinate + formaldehyde + CO2
-
-
-
-
?
histone H3 N6-methyl-L-lysine4 + 2-oxoglutarate + O2
histone H3 L-lysine4 + succinate + formaldehyde + CO2
-
-
-
?
[histone H3]-N6,N6-dimethyl-L-lysine 4 + 2-oxoglutarate + O2
[histone H3]-N6-methyl-L-lysine 4 + succinate + formaldehyde + CO2
-
-
-
?
[histone H3]-N6,N6-dimethyl-L-lysine 4 + 2-oxoglutarate + O2
[histone H3]-N6-methyl-L-lysine 4 + succinate + formaldehyde + CO2
-
-
-
-
?
[histone H3]-N6,N6-dimethyl-L-lysine 4 + 2-oxoglutarate + O2
[histone H3]-N6-methyl-L-lysine 4 + succinate + formaldehyde + CO2
-
-
-
?
[histone H3]-N6,N6-dimethyl-L-lysine4 + 2 2-oxoglutarate + 2 O2
[histone H3]-L-lysine4 + 2 succinate + 2 formaldehyde + 2 CO2
-
-
-
-
?
[histone H3]-N6,N6-dimethyl-L-lysine4 + 2 2-oxoglutarate + 2 O2
[histone H3]-L-lysine4 + 2 succinate + 2 formaldehyde + 2 CO2
-
lack of H3K4diMe is possibly due to complex epigenetic regulation involving Ash2 and LSD1
-
-
?
[histone H3]-N6-methyl-L-lysine 4 + 2-oxoglutarate + O2
[histone H3]-L-lysine 4 + succinate + formaldehyde + CO2
-
-
-
?
[histone H3]-N6-methyl-L-lysine 4 + 2-oxoglutarate + O2
[histone H3]-L-lysine 4 + succinate + formaldehyde + CO2
-
-
-
-
?
[histone H3]-N6-methyl-L-lysine 4 + 2-oxoglutarate + O2
[histone H3]-L-lysine 4 + succinate + formaldehyde + CO2
-
-
-
?
additional information
?
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LSD1 interacts with several interaction partners and transcription factors for performing its role in gene regulation, overview. LSD1 forms a complex with CoREST, structure with bound histone H3 peptide substrate, overview. LSD1 tightly associates with the CoREST C-terminal SANT domain. This intermolecular association is mediated by the LSD1 tower domain, whose alpha-helices are embraced by a helical segment of CoREST, generating an intermolecular helical coil. The histone H3 N-terminal peptide binds deeply in the LSD1 amine oxidase domain in proximity to the flavin cofactor
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additional information
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functional interplay between histone demethylase and histone deacetylase
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additional information
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LSD1 forms a complex with CoREST and histone deacetylase 1. LSD1 mediates the transrepressive function of TLX, an orphan nuclear receptor, also called NR2E1, that regulates the expression of target genes by functioning as a constitutive transrepressor, through direct interaction via its SWIRM and amine oxidase domains. Physiological significance of TLX in the cytodifferentiation of neural cells in the brain
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additional information
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LSD1 forms a stable complex with Rb, but with E2F1, cell cycle regulatory proteins. LSD1 binds to Epstein-Barr virus C promoter Cp in a cell cycle-dependent manner, as do the the cell cycle regulatory proteins E2F1 and Rb. Rb and LSD1 binding to Cp increase after the S phase, corresponding to a decrease in histone H3 K4 methylation and Cp transcription, overview
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additional information
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LSD1 interacts with CoREST, a co-repressor protein that binds REST and recruits other histone-modifying enzymes such as histone deacetylases 1 ? 2. The function of the LSD1CoRESThistone deacetylase subcomplex in transcriptional repression events is not limited to REST-regulated neuronal genes, but can be extended to other contexts such as hematopoietic differentiation and the telomerase reverse transcriptase genes
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additional information
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LSD1 removes the methyl groups from lysines 4 and 9 of histone 3 with the generation of formaldehyde from the methyl group
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additional information
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LSD1 directly binds to the promoter of P21 where it catalyzes H3K4me2 demethylation. FEZF1-AS1, a 2564 bp RNA overexpressed in gastric cancer, epigenetically represses the expression of P21 via binding with LSD1
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additional information
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lysine-specific demethylase 1(LSD1) demethylates mono- and dimethylated residues of lysine-4 on histone H3 (H3K4me1 and H3K4me2) and lysine-9 on histone H3 (H3K9me1 and H3K9me2)
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COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
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LSD1 recruitment to sites of DNA damage is dependent on E3 ligase RNF168, RNF168 interacts with LSD1, overview. Rapid, transient recruitment of RNF168 to damage sites is H2A.X independent
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FAD
dependent on, required for catalysis. THe FAD is noncovalently bound at the amine oxidase domain (AOD)
FAD
FAD treatment of cells enables an increase in the amount of intracellular FAD and promotes neuronal differentiation of human neural stem cells derived from fetal brain or from induced pluripotent stem cells. Depression of FAD-dependent histone demethylase, lysine-specific demethylase-1 (LSD1), prevents FAD-induced neuronal differentiation. FAD influx facilitates nuclear localization of LSD1 and its enzymatic activity
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Fe2+
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
biguanide
inhibits LSD1 and is capable of reactivating genes that are pathologically silenced in the development of colon cancer
bisguanidine polyamine analogues
inhibit LSD1 and are capable of reactivating genes that are pathologically silenced in the development of colon cancer
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tranylcypromine
inhibits LSD1 by forming a covalent adduct with the flavin moiety through the opening of the inhibitor cyclopropyl ring, binding structure, overview
(2-hydroxyacetyl)-L-alanyl-L-arginyl-L-threonyl-L-methionyl-L-glutaminyl-L-threonyl-L-alanyl-L-arginyl-L-lysyl-L-seryl-L-threonylglycylglycyl-L-lysyl-L-alanyl-L-prolyl-L-arginyl-L-lysyl-L-glutaminyl-L-leucine
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(2-hydroxyacetyl)-L-arginyl-L-threonyl-L-methionyl-L-glutaminyl-L-threonyl-L-alanyl-L-arginyl-L-lysyl-L-seryl-L-threonylglycylglycyl-L-lysyl-L-alanyl-L-prolyl-L-arginyl-L-lysyl-L-glutaminyl-L-leucine
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(2Z)-N-ethyl-N'-[4-[(4-[[(2Z)-4-(ethylamino)but-2-en-1-yl]amino]butyl)amino]butyl]but-2-ene-1,4-diamine
(2Z)-N-[4-(ethylamino)butyl]-N'-(4-[[4-(ethylamino)butyl]amino]butyl)but-2-ene-1,4-diamine
1,1'-[butane-1,4-diylbis(iminopropane-3,1-diyl)]bis[3-(2,2-diphenylethyl)guanidine]
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1,1'-[butane-1,4-diylbis(iminopropane-3,1-diyl)]bis[3-(3,3-diphenylpropyl)guanidine]
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1,1'-[heptane-1,7-diylbis(iminopropane-3,1-diyl)]bis(3-methylguanidine)
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1,1'-[heptane-1,7-diylbis(iminopropane-3,1-diyl)]bis(3-phenylguanidine)
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1,1'-[propane-1,3-diylbis(iminopropane-3,1-diyl)]bis(2,3-dimethylguanidine)
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1,1'-[propane-1,3-diylbis(iminopropane-3,1-diyl)]bis(3-methylguanidine)
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1,1'-[propane-1,3-diylbis(iminopropane-3,1-diyl)]bis(3-phenylguanidine)
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1,11-bis-[3-[1-(1,1-diphenylmethyl)thioureado]]-4,8-diazaundecane
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48.9% inhibition at 0.01 mM
1,11-bis-[3-[1-(2,2-diphenylethyl)thioureado]]-4,8-diazaundecane
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75.2% inhibition at 0.01 mM
1,11-bis-[3-[1-(3,3-diphenylpropyl)thioureado]]-4,8-diazaundecane
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7.8% inhibition at 0.01 mM
1,11-bis-[3-[1-(3,3-diphenylpropyl)ureado]]-4,8-diazaundecane
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7.1% inhibition at 0.01 mM
1,11-bis-[3-[1-(benzyl)thioureado]]-4,8-diazaundecane
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47.9% inhibition at 0.01 mM
1,11-bis-[3-[1-(ethyl)thioureado]]-4,8-diazaundecane
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63.8% inhibition at 0.01 mM
1,11-bis-[5-[1-(N,N-diphenyl)carbamyl]ureado]-4,8-diazaundecane
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8.5% inhibition at 0.01 mM
1,12-bis-[3-[1-(1,1-diphenylmethyl)thioureado]]-4,9-diazadodecane
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65.6% inhibition at 0.01 mM
1,12-bis-[3-[1-(2,2-diphenylethyl)thioureado]]-4,9-diazadodecane
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82.9% inhibition at 0.01 mM
1,12-bis-[3-[1-(3,3-diphenylpropyl)thioureado]]-4,9-diazadodecane
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21.4% inhibition at 0.01 mM
1,12-bis-[3-[1-(3,3-diphenylpropyl)ureado]]-4,9-diazadodecane
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25.4% inhibition at 0.01 mM
1,12-bis-[3-[1-(ethyl)thioureado]]-4,9-diazadodecane
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60% inhibition at 0.01 mM
1,12-bis-[3-[1-(n-propyl)thioureado]]-4,9-diazadodecane
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10.4% inhibition at 0.01 mM
1,12-bis-[5-[1-(N,N-diphenyl)carbamyl]ureado]-4,9-diazadodecane
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73.9% inhibition at 0.01 mM
1,15-bis-[3-[1-(1,1-diphenylmethyl)thioureado]]-4,12-diazapentadecane
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71.1% inhibition at 0.01 mM
1,15-bis-[3-[1-(2,2-diphenylethyl)thioureado]]-4,12-diazapentadecane
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80.5% inhibition at 0.01 mM
1,15-bis-[3-[1-(3,3-diphenylpropyl)thioureado]]-4,12-diazapentadecane
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22.7% inhibition at 0.01 mM
1,15-bis-[3-[1-(3,3-diphenylpropyl)ureado]]-4,12-diazapentadecane
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48.5% inhibition at 0.01 mM
1,15-bis-[3-[1-(benzyl)thioureado]]-4,12-diazapentadecane
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64.1% inhibition at 0.01 mM
1,15-bis-[3-[1-(n-propyl)ureado]]-4,12-diazapentadecane
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8.5% inhibition at 0.01 mM
1,15-bis-[5-[1-(N,N-diphenyl)carbamyl]ureado]-4,12-diazapentadecane
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30.0% inhibition at 0.01 mM
3-[(E)-2-[2-(5-fluoro-2-hydroxyphenyl)pyridin-4-yl]ethenyl]N'-hydroxybenzene-1-carboximidamide
potently inhibits LSD1 in a reversible and FAD competitive manner. Compound is capable of upregulating the expression of the surrogate cellular biomarker CD86 in THP-1 human leukemia cells and shows good inhibition against THP-1 and MOLM-13 cells with IC50 values of 5.76 and 8.34 microM
4-([[(1S,2R)-2-phenylcyclopropyl]amino]ethyl)benzamide
tranylcypromine-based inhibitor with selectivity for LSD1 over MAO-A and MAO-B
4-([[(1S,2R)-2-phenylcyclopropyl]amino]ethyl)benzene-1-sulfonamide
tranylcypromine-based inhibitor with selectivity for LSD1 over MAO-A and MAO-B
HCF-1
a component of the Set1 and MLL1 histone H3 Lys4 methyltransferase complexes, which coordinates modulation of repressive H3 Lys9 methylation levels with addition of activating H3 Lys4 trimethylation marks
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histone H3-1-21
peptide corresponding to the first 21 amino acids of the N-terminal tail of histone H3, competitive inhibitor
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L-alanyl-L-arginyl-L-threonyl-6-(aziridin-1-yl)norleucyl-L-glutaminyl-L-threonyl-L-alanyl-L-arginyl-L-lysyl-L-seryl-L-threonylglycylglycyl-L-lysyl-L-alanyl-L-prolyl-L-arginyl-L-lysyl-L-glutaminyl-L-leucyl-L-alanine
compound 2 decomposes when lyophilized to dryness
L-alanyl-L-arginyl-L-threonyl-6-hydroxynorleucyl-L-glutaminyl-L-threonyl-L-alanyl-L-arginyl-L-lysyl-L-seryl-L-threonylglycylglycyl-L-lysyl-L-alanyl-L-prolyl-L-arginyl-L-lysyl-L-glutaminyl-L-leucyl-L-alanine
a peptide containing an oxa-analogue of lysine at the fourth position of a 21 amino acid N-terminal histone H3 tail
L-alanyl-L-arginyl-L-threonyl-6-[(methylsulfonyl)oxy]norleucyl-L-glutaminyl-L-threonyl-L-alanyl-L-arginyl-L-lysyl-L-seryl-L-threonylglycylglycyl-L-lysyl-L-alanyl-L-prolyl-L-arginyl-L-lysyl-L-glutaminyl-L-leucyl-L-alanine
mesylate peptide
L-alanyl-L-arginyl-L-threonyl-L-methionyl-L-glutaminyl-L-threonyl-L-alanyl-L-arginyl-L-lysyl-L-seryl-L-threonylglycylglycyl-L-lysyl-L-alanyl-L-prolyl-L-arginyl-L-lysyl-L-glutaminyl-L-leucine
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L-alanyl-L-arginyl-L-threonyl-N6-(prop-2-yn-1-yl)lysyl-L-glutaminyl-L-threonyl-L-alanyl-L-arginyl-L-lysyl-L-seryl-L-threonylglycylglycyl-L-lysyl-L-alanyl-L-prolyl-L-arginyl-L-lysyl-L-glutaminyl-L-leucyl-L-alanine
a propargyl-Lys-derivatized peptide, MALDI-TOF spectrum of inhibitor-FAD conjugate, the reduced FAD (FADH2) undergoes nucleophilic attack on the propargylic imine and creates the covalent adduct
L-arginyl-L-threonyl-L-methionyl-L-glutaminyl-L-threonyl-L-alanyl-L-arginyl-L-lysyl-L-seryl-L-threonylglycylglycyl-L-lysyl-L-alanyl-L-prolyl-L-arginyl-L-lysyl-L-glutaminyl-L-leucine
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L-homoseryseryl-L-arginyl-L-threonyl-L-methionyl-L-glutaminyl-L-threonyl-L-alanyl-L-arginyl-L-lysyl-L-seryl-L-threonylglycylglycyl-L-lysyl-L-alanyl-L-prolyl-L-arginyl-L-lysyl-L-glutaminyl-L-leucyl-(N6-(L-homoseryl))-L-lysine
enzyme binding structure, overview
L-seryl-L-arginyl-L-threonyl-L-methionyl-L-glutaminyl-L-threonyl-L-alanyl-L-arginyl-L-lysyl-L-seryl-L-threonylglycylglycyl-L-lysyl-L-alanyl-L-prolyl-L-arginyl-L-lysyl-L-glutaminyl-L-leucine
enzyme binding structure, overview
N,N''''-[butane-1,4-diylbis(iminopropane-3,1-diyl)]bis[N'-(2,2-diphenylethyl)(imidodicarbonimidic diamide)]
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N,N''''-[butane-1,4-diylbis(iminopropane-3,1-diyl)]bis[N'-(3,3-diphenylpropyl)(imidodicarbonimidic diamide)]
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N,N''''-[heptane-1,7-diylbis(iminopropane-3,1-diyl)]bis[N'-(2,2-diphenylethyl)(imidodicarbonimidic diamide)]
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N,N''''-[heptane-1,7-diylbis(iminopropane-3,1-diyl)]bis[N'-(3,3-diphenylpropyl)(imidodicarbonimidic diamide)]
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N,N''''-[propane-1,3-diylbis(iminopropane-3,1-diyl)]bis[N'-(2,2-diphenylethyl)(imidodicarbonimidic diamide)]
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N,N''''-[propane-1,3-diylbis(iminopropane-3,1-diyl)]bis[N'-(3,3-diphenylpropyl)(imidodicarbonimidic diamide)]
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N-(hydroxyacetyl)-L-alanyl-L-arginyl-L-threonyl-L-methionyl-L-glutaminyl-L-threonyl-L-alanyl-L-arginyl-L-lysyl-L-seryl-L-threonylglycylglycyl-L-lysyl-L-alanyl-L-prolyl-L-arginyl-N6-(hydroxyacetyl)-L-lysyl-L-glutaminyl-L-leucine
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N-(hydroxyacetyl)-L-alanyl-L-arginyl-L-threonyl-L-methionyl-L-glutaminyl-L-threonyl-L-alanyl-L-arginyl-L-lysyl-L-seryl-L-threonylglycylglycyl-N6-(hydroxyacetyl)-L-lysyl-L-alanyl-L-prolyl-L-arginyl-L-lysyl-L-glutaminyl-L-leucine
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N-ethyl-N'-[[2-([[4-([[2-([[4-(ethylamino)butyl]amino]methyl)cyclopropyl]methyl]amino)butyl]amino]methyl)cyclopropyl]methyl]butane-1,4-diamine
N2-L-alanyl-L-arginyl-L-threonyl-L-methionyl-L-glutaminyl-L-threonyl-L-alanyl-L-arginyl-L-lysyl-L-seryl-L-threonylglycylglycyl-L-lysyl-L-alanyl-L-prolyl-L-arginyl-N6-(2-hydroxyacetyl)-L-lysyl-L-glutaminyl-L-leucine
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N2-L-alanyl-L-arginyl-L-threonyl-L-methionyl-L-glutaminyl-L-threonyl-L-alanyl-L-arginyl-L-lysyl-L-seryl-L-threonylglycylglycyl-N6-(2-hydroxyacetyl)-L-lysyl-L-alanyl-L-prolyl-L-arginyl-L-lysyl-L-glutaminyl-L-leucine
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N2-L-seryl-L-arginyl-L-threonyl-L-methionyl-L-glutaminyl-L-threonyl-L-alanyl-L-arginyl-L-lysyl-L-seryl-L-threonylglycylglycyl-L-lysyl-L-alanyl-L-prolyl-L-arginyl-(N6-(L-seryl))-L-lysyl-L-glutaminyl-L-leucine
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N2-L-seryl-L-arginyl-L-threonyl-L-methionyl-L-glutaminyl-L-threonyl-L-alanyl-L-arginyl-L-lysyl-L-seryl-L-threonylglycylglycyl-L-lysyl-L-alanyl-L-prolyl-L-arginyl-L-lysyl-L-glutaminyl-L-leucyl-(N6-(L-seryl))-L-lysine-amide
enzyme binding structure, overview
N2-L-seryl-L-arginyl-L-threonyl-L-methionyl-L-glutaminyl-L-threonyl-L-alanyl-L-arginyl-L-lysyl-L-seryl-L-threonylglycylglycyl-L-lysyl-L-alanyl-L-prolyl-L-arginyl-L-lysyl-L-glutaminyl-L-leucyl-L-alanyl-L-threonyl-(N6-(L-seryl))-L-lysine-amide
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PCPA-Lys-4 H3-11
11-mer histone H3 peptide because the 11-mer bearing a trans-2-phenylcyclopropylamine moiety at Lys-4
PCPA-Orn-4 H3-11
11-mer histone H3 peptide because the 11-mer bearing a trans-2-phenylcyclopropylamine moiety at Orn-4
peptide H3K4M
the modified H3 peptide with substitution of Lys4 to Met [H3K4M] is known to be a potent competitive inhibitor of LSD1
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trans-2-phenylcyclopropylamine
i.e. tranylcypromine; Parnate. Mechanism-based suicide inactivator, inactivation of LSD1 occurs with similar rates as the demethylation of substrates
(19E)-N,N'-diethyl-6,12,17,22,27,33-hexaazaoctatriacont-19-ene-1,38-diamine
i.e PG-11144, exhibits competitive inhibition kinetics at concentrations below 0.010 mmol/l. PG-11144 combined with a DNMT inhibitor increases H3K4 methylation and profoundly inhibits growth of established tumors in vivo
(19Z)-N,N'-diethyl-6,12,17,22,27,33-hexaazaoctatriacont-19-ene-1,38-diamine
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(25E)-N,N'-diethyl-5,11,17,23,28,33,39,45-octaazapentacont-25-ene-1,50-diamine
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(25E)-N,N'-diethyl-5,11,17,23,28,33,39,45-octaazapentacont-25-ene-1,50-diamine
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(25Z)-N,N'-diethyl-6,12,18,23,28,33,39,45-octaazapentacont-25-ene-1,50-diamine
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(25Z)-N,N'-diethyl-6,12,18,23,28,33,39,45-octaazapentacont-25-ene-1,50-diamine
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(2Z)-N-ethyl-N'-[4-[(4-[[(2Z)-4-(ethylamino)but-2-en-1-yl]amino]butyl)amino]butyl]but-2-ene-1,4-diamine
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(2Z)-N-ethyl-N'-[4-[(4-[[(2Z)-4-(ethylamino)but-2-en-1-yl]amino]butyl)amino]butyl]but-2-ene-1,4-diamine
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(2Z)-N-[4-(ethylamino)butyl]-N'-(4-[[4-(ethylamino)butyl]amino]butyl)but-2-ene-1,4-diamine
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(2Z)-N-[4-(ethylamino)butyl]-N'-(4-[[4-(ethylamino)butyl]amino]butyl)but-2-ene-1,4-diamine
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1,11-bis-[3-[1-(n-propyl)ureado]]-4,8-diazaundecane
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48.7% inhibition at 0.01 mM
histone H3
full-length histone H3, which lacks any posttranslational modifications, is a tight-binding, competitive inhibitor
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histone H3
full-length histone H3, which lacks any posttranslational modifications, is a tight-binding, competitive inhibitor of KDM1A demethylation activity with a Ki of 18.9 nM, a value that is approximately 100fold higher than that of the 21-mer peptide of H3. The relative H3 affinity is independent of preincubation time, suggesting that H3 rapidly reaches equilibrium with KDM1A, tight-binding nature of the H3/KDM1A interaction, kinetics, overview. No other core histones exhibits inhibition of KDM1A demethylation activity, which is consistent with H3 being the preferred histone substrate of KDM1A versus H2A, H2B, and H4. Inhibition profiling of full-length histone H3 against KDM1A
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N-ethyl-N'-[[2-([[4-([[2-([[4-(ethylamino)butyl]amino]methyl)cyclopropyl]methyl]amino)butyl]amino]methyl)cyclopropyl]methyl]butane-1,4-diamine
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N-ethyl-N'-[[2-([[4-([[2-([[4-(ethylamino)butyl]amino]methyl)cyclopropyl]methyl]amino)butyl]amino]methyl)cyclopropyl]methyl]butane-1,4-diamine
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tranylcypromine
an amino oxidase inhibitor, upregulates hTERT expression and telomerase activity concomitant with elevated H3K4me2 levels and H3 acetylation at the hTERT proximal promoter in cancer cells
tranylcypromine
i.e. Parnate, binding structure analysis and modeling, overview. The LSD1-tranylcypromine complex is not completely composed of the five-membered adduct, but partially contains an intermediate. LSD1-flavin is the only place modified by this inhibition
additional information
design and development of LSD1 inhibitors, overview
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additional information
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(bis)urea and (bis)thiourea inhibitors of lysine-specific demethylase 1 as epigenetic modulators with the potential for use as antitumor agents, overview. No inhibition by 7 and 17, poor inhibition by 11
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additional information
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oligoamine analogues inhibit lysine-specific demethylase 1 and induce reexpression of epigenetically silenced genes, overview. Treatment of HCT-116 colon adenocarcinoma cells in vitro results in increased H3K4 methylation and reexpression of silenced SFRP genes. This reexpression is also accompanied by a decrease in H3K9me2 repressive mark
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additional information
structural analysis of homoserine-substituted inhibitor peptide-bound LSD1-CoREST complex, overview
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additional information
a suicide inhibitor consisting of a 21-residue histone H3 peptide, in which K4 is modified by an N-methylpropargyl group, forms a covalent adduct with the reactive N5 atom of the flavin isoalloxazine ring via the N-methylpropargyl group, permitting the visualization of the first seven residues in the histone H3 peptide in the crystal structure. The residues adopt three successive gamma-turns, resulting in an approximately W-shaped conformation of the H3 peptide backbone. The inhibitor and LSD1 interact through a series of main and side chain hydrogen bonds and van der Waals contacts, further stabilizing the compact conformation of the H3 peptide. Notable interactions with the inhibitor include hydrogen bonds to its R2 and Q5 side chains and a salt bridge interaction between the alpha-amine of A1 and Asp555 in LSD. The addition of acetyl or glycyl blocking groups to the N-terminus of the H3K4me2 peptide or the substitution of the epsilon-amine of A1 with a methyl group disrupts the ionic interaction between Asp555 in LSD1 and the H3 peptide alpha-amine, diminishing specificity over 20fold. And analysis of the LSD1/CoREST-C complex co-crystallized with a 20-residue histone H3 peptide inhibitor in which Lys4 is mutated to a methionine (H3K4M). The overall conformation of the H3K4M peptide is roughly U-shaped, a binding mode that is strikingly different than the gamma-turn geometry adopted by the suicide inhibitor. The peptide's binding is stabilized by a complex network of intramolecular hydrogen bonds and intermolecular hydrogen bonds and van der Waals contacts with residues comprising the substrate binding cleft of LSD1. In particular, multiple hydrogen bonds and salt bridge interactions with the guanidinium groups of R2 and R8 in H3K4M appear to be important in maintaining the peptide's conformation and interactions with LSD1. This binding mode positions M4, which functions as a methyllysine mimic, into the pocket adjacent to the flavin moiety of FAD. Modeling of K4me2 based on the coordinates of the M4 side chain indicates that the dimethyl epsilon-amine group is at an appropriate distance for hydride transfer to the N5 atom in the FAD isoalloxazine ring
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additional information
besides histone H3, no other core histones exhibit inhibition of KDM1A demethylation activity
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additional information
biguanide and bisguanidine polyamine analogues are potent inhibitors of LSD1. These analogues inhibit LSD1 in human colon carcinoma cells and affect a reexpression of multiple, aberrantly silenced genes important in the development of colon cancer, including members of the secreted frizzle-related proteins (SFRPs) and the GATA family of transcription factors. Reexpression is concurrent with increased H3K4me2 and acetyl-H3K9 marks, decreased H3K9me1 and H3K9me2 repressive marks. Inhibition detection via global H3K4me1 and H3K4me2 levels. HCT116 cells are exposed to increasing concentrations of the indicated compound for 48 h,and 00.03 mg of nuclear protein per lane is analyzed for expression of H3K4me1, H3K4me2, and H3K9me2, overview. Exposure to compounds 1c and 2d produces significant increases in both H3K4me1 and H3K4me2, without affecting global H3K9me2 levels
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additional information
demethylation activity is decreased by other modifications on the H3 tail, such as acetylation and phosphorylation, suggesting possible regulatory mechanisms
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additional information
depletion of LSD1 or inhibition of its activity with monoamine oxidase inhibitors (MAOIs) results in the accumulation of repressive chromatin and a block to viral gene expression
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additional information
histone deacetylase (HDAC) inhibitors are a promising class of anticancer agents for the treatment of solid and hematological malignancies. HDAC inhibitors diminish histone H3 lysine 4 (H3K4) demethylation by LSD1 in vitro. In vivo analysis reveals an increased H3K4 methylation concomitant with inhibition of nucleosomal deacetylation by HDAC inhibitors. Histone H3K4 demethylation is a secondary target of HDAC inhibitors
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additional information
inhibitor synthesis and proposed inactivation mechanism of LSD1, overview
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additional information
KDM1A tolerance for 3-[(3-cholamidopropyl)-dimethylammonio]-1-propanesulfonate (CHAPS) at 0.01% w/v and dimethyl sulfoxide (DMSO) at 10% v/v
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additional information
N-substituted tranylcypromine derivatives without a basic function or even a polar group are potent inhibitors of LSD1 in vitro and effectively inhibit colony formation of leukemic cells in culture, but block the structurally related monoamine oxidases. The introduction of a polar, non-basic function leads to optimized structures that retain potent LSD1 inhibitors but exhibit selectivity over MAOs and are highly potent in the suppression of colony formation of cultured leukemic cells
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additional information
oligoamine analogues are competitive inhibitors of recombinant LSD1. Oligoamine analogues inhibit lysine-specific demethylase 1 and induce reexpression of epigenetically silenced genes, overview. Treatment of HCT-116 colon adenocarcinoma cells in vitro results in increased H3K4 methylation and reexpression of silenced SFRP genes. This reexpression is also accompanied by a decrease in H3K9me2 repressive mark. Use of LSD1 inhibitors in combination with a DNA methyltransferase (DNMT) inhibitors (5-aza-2'-deoxycitidine and 5-azacytidine) is a combination that is not only more efficacious in reactivating specific aberrantly silenced genes but also leads to profound inhibition of the growth of established human colon cancer xenografts in a nude mouse model
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additional information
small molecule inhibitors of LSD1 inhibit xenograft tumor growth
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additional information
trans-2-phenylcyclopropylamine-modified peptides containing a longer side chain, which can react with FAD in the active site, are potent LSD1-selective inhibitors
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
-
binding kinetic analysis of folate derivatives, e.g. folates bound to glutamates, the (6R,S) form of the natural pentaglutamate form of tetrahydrofolate bound with the highest affinity to full-length LSD1, overview
-
CoREST
-
the co-repressor CoREST stabilizes LSD1 and increases in vitro LSD1 activity by approximately twofold and is essential for LSD1-mediated demethylation in intact nucleosomes in vivo and for the in vitro demethylation of nucleosomal particles, binding structure, overview
-
CoREST
i.e. REST corepressor 1, regulates LSD1 activity towards nucleosomes. CoREST does not alter the catalytic efficiency toward minimal peptide substrat
-
tetrahydrofolate
binding kinetic analysis of folate derivatives, e.g. folates bound to glutamates, the (6R,S) form of the natural pentaglutamate form of tetrahydrofolate bound with the highest affinity to full-length LSD1, binding of different forms of folate to LSD1, and binding structures, overview
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.195
O2
recombinant enzyme LSD1, pH 7.5, 25°C, with H3K4me2 (1-21 aa) peptide
0.00446
H3K4me2 1-21 peptide
pH 7.5, 25°C, recombinant N-terminally truncated KDM1A
-
0.00814
H3K4me2 1-21 peptide
pH 7.5, 25°C, recombinant N-terminally truncated KDM1A-CoREST-C complex
-
0.00889
H3K4me2 1-21 peptide
pH 7.5, 25°C, recombinant N-terminally truncated KDM1A-CoREST-Linker complex
-
0.00446
[histone H3]-N6,N6-L-dimethyllysine4-1-21
recombinant enzyme, pH 7.5, 25°C
-
0.00814
[histone H3]-N6,N6-L-dimethyllysine4-1-21
recombinant enzyme, presence of activator CoREST, pH 7.5, 25°C
-
0.00889
[histone H3]-N6,N6-L-dimethyllysine4-1-21
recombinant enzyme, presence of a protein corresponding to the linker region of activator CoREST, pH 7.5, 25°C
-
additional information
additional information
dissociation constant for substrate H3K4me2 peptide 3-21 is 0.080 mM
-
additional information
additional information
Michaelis-Menten steady-state kinetics of N-terminally truncated KDM1A and differential KDM1A/CoREST complexes using an H3K4me2 1-21 peptide substrate
-
additional information
additional information
Michaelis-Menten steady-state kinetics, stopped-flow data, kinetic isotope effects at different pH values from pH 7.0-9.5, overview
-
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.1
H3K4me2 1-21 peptide
pH 7.5, 25°C, recombinant N-terminally truncated KDM1A
-
0.157
H3K4me2 1-21 peptide
pH 7.5, 25°C, recombinant N-terminally truncated KDM1A-CoREST-Linker complex
-
0.159
H3K4me2 1-21 peptide
pH 7.5, 25°C, recombinant N-terminally truncated KDM1A-CoREST-C complex
-
0.1
[histone H3]-N6,N6-L-dimethyllysine4-1-21
recombinant enzyme, pH 7.5, 25°C
-
0.157
[histone H3]-N6,N6-L-dimethyllysine4-1-21
recombinant enzyme, presence of a protein corresponding to the linker region of activator CoREST, pH 7.5, 25°C
-
0.159
[histone H3]-N6,N6-L-dimethyllysine4-1-21
recombinant enzyme, presence of activator CoREST, pH 7.5, 25°C
-
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
17.66
H3K4me2 1-21 peptide
pH 7.5, 25°C, recombinant N-terminally truncated KDM1A-CoREST-Linker complex
-
19.53
H3K4me2 1-21 peptide
pH 7.5, 25°C, recombinant N-terminally truncated KDM1A-CoREST-C complex
-
22.42
H3K4me2 1-21 peptide
pH 7.5, 25°C, recombinant N-terminally truncated KDM1A
-
17.67
[histone H3]-N6,N6-L-dimethyllysine4-1-21
recombinant enzyme, presence of a protein corresponding to the linker region of activator CoREST, pH 7.5, 25°C
-
19.5
[histone H3]-N6,N6-L-dimethyllysine4-1-21
recombinant enzyme, presence of activator CoREST, pH 7.5, 25°C
-
22.5
[histone H3]-N6,N6-L-dimethyllysine4-1-21
recombinant enzyme, pH 7.5, 25°C
-
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.5
(2-hydroxyacetyl)-L-alanyl-L-arginyl-L-threonyl-L-methionyl-L-glutaminyl-L-threonyl-L-alanyl-L-arginyl-L-lysyl-L-seryl-L-threonylglycylglycyl-L-lysyl-L-alanyl-L-prolyl-L-arginyl-L-lysyl-L-glutaminyl-L-leucine
pH 7.5, 25°C
0.17
(2-hydroxyacetyl)-L-arginyl-L-threonyl-L-methionyl-L-glutaminyl-L-threonyl-L-alanyl-L-arginyl-L-lysyl-L-seryl-L-threonylglycylglycyl-L-lysyl-L-alanyl-L-prolyl-L-arginyl-L-lysyl-L-glutaminyl-L-leucine
pH 7.5, 25°C
0.0156
L-alanyl-L-arginyl-L-threonyl-6-(aziridin-1-yl)norleucyl-L-glutaminyl-L-threonyl-L-alanyl-L-arginyl-L-lysyl-L-seryl-L-threonylglycylglycyl-L-lysyl-L-alanyl-L-prolyl-L-arginyl-L-lysyl-L-glutaminyl-L-leucyl-L-alanine
pH and temperature not specified in the publication
0.000098
L-alanyl-L-arginyl-L-threonyl-L-methionyl-L-glutaminyl-L-threonyl-L-alanyl-L-arginyl-L-lysyl-L-seryl-L-threonylglycylglycyl-L-lysyl-L-alanyl-L-prolyl-L-arginyl-L-lysyl-L-glutaminyl-L-leucine
pH 7.5, 25°C
0.0043
L-alanyl-L-arginyl-L-threonyl-N6-(prop-2-yn-1-yl)lysyl-L-glutaminyl-L-threonyl-L-alanyl-L-arginyl-L-lysyl-L-seryl-L-threonylglycylglycyl-L-lysyl-L-alanyl-L-prolyl-L-arginyl-L-lysyl-L-glutaminyl-L-leucyl-L-alanine
pH and temperature not specified in the publication
0.5
L-arginyl-L-threonyl-L-methionyl-L-glutaminyl-L-threonyl-L-alanyl-L-arginyl-L-lysyl-L-seryl-L-threonylglycylglycyl-L-lysyl-L-alanyl-L-prolyl-L-arginyl-L-lysyl-L-glutaminyl-L-leucine
pH 7.5, 25°C
0.0063
L-homoseryseryl-L-arginyl-L-threonyl-L-methionyl-L-glutaminyl-L-threonyl-L-alanyl-L-arginyl-L-lysyl-L-seryl-L-threonylglycylglycyl-L-lysyl-L-alanyl-L-prolyl-L-arginyl-L-lysyl-L-glutaminyl-L-leucyl-(N6-(L-homoseryl))-L-lysine
pH 7.5, 25°C
0.00003
L-seryl-L-arginyl-L-threonyl-L-methionyl-L-glutaminyl-L-threonyl-L-alanyl-L-arginyl-L-lysyl-L-seryl-L-threonylglycylglycyl-L-lysyl-L-alanyl-L-prolyl-L-arginyl-L-lysyl-L-glutaminyl-L-leucine
pH 7.5, 25°C
0.5
N-(hydroxyacetyl)-L-alanyl-L-arginyl-L-threonyl-L-methionyl-L-glutaminyl-L-threonyl-L-alanyl-L-arginyl-L-lysyl-L-seryl-L-threonylglycylglycyl-L-lysyl-L-alanyl-L-prolyl-L-arginyl-N6-(hydroxyacetyl)-L-lysyl-L-glutaminyl-L-leucine
pH 7.5, 25°C
0.5
N-(hydroxyacetyl)-L-alanyl-L-arginyl-L-threonyl-L-methionyl-L-glutaminyl-L-threonyl-L-alanyl-L-arginyl-L-lysyl-L-seryl-L-threonylglycylglycyl-N6-(hydroxyacetyl)-L-lysyl-L-alanyl-L-prolyl-L-arginyl-L-lysyl-L-glutaminyl-L-leucine
pH 7.5, 25°C
0.0014
N2-L-alanyl-L-arginyl-L-threonyl-L-methionyl-L-glutaminyl-L-threonyl-L-alanyl-L-arginyl-L-lysyl-L-seryl-L-threonylglycylglycyl-L-lysyl-L-alanyl-L-prolyl-L-arginyl-N6-(2-hydroxyacetyl)-L-lysyl-L-glutaminyl-L-leucine
pH 7.5, 25°C
0.0098
N2-L-alanyl-L-arginyl-L-threonyl-L-methionyl-L-glutaminyl-L-threonyl-L-alanyl-L-arginyl-L-lysyl-L-seryl-L-threonylglycylglycyl-N6-(2-hydroxyacetyl)-L-lysyl-L-alanyl-L-prolyl-L-arginyl-L-lysyl-L-glutaminyl-L-leucine
pH 7.5, 25°C
0.00038
N2-L-seryl-L-arginyl-L-threonyl-L-methionyl-L-glutaminyl-L-threonyl-L-alanyl-L-arginyl-L-lysyl-L-seryl-L-threonylglycylglycyl-L-lysyl-L-alanyl-L-prolyl-L-arginyl-(N6-(L-seryl))-L-lysyl-L-glutaminyl-L-leucine
pH 7.5, 25°C
0.00006
N2-L-seryl-L-arginyl-L-threonyl-L-methionyl-L-glutaminyl-L-threonyl-L-alanyl-L-arginyl-L-lysyl-L-seryl-L-threonylglycylglycyl-L-lysyl-L-alanyl-L-prolyl-L-arginyl-L-lysyl-L-glutaminyl-L-leucyl-(N6-(L-seryl))-L-lysine-amide
pH 7.5, 25°C
0.00029
N2-L-seryl-L-arginyl-L-threonyl-L-methionyl-L-glutaminyl-L-threonyl-L-alanyl-L-arginyl-L-lysyl-L-seryl-L-threonylglycylglycyl-L-lysyl-L-alanyl-L-prolyl-L-arginyl-L-lysyl-L-glutaminyl-L-leucyl-L-alanyl-L-threonyl-(N6-(L-seryl))-L-lysine-amide
pH 7.5, 25°C
additional information
additional information
inhibition kinetics, steady-state progress curves are obtained for the inactivation of LSD1
-
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.283
3-[(E)-2-[2-(5-fluoro-2-hydroxyphenyl)pyridin-4-yl]ethenyl]N'-hydroxybenzene-1-carboximidamide
Homo sapiens
pH not specified in the publication, temperature not specified in the publication
0.000195
4-([[(1S,2R)-2-phenylcyclopropyl]amino]ethyl)benzamide
Homo sapiens
pH 8.5, 22°C
0.000147
4-([[(1S,2R)-2-phenylcyclopropyl]amino]ethyl)benzene-1-sulfonamide
Homo sapiens
pH 8.5, 22°C
0.000154
PCPA-Lys-4 H3-11
Homo sapiens
pH not specified in the publication, temperature not specified in the publication
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
7.2 - 7.5
8.5
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
22
25
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
during the differentiation of leukemic HL60 cells, the decreased hTERT expression is accompanied by the LSD1 recruitment to the hTERT promoter
lysine-specific demethylase 1 is strongly expressed in poorly differentiated neuroblastoma
additional information
-
BALB c nu/nu athymic nude mice are implanted with the human colorectal cancer HCT-116 cells
nuclear extracts of HeLa cells contain LSD1 that is associated with folate
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
additional information
-
H3K4me2 demethylation marks sites of DNA damage and occurs primarily in late S/G2
-
-
-
association of LSD1 with sites of DNA damage, immunohistochemic localization, overview
presence of FAD facilitates the nuclear localization of LSD1
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
physiological function
generally LSD1 shows an extensive involvement in gene activation, rather than repression, dual role of LSD1 in gene repression and activation is demonstrated by the fine regulation of growth hormone expression during pituitary development
evolution
malfunction
metabolism
physiological function
additional information
evolution
histone methylation can be reversed by several histone demethylases, including PAD4/PADI4, BHC110/LSD1, and JmjC domain-containing demethylases. a family of multiprotein complexes contains histone deacetylase 1/2 (HDAC1/2) and the histone demethylase LSD1 (BHC110). LSD1 demethylates mono- and dimethyl histone H3 lysine 4 (H3K4) and belongs to a family of FAD-dependent polyamine oxidases which use molecular oxygen as an electron acceptor to oxidize an amine group
evolution
LSD1 belongs to the amine oxidase family which are flavin-dependent enzymes that utilize O2 and generate H2O2 and formaldehyde as byproducts
evolution
LSD1 belongs to the flavin adenine dinucleotide (FAD)-dependent amino oxidase family and is conserved in Schizosaccharomyces pombe through humans
malfunction
-
loss of LSD1 causes gamma-irradiation hypersensitivity and increased homologous recombination
malfunction
depletion of LSD1 or inhibition of its activity with monoamine oxidase inhibitors (MAOIs) results in the accumulation of repressive chromatin and a block to viral gene expression. HCF-1 depletion resulted in a concomitant decrease in the recruitment of LSD1
malfunction
Differentiation of neuroblastoma cells results in down-regulation of LSD1. Small interfering RNA-mediated knockdown of LSD1 decreases cellular growth, induces expression of differentiation-associated genes, and increases target gene-specific H3K4 methylation. LSD1 inhibition using monoamine oxidase inhibitors results in an increase of global H3K4 methylation and growth inhibition of neuroblastoma cells in vitro. Small molecule inhibitors of LSD1 inhibit xenograft tumor growth
malfunction
in normal human fibroblasts with a tight hTERT repression, a pharmacological inhibition of LSD1 leads to a weak hTERT expression, and a robust induction of hTERT mRNA occurs when LSD1 and histone deacetylases are both inhibited. Small interference RNA-mediated depletion of both LSD1 and CoREST, a co-repressor in HDAC-containing complexes, synergistically activate hTERT transcription. In cancer cells, inhibition of LSD1 activity or knocking-down of its expression lead to significant increases in levels of hTERT mRNA and telomerase activity, phenotype, overview. LSD1 occupies the hTERT proximal promoter, and its depletion results in elevated dimethylation of histone H3-K4 accompanied by increased H3 acetylation locally in cancer cells
malfunction
inhibition of LSD1 by polyamine analogues increases activating H3K4me2 and acetyl H3K9 marks and decreases repressive H3K9me1 and H3K9me2 marks at the promoters of reexpressed genes
malfunction
knockdown of LSD1 diminishes LSD1 occupancy on the IL1beta and the IL6 promoter, while promoter occupancy on those promoters cannot be detected with an IgG control antibody. Inhibition of LSD1 by an siRNA approach is accompanied by an increase of the active histone mark H3K4me2 and a decrease in the repressive H3K9me2 mark, resulting in activation of IL1beta and IL6 genes after LSD1 silencing
malfunction
treatment of HCT-116 colon adenocarcinoma cells with oligoamine analogues inhibitors in vitro results in increased H3K4 methylation and reexpression of silenced SFRP genes. This reexpression is also accompanied by a decrease in H3K9me2 repressive mark
metabolism
-
histone methylation is a dynamic process regulated by the addition of methyl groups by histone methyltransferases and removal of methyl groups from mono- and dimethyllysines by lysine specific demethylase 1, LSD1, and from mono-, di, and trimethyllysines by specific JumonjiC, JmjC, domain-containing demethylases
metabolism
a family of multiprotein complexes contains histone deacetylase 1/2 (HDAC1/2) and the histone demethylase BHC110 (LSD1). Reconstitution of recombinant complexes reveals a functional connection between HDAC1 and BHC110 only when nucleosomal substrates are present. The enzymatic activity of BHC110 is required to achieve optimal deacetylation in vitro. In vivo functional cross talk between the demethylase and deacetylase enzymes is detected. Demethylation of nucleosomes enhances deacetylation
metabolism
demethylation activity is decreased by other modifications on the H3 tail, such as acetylation and phosphorylation, suggesting possible regulatory mechanisms
metabolism
histone modification is a major mechanism of regulation in gene expression, replication, and repair
metabolism
LincRNAFEZF1-AS1 represses p21 expression to promote gastric cancer proliferation through LSD1-mediated H3K4me2 demethylation. FEZF1-AS1 recruits and binds to LSD1 to epigenetically repress downstream gene p21, thereby promoting proliferation in advanced stages of gastric cancer. FEZF1-AS1 is a long non-coding RNA (lncRNA) producing a 2564 bp transcript, located in chromosome 7. FEZF1-AS1 upregulation is associated with tumor size, stage and poor survival of gastric cancer patients. FEZF1-AS1 promotes gastric cancer cells proliferation in vitro and vivo
physiological function
-
LSD1 acts as a prime corepressor for TLX, LSD1 interacts directly with TLX via its SWIRM and amine oxidase domains potentiating the transrepressive function of TLX through its histone demethylase activity. LSD1 and TLX are recruited to a TLX-binding site in the PTEN gene promoter, accompanied by the demethylation of H3K4me2 and deacetylation of H3
physiological function
-
LSD1 plays a role in gene expression regulation, it is a multidomain protein and its involvement in many diverse gene-expression programs is strictly related to its domain organization
physiological function
-
LSD1 plays an important role in the epigenetic control of gene expression, and aberrant gene silencing secondary to LSD1 overexpression is thought to contribute to the development of cancer
physiological function
-
H3K4me2 demethylation marks sites of DNA damage and is cell cycle and LSD1 dependent. LSD1 recruitment to sites of DNA damage is dependent on E3 ligase RNF168, overview. LSD1 is recruited to sites of DNA damage but its retention is relatively transient. LSD1 promotes 53BP1 foci formation primarily in late S/G2 cells, and LSD1 promotes H2A/H2A.X ubiquitylation upon DNA damage
physiological function
methylation on the N-terminal tails of histone lysines serves as an epigenetic control mechanism, which is regulated by demathylases
physiological function
-
methylation on the N-terminal tails of histone lysines serves as an epigenetic control mechanism, which is regulated by demethylases
physiological function
enzyme LSD1 participates in development and differentiation regulation of chromatin remodeling and histone demethylation, and specifically catalyses the demethylation of mono- and di-methylated histone H3 lysine 4 (H3K4) and H3 lysine 9 (H3K9) through a redox process. LSD1 directly binds to the promoter of P21 where it catalyzes H3K4me2 demethylation. FEZF1-AS1, a 2564 bp RNA overexpressed in gastric cancer, epigenetically represses the expression of P21 via binding with LSD1. Knockdown FEZF1-AS1 significantly inhibits gastric cancer cells proliferation by inducing G1 arrest and apoptosis, whereas endogenous expression FEZF1-AS1 promotes cell growth. FEZF1-AS1 epigenetically silences P21 transcription through LSD1-mediated H3K4me2 demethylation
physiological function
dimethyl-lysine 4 histone H3 (H3K4me2) is a transcription-activating chromatin mark at gene promoters, and demethylation of this mark by the lysine-specific demethylase 1 (LSD1), a homologue of polyamine oxidases, broadly represses gene expression. Role of LSD1 in the regulation of gene expression, overview
physiological function
enzyme LSD1 participates in development and differentiation regulation of chromatin remodeling and histone demethylation, and specifically catalyses the demethylation of mono- and di-methylated histone H3 lysine 4 (H3K4) and H3 lysine 9 (H3K9) through a redox process. LSD1 directly binds to the promoter of P21 where it catalyzes H3K4me2 demethylation
physiological function
in non-neural cells, LSD1 removes the transcriptionally active mark of histone H3 Lys4 (H3K4) methyl groups, thereby repressing neuron-specific genes. Recombinant LSD1 alone cannot demethylate nucleosomal H3K4, and CoREST, another component of the complex, is required for the nucleosome-dependent demethylation. LSD1 can act as a transcriptional activator. LSD1 can target different lysine residues and regulate transcription positively or negatively, depending on its binding partners. The large number of LSD1-enriched promoters suggest a broad role in transcriptional regulation for LSD1
physiological function
infection by the alpha-herpesviruses Herpes simplex virus and Varicella zoster virus results in the rapid accumulation of chromatin bearing repressive histone H3 Lys9 methylation. To enable expression of viral immediate early (IE) genes, both viruses use the cellular transcriptional coactivator host cell factor-1, HCF-1, to recruit the lysine-specific demethylase-1, LSD1, to the viral immediate early promoters. LSD1 has a role in viral IE62-mediated activation, LSD1 is crucial for IE gene expression during viral infection, HCF-1-LSD1 complex is essential for alpha-herpesvirus IE gene transcription. Reversible methylation of histone tails serves as either a positive signal recognized by transcriptional assemblies or a negative signal that result in repression. The H3K9 demethylase activity of LSD1 is crucial for nuclear hormone receptor-dependent transcription and cell fate determination, and LSD1 is crucial for viral activator-mediated transcription of herpes simplex virus and varicella zoster virus IE model promoters. As LSD1 can demethylate both H3K4 and H3K9, the coupling of this protein in the HCF-1 Set1 or MLL methyltransferase complex may enhance H3K9 demethylation or preferentially target it to this substrate, although additional histone modifications and modification activities may also contribute to the H3K4 or H3K9 recognition and specificity
physiological function
LSD1 allows transcription factors or corepressor complexes to selectively initiate or repress transcription via demethylation of lysine residues 4 or 9 of histone 3, thereby controlling gene expression programs. LSD1 modulates tumor cell biology by demethylating monomethyl and dimethyl lysines 4 or 9 in histone H3. LSD1 specificity and mechanism of action are complex-dependent. Expression of the chromatin-modifying enzyme lysine-specific demethylase 1 in neuroblastoma is correlated with adverse outcome and inversely correlated with differentiation in neuroblastic tumors
physiological function
LSD1 can repress gene expression through the demethylation H3K4me1/2, this methylation site is associated with transcriptionally poised or active genes. But LSD1 also associates with the androgen receptor (AR) to enhance the expression of AR target genes. LSD1 is implicated in AR-dependent demethylation of H3K9me1/2, a methylation site enriched in silent chromatin. Enzyme Lsd1 demethylate mono- and dimethylated Lys370 in the regulatory domain of the tumor suppressor p53, precluding the binding of the transcriptional coactivator 53BP1. The complexes in which LSD1 resides tightly coordinate its gene regulatory functions and also influence its specificity for histone and non-histone substrates. LSD1 possesses coactivator functions
physiological function
LSD1 catalyzes the demethylation of mono- and dimethylated histone H3-K4 and also H3-K9, it exhibits diverse transcriptional activities by mediating chromatin reconfiguration. LSD1 represses hTERT transcription via demethylating H3-K4 in normal and cancerous cells, and together with HDACs, participates in the establishment of a stable repression state of the hTERT gene in normal or differentiated malignant cells. Role for LSD1 in controlling hTERT transcription
physiological function
LSD1 is a nuclear amine oxidase that utilizes oxygen as an electron acceptor to reduce methylated lysine to form lysine. It demethylates H3K4m1 and H3K4m2, as well as H3K9m1 and H3K9m2 as a removal of the active methylation mark. LSD1 is associated with co-repressor complexes and promotes suppression or activation of gene expression, e.g. LSD1 might be associated to cooperative recruitment to the NFkappaB p65 site for activation in hyperglycemia
physiological function
LSD1 is a substrate and an interacting partner of protein kinase CK2. The N-terminal region of LSD1 contains CK2 phosphosites Ser131, Ser137 and Ser166. This domain is not essential for LSD1 catalytic activity but may modulate the interaction with CK2 and with other partners in gene repressing and activating complexes
physiological function
lysine-specific demethylase 1A (KDM1A/LSD1) is a FAD-dependent enzyme that catalyzes the oxidative demethylation of histone H3K4me1/2 and H3K9me1/2 repressing and activating transcription, respectively
physiological function
the catalytic activity of lysine-specific demethylase 1 (LSD1) is required for regulation of inflammatory cytokines. LSD1 functions as a transcriptional coregulator through demethylating histone H3 on lysine 4 and lysine 9. Repressive role of LSD1 in proinflammatory cytokine expression such as interleukins IL1alpha, IL1beta, IL6, and IL8 and classical complement components, LSD1 occupies and regulates the promoter of these genes. LSD1 regulates several genes of the complement system in Hep-G2 cells. LSD1 binds directly to the promoter of the IL1beta and IL6 genes
additional information
-
inhibition of LSD1 by oligoamines increases activating H3K4me2 and H3K4me1 marks and decreases repressive H3K9me2 marks at the promoters of reexpressed genes
additional information
-
mechanism of histone H3 demethylation by demethylase LSD1, overview
additional information
mechanism of histone H3 demethylation by demethylase LSD1, overview
additional information
although the active site is expanded compared to that of members of the greater amine oxidase superfamily, it is too much sterically restricted to encompass the minimal 21-mer peptide substrate footprint. The remainder of the substrate/product is therefore expected to extend along the surface of KDM1A
additional information
demethylation by LSD1 is consistent with an amine oxidase-based mechanism in which the methyllysine Nepsilon-CH3 bond is oxidized to an imine intermediate. The reducing equivalents are concomitantly transferred to FAD yielding FADH2, which is recycled to its oxidized state through reduction of molecular oxygen to hydrogen peroxide. The methyllysine imine intermediate subsequently undergoes hydrolysis, resulting in the demethylation of the lysine epsilon-amine group and the release of the byproduct formaldehyde. The reaction mechanism of LSD1 requires a protonatable lysine epsilon-amine for amine oxidation
additional information
transient hyperglycemia induces recruitment of LSD1 to gene regulation sites/promoters
additional information
-
transient hyperglycemia induces recruitment of LSD1 to gene regulation sites/promoters
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). MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
100000
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
monomer
additional information
additional information
from N- to C-terminus, KDM1A is composed of an unstructured region that contains the nuclear localization signal and three structured domains: a SWI3p, Rsc8p, and Moira (SWIRM) domain, an amine oxidase domain (AOD), and an unprecedented intervening domain within the AOD colloquially known as the tower. The tower domain of KDM1A is composed of two antiparallel alpha-helices (termed TalphaA and TbetaB) that form a coiled coil and extend approximately 100 A from the amine oxidase domain (AOD)
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
crystal structure determination of LSD1/CoREST complex bound to histone H3 peptides, and of LSD1 complexed with a suicide inhibitor consisting of a 21-residue histone H3 peptide in which K4 is modified by an N-methylpropargyl group
enzyme complex LSD1-CoREST crystal structure in complex with a histone H3 peptide, overview
-
in complex with inhibitor tranylcypromine, diffraction to 2.25 A. In the inhibitor-free structure, a water molecule forms a hydrogen bond with the flavin N(5) atom and Lys661. The LSD1-tranylcypromine complex is not completely composed of the five-membered adduct, but partially contains an intermediate
modeling of the complex composed of LSD1, cofactor CoREST, and histone substrate
molecular docking of inhibitor 3-[(E)-2-[2-(5-fluoro-2-hydroxyphenyl)pyridin-4-yl]ethenyl]N'-hydroxybenzene-1-carboximidamide. Compound can be well docked into the FAD binding site of LSD1
purified recombinant truncated enzyme LSD1 comprising residues 172-833 in complex with recombinant human CoREST residues 308-440, and peptide inhibitors 9, N2-L-seryl-L-arginyl-L-threonyl-L-methionyl-L-glutaminyl-L-threonyl-L-alanyl-L-arginyl-L-lysyl-L-seryl-L-threonylglycylglycyl-L-lysyl-L-alanyl-L-prolyl-L-arginyl-L-lysyl-L-glutaminyl-L-leucyl-(N6-(L-seryl))-L-lysine-amide, and L-homoseryseryl-L-arginyl-L-threonyl-L-methionyl-L-glutaminyl-L-threonyl-L-alanyl-L-arginyl-L-lysyl-L-seryl-L-threonylglycylglycyl-L-lysyl-L-alanyl-L-prolyl-L-arginyl-L-lysyl-L-glutaminyl-L-leucyl-(N6-(L-homoseryl))-L-lysine, by hanging drop vapor diffusion method, mixing of 0.001 ml of 9 mg/m protein solution with 0.001 ml of reservoir solution containing 100 mM N-(carbamoylmethyl)iminodiacetic acid, pH 5.5, and 1.18-1.28M potassium sodium tartrate tetrahydrate, 20°C, crystals are soaked in a solution containing 100 mM N-(carbamoylmethyl) iminodiacetic acid buffer, pH 5.5, with 1.14 M potassium sodium tartrate tetrahydrate, 10% glycerol, and 2 mM LSD1 inhibitor peptide L-seryl-L-arginyl-L-threonyl-L-methionyl-L-glutaminyl-L-threonyl-L-alanyl-L-arginyl-L-lysyl-L-seryl-L-threonylglycylglycyl-L-lysyl-L-alanyl-L-prolyl-L-arginyl-L-lysyl-L-glutaminyl-L-leucine, 11 or 13 for 2 h, X-ray diffraction structure determination and analysis at 2.53-2.69 A resolution
purified recombinant truncated enzyme LSD1 comprising residues 172-833 in complex with recombinant human CoREST residues 308-440, and peptide inhibitors L-seryl-L-arginyl-L-threonyl-L-methionyl-L-glutaminyl-L-threonyl-L-alanyl-L-arginyl-L-lysyl-L-seryl-L-threonylglycylglycyl-L-lysyl-L-alanyl-L-prolyl-L-arginyl-L-lysyl-L-glutaminyl-L-leucine, N2-L-seryl-L-arginyl-L-threonyl-L-methionyl-L-glutaminyl-L-threonyl-L-alanyl-L-arginyl-L-lysyl-L-seryl-L-threonylglycylglycyl-L-lysyl-L-alanyl-L-prolyl-L-arginyl-L-lysyl-L-glutaminyl-L-leucyl-(N6-(L-seryl))-L-lysine-amide, and L-homoseryseryl-L-arginyl-L-threonyl-L-methionyl-L-glutaminyl-L-threonyl-L-alanyl-L-arginyl-L-lysyl-L-seryl-L-threonylglycylglycyl-L-lysyl-L-alanyl-L-prolyl-L-arginyl-L-lysyl-L-glutaminyl-L-leucyl-(N6-(L-homoseryl))-L-lysine, by hanging drop vapor diffusion method, mixing of 0.001 ml of 9 mg/ml protein solution with 0.001 ml of reservoir solution containing 100 mM N-(carbamoylmethyl)iminodiacetic acid, pH 5.5, and 1.18-1.28M potassium sodium tartrate tetrahydrate, 20°C, crystals are soaked in a solution containing 100 mM N-(carbamoylmethyl) iminodiacetic acid buffer, pH 5.5, with 1.14 M potassium sodium tartrate tetrahydrate, 10% glycerol, and 2 mM LSD1 inhibitor peptide for 2 h, X-ray diffraction structure determination and analysis at 2.53-2.69 A resolution
recombinant enzyme, hanging-drop vapor diffusion method, 2.8 A-resolution crystal structure
-
recombinant GST-tagged enzyme fragment in complex with inhibitor tranylcypromine, X-ray diffraction structure determination and analysis at 2.25 A resolution
structure of LSD1 in complex with cofactor CoREST and inhibitor rans-2-phenylcyclopropylamine. The inhibitor forms a covalent adduct with FAD in LSD1. The phenyl ring of the FAD-inhibitor adduct does not form extensive interactions with active-site residues
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
K661A
additional information
additional information
-
depletion of LSD1 by small interfering RNAs inhibits Cp basal transcription levels, and overexpression of LSD1 alters the cell cycle profile in p53-positive, but not p53-negative, HCT cells
additional information
-
knockdown of either TLX or LSD1 derepresses expression of the endogenous PTEN gene and inhibits cell proliferation of Y79 cells
additional information
construction of an enzyme mutant with a deletion of the NH2-terminal 184 amino acid residues (DELTA184 LSD1)
additional information
LSD1 knockdown by transient siRNA transfection in HCT-116 cells
additional information
MDA-MB231 cells are transiently transfected with three different siRNA directed against LSD1 causing significant knockdown of LSD1 in all samples on both mRNA and protein level. LSD1 knockdown leads to significant induction of the steady state transcript levels of interleukin 1alpha, 1beta, 6 and 8 genes. Interleukin 1beta protein levels are significantly enhanced in the supernatant of the cells after LSD1 knockdown
additional information
small interference RNA-mediated depletion of both LSD1
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant FLAG-tagged wild-type and mutant enzymes from Escherichia coli strain BL21 by M2 affinity chromatography, recombinant FLAG-tagged wild-type enzyme from insect Sf21 cells by M2 affinity chromatography
recombinant full-length His6-tagged LSD1 from Escherichia coli strain BL21(DE3) by nickel affinity chromatography and dialysis
recombinant N-terminally His-tagged enzyme by nickel affinity chromatography from Escherichia coli BL21(DE3), or by ammonium sulfate fractionation and anion exchange chromatography, recombinant N-terminally truncated GST-tagged LSD1 by glutathione affinity chromatography
two LSD1 truncated forms, lacking the first 157 and 184 amino acids, respectively
-
recombinant N-terminally His-tagged enzyme by nickel affinity chromatography from Escherichia coli BL21(DE3), or by ammonium sulfate fractionation and anion exchange chromatography, recombinant N-terminally truncated GST-tagged LSD1 by glutathione affinity chromatography
-
recombinant N-terminally His-tagged enzyme by nickel affinity chromatography from Escherichia coli BL21(DE3), or by ammonium sulfate fractionation and anion exchange chromatography, recombinant N-terminally truncated GST-tagged LSD1 by glutathione affinity chromatography
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
fragment consisting of residues 172-833, expression as glutathione S-transferase fusion protein in Escherichia coli
gene KDM1A, codon optimized, recombinant expression of the enzyme LSD1, residues 151-852, in Escherichia coli
gene KDM1A, recombinant expression of FLAG-tagged wild-type and mutant enzymes in Escherichia coli strain BL21, recombinant expression of FLAG-tagged wild-type enzyme in Spodoptera frugiperda SF21 cells via baculovrial expression system. Ectopic expression of the LSD1 enzymatically dead mutant K661A
gene KDM1A, recombinant expression of full-length His6-tagged human LSD1 from pET15b bacterial expression vector in Escherichia coli strain BL21(DE3)
gene KDM1A, recombinant expression of N-terminally His-tagged full-length LSD1 protein and deletion mutant DELTA184 LSD1lacking the N-terminal 184 amino acid residues
gene lsd1, real-time reverse transcription-PCR expression enzyme analysis
gene lsd1, recombinant expression of GST-tagged enzyme fragment consisting of residues 172-833 in Escherichia coli
recombinant expression of N-terminally His-tagged enzyme in Escherichia coli BL21(DE3), recombinant expression of N-terminally truncated GST-tagged LSD1
two LSD1 truncated forms, lacking the first 157 and 184 amino acids, respectively, expression in Escherichia coli
-
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
differentiation of neuroblastoma cells results in down-regulation of LSD1
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
drug development
potential pharmacological value of LSD1 as a drug target originating from it being a flavin-dependent demethylase, rather than an iron-dependent enzyme of the Jumonji class
diagnostics
-
dimethylation of histone H3 at lysine 4 in combination with trimethylation of histone H3 at lysine 4 is associated with an activated transcriptional state. An increase of H3K4diMe in neoplastic tissues is predictive of clinical outcome. In particular, tumor recurrence occurs earlier in low-grade prostate carcinoma patients with low H3K4diMe, independently of other clinical and pathologic parameters. Similarly, in large cell and squamous cell carcinomas, low H3K4diMe expression correlates with short survival
additional information
LSD1 is a rational target for inducing the reexpression of aberrantly silenced genes
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Forneris, F.; Binda, C.; Vanoni, M.A.; Mattevi, A.; Battaglioli, E.
Histone demethylation catalysed by LSD1 is a flavin-dependent oxidative process
FEBS Lett.
579
2203-2207
2005
Homo sapiens
Chen, Y.; Yang, Y.; Wang, F.; Wan, K.; Yamane, K.; Zhang, Y.; Lei, M.
Crystal structure of human histone lysine-specific demethylase 1 (LSD1)
Proc. Natl. Acad. Sci. USA
103
13956-13961
2006
Homo sapiens
Mimasu, S.; Sengoku, T.; Fukuzawa, S.; Umehara, T.; Yokoyama, S.
Crystal structure of histone demethylase LSD1 and tranylcypromine at 2.25 A
Biochem. Biophys. Res. Commun.
366
15-22
2008
Homo sapiens (O60341)
Forneris, F.; Battaglioli, E.; Mattevi, A.; Binda, C.
New roles of flavoproteins in molecular cell biology: histone demethylase LSD1 and chromatin
FEBS J.
276
4304-4312
2009
Arabidopsis thaliana, Caenorhabditis elegans, Drosophila melanogaster, Homo sapiens
Magerl, C.; Ellinger, J.; Braunschweig, T.; Kremmer, E.; Koch, L.K.; Hoeller, T.; Buettner, R.; Luescher, B.; Guetgemann, I.
H3K4 dimethylation in hepatocellular carcinoma is rare compared with other hepatobiliary and gastrointestinal carcinomas and correlates with expression of the methylase Ash2 and the demethylase LSD1
Hum. Pathol.
41
181-189
2009
Homo sapiens
Chau, C.M.; Deng, Z.; Kang, H.; Lieberman, P.M.
Cell cycle association of the retinoblastoma protein Rb and the histone demethylase LSD1 with the Epstein-Barr virus latency promoter Cp
J. Virol.
82
3428-3437
2008
Homo sapiens
Yokoyama, A.; Takezawa, S.; Schuele, R.; Kitagawa, H.; Kato, S.
Transrepressive function of TLX requires the histone demethylase LSD1
Mol. Cell. Biol.
28
3995-4003
2008
Homo sapiens
Forneris, F.; Binda, C.; Battaglioli, E.; Mattevi, A.
LSD1: oxidative chemistry for multifaceted functions in chromatin regulation
Trends Biochem. Sci.
33
181-189
2008
Drosophila melanogaster, Homo sapiens (O75164)
Huang, Y.; Stewart, T.M.; Wu, Y.; Baylin, S.B.; Marton, L.J.; Perkins, B.; Jones, R.J.; Woster, P.M.; Casero, R.A.
Novel oligoamine analogues inhibit lysine-specific demethylase 1 and induce reexpression of epigenetically silenced genes
Clin. Cancer Res.
15
7217-7228
2009
Homo sapiens
Sharma, S.K.; Wu, Y.; Steinbergs, N.; Crowley, M.L.; Hanson, A.S.; Casero, R.A.; Woster, P.M.
(Bis)urea and (bis)thiourea inhibitors of lysine-specific demethylase 1 as epigenetic modulators
J. Med. Chem.
53
5197-5212
2010
Homo sapiens
Luka, Z.; Moss, F.; Loukachevitch, L.V.; Bornhop, D.J.; Wagner, C.
Histone demethylase LSD1 is a folate-binding protein
Biochemistry
50
4750-4756
2011
Homo sapiens
Mosammaparast, N.; Kim, H.; Laurent, B.; Zhao, Y.; Lim, H.J.; Majid, M.C.; Dango, S.; Luo, Y.; Hempel, K.; Sowa, M.E.; Gygi, S.P.; Steen, H.; Harper, J.W.; Yankner, B.; Shi, Y.
The histone demethylase LSD1/KDM1A promotes the DNA damage response
J. Cell Biol.
203
457-470
2013
Homo sapiens
Burg, J.M.; Gonzalez, J.J.; Maksimchuk, K.R.; McCafferty, D.G.
Lysine-specific demethylase 1A (KDM1A/LSD1) product recognition and kinetic analysis of full-length histones
Biochemistry
55
1652-1662
2016
Homo sapiens (O60341)
Amano, Y.; Kikuchi, M.; Sato, S.; Yokoyama, S.; Umehara, T.; Umezawa, N.; Higuchi, T.
Development and crystallographic evaluation of histone H3 peptide with N-terminal serine substitution as a potent inhibitor of lysine-specific demethylase 1
Bioorg. Med. Chem.
25
2617-2624
2017
Homo sapiens (O60341)
Liu, Y.W.; Xia, R.; Lu, K.; Xie, M.; Yang, F.; Sun, M.; De, W.; Wang, C.; Ji, G.
LincRNAFEZF1-AS1 represses p21 expression to promote gastric cancer proliferation through LSD1-mediated H3K4me2 demethylation
Mol. Cancer
16
39
2017
Homo sapiens (O60341)
Mimasu, S.; Sengoku, T.; Fukuzawa, S.; Umehara, T.; Yokoyama, S.
Crystal structure of histone demethylase LSD1 and tranylcypromine at 2.25 A
Biochem. Biophys. Res. Commun.
366
15-22
2008
Homo sapiens (O60341)
Janzer, A.; Lim, S.; Fronhoffs, F.; Niazy, N.; Buettner, R.; Kirfel, J.
Lysine-specific demethylase 1 (LSD1) and histone deacetylase 1 (HDAC1) synergistically repress proinflammatory cytokines and classical complement pathway components
Biochem. Biophys. Res. Commun.
421
665-670
2012
Homo sapiens (O60341)
Yang, M.; Culhane, J.C.; Szewczuk, L.M.; Jalili, P.; Ball, H.L.; Machius, M.; Cole, P.A.; Yu, H.
Structural basis for the inhibition of the LSD1 histone demethylase by the antidepressant trans-2-phenylcyclopropylamine
Biochemistry
46
8058-8065
2007
Homo sapiens (O60341)
Gaweska, H.; Henderson Pozzi, M.; Schmidt, D.M.; McCafferty, D.G.; Fitzpatrick, P.F.
Use of pH and kinetic isotope effects to establish chemistry as rate-limiting in oxidation of a peptide substrate by LSD1
Biochemistry
48
5440-5445
2009
Homo sapiens (O60341)
Luka, Z.; Moss, F.; Loukachevitch, L.V.; Bornhop, D.J.; Wagner, C.
Histone demethylase LSD1 is a folate-binding protein
Biochemistry
50
4750-4756
2011
Homo sapiens (O60341)
Marmorstein, R.; Trievel, R.C.
Histone modifying enzymes structures, mechanisms, and specificities
Biochim. Biophys. Acta
1789
58-68
2009
Homo sapiens (O60341)
Costa, R.; Arrigoni, G.; Cozza, G.; Lolli, G.; Battistutta, R.; Izpisua Belmonte, J.C.; Pinna, L.A.; Sarno, S.
The lysine-specific demethylase 1 is a novel substrate of protein kinase CK2
Biochim. Biophys. Acta
1844
722-729
2014
Homo sapiens (O60341)
Duan, Y.; Qin, W.; Suo, F.; Zhai, X.; Guan, Y.; Wang, X.; Zheng, Y.; Liu, H.
Design, synthesis and in vitro evaluation of stilbene derivatives as novel LSD1 inhibitors for AML therapy
Bioorg. Med. Chem.
26
6000-6014
2018
Homo sapiens (O60341)
Kakizawa, T.; Ota, Y.; Itoh, Y.; Suzuki, T.
Histone H3 peptides incorporating modified lysine residues as lysine-specific demethylase 1 inhibitors
Bioorg. Med. Chem. Lett.
28
167-169
2018
Homo sapiens (O60341)
Schulte, J.H.; Lim, S.; Schramm, A.; Friedrichs, N.; Koster, J.; Versteeg, R.; Ora, I.; Pajtler, K.; Klein-Hitpass, L.; Kuhfittig-Kulle, S.; Metzger, E.; Schuele, R.; Eggert, A.; Buettner, R.; Kirfel, J.
Lysine-specific demethylase 1 is strongly expressed in poorly differentiated neuroblastoma implications for therapy
Cancer Res.
69
2065-2071
2009
Homo sapiens (O60341)
Huang, Y.; Stewart, T.M.; Wu, Y.; Baylin, S.B.; Marton, L.J.; Perkins, B.; Jones, R.J.; Woster, P.M.; Casero, R.A.
Novel oligoamine analogues inhibit lysine-specific demethylase 1 and induce reexpression of epigenetically silenced genes
Clin. Cancer Res.
15
7217-7228
2009
Homo sapiens (O60341)
Brasacchio, D.; Okabe, J.; Tikellis, C.; Balcerczyk, A.; George, P.; Baker, E.K.; Calkin, A.C.; Brownlee, M.; Cooper, M.E.; El-Osta, A.
Hyperglycemia induces a dynamic cooperativity of histone methylase and demethylase enzymes associated with gene-activating epigenetic marks that coexist on the lysine tail
Diabetes
58
1229-1236
2009
Homo sapiens (O60341), Homo sapiens, Mus musculus (Q6ZQ88), Mus musculus C57BL/6 (Q6ZQ88)
Schulz-Fincke, J.; Hau, M.; Barth, J.; Robaa, D.; Willmann, D.; Kuerner, A.; Haas, J.; Greve, G.; Haydn, T.; Fulda, S.; Luebbert, M.; Luedeke, S.; Berg, T.; Sippl, W.; Schuele, R.; Jung, M.
Structure-activity studies on N-substituted tranylcypromine derivatives lead to selective inhibitors of lysine specific demethylase 1 (LSD1) and potent inducers of leukemic cell differentiation
Eur. J. Med. Chem.
144
52-67
2018
Homo sapiens (O60341)
Forneris, F.; Binda, C.; Vanoni, M.A.; Mattevi, A.; Battaglioli, E.
Histone demethylation catalysed by LSD1 is a flavin-dependent oxidative process
FEBS Lett.
579
2203-2207
2005
Homo sapiens (O60341)
Hirano, K.; Namihira, M.
FAD influx enhances neuronal differentiation of human neural stem cells by facilitating nuclear localization of LSD1
FEBS open bio
7
1932-1942
2017
Homo sapiens (O60341)
Culhane, J.C.; Szewczuk, L.M.; Liu, X.; Da, G.; Marmorstein, R.; Cole, P.A.
A mechanism-based inactivator for histone demethylase LSD1
J. Am. Chem. Soc.
128
4536-4537
2006
Homo sapiens (O60341)
Lee, M.G.; Wynder, C.; Bochar, D.A.; Hakimi, M.A.; Cooch, N.; Shiekhattar, R.
Functional interplay between histone demethylase and deacetylase enzymes
Mol. Cell. Biol.
26
6395-6402
2006
Homo sapiens (O60341)
Liang, Y.; Vogel, J.; Narayanan, A.; Peng, H.; Kristie, T.
Inhibition of the histone demethylase LSD1 blocks alpha-herpesvirus lytic replication and reactivation from latency
Nat. Med.
15
1312-1317
2009
Homo sapiens (O60341)
Zhu, Q.; Liu, C.; Ge, Z.; Fang, X.; Zhang, X.; Straat, K.; Bjoerkholm, M.; Xu, D.
Lysine-specific demethylase 1 (LSD1) is required for the transcriptional repression of the telomerase reverse transcriptase (hTERT) gene
PLoS ONE
3
e1446
2008
Homo sapiens (O60341)
Kong, X.; Ouyang, S.; Liang, Z.; Lu, J.; Chen, L.; Shen, B.; Li, D.; Zheng, M.; Li, K.K.; Luo, C.; Jiang, H.
Catalytic mechanism investigation of lysine-specific demethylase 1 (LSD1) a computational study
PLoS ONE
6
e25444
2011
Homo sapiens (O60341)
Huang, Y.; Greene, E.; Murray Stewart, T.; Goodwin, A.C.; Baylin, S.B.; Woster, P.M.; Casero, R.A.
Inhibition of lysine-specific demethylase 1 by polyamine analogues results in reexpression of aberrantly silenced genes
Proc. Natl. Acad. Sci. USA
104
8023-8028
2007
Homo sapiens (O60341)
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