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Literature summary extracted from
- Lysine-specific demethylase 1A (KDM1A/LSD1) product recognition and kinetic analysis of full-length histones (2016), Biochemistry, 55, 1652-1662 .
Activating Compound
| EC Number | Activating Compound | Comment | Organism | Structure |
|---|---|---|---|---|
| 1.14.99.66 | CoREST | i.e. REST corepressor 1, regulates LSD1 activity towards nucleosomes. CoREST does not alter the catalytic efficiency toward minimal peptide substrat | Homo sapiens |
Cloned(Commentary)
| EC Number | Cloned (Comment) | Organism |
|---|---|---|
| 1.14.11.65 | gene KDM1A, codon optimized, recombinant expression of the enzyme LSD1, residues 151-852, in Escherichia coli | Homo sapiens |
| 1.14.99.66 | gene KDM1A, codon optimized, recombinant expression of the enzyme LSD1, residues 151-852, in Escherichia coli | Homo sapiens |
Inhibitors
| EC Number | Inhibitors | Comment | Organism | Structure |
|---|---|---|---|---|
| 1.14.11.65 | H3 1-21 peptide | 21-mer H3-derived peptide | Homo sapiens | |
| 1.14.11.65 | histone H3 | full-length histone H3, H3_1-135, which lacks any posttranslational modifications, is a tight-binding, competitive inhibitor of KDM1A demethylation activity. Full-length H3 rapidly reaches equilibrium with KDM1A and shows 100fold increased binding affinity compared to a 21-mer H3-derived peptide; 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 | Homo sapiens | |
| 1.14.11.65 | 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; no other core histones exhibit inhibition of KDM1A demethylation activity. Kinetic analysis of full-length histone products against KDM1A | Homo sapiens | |
| 1.14.11.65 | peptide H31-21 | 21-mer H3-derived peptide | Homo sapiens | |
| 1.14.99.66 | histone H3 | full-length histone H3, which lacks any posttranslational modifications, is a tight-binding, competitive inhibitor; 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 | Homo sapiens | |
| 1.14.99.66 | histone H3 1-21 peptide | 21-mer H3-derived peptide | Homo sapiens | |
| 1.14.99.66 | histone H3-1-21 | peptide corresponding to the first 21 amino acids of the N-terminal tail of histone H3, competitive inhibitor | Homo sapiens | |
| 1.14.99.66 | additional information | besides histone H3, no other core histones exhibit inhibition of KDM1A demethylation activity; KDM1A tolerance for 3-[(3-cholamidopropyl)-dimethylammonio]-1-propanesulfonate (CHAPS) at 0.01% w/v and dimethyl sulfoxide (DMSO) at 10% v/v | Homo sapiens |
KM Value [mM]
| EC Number | KM Value [mM] | KM Value Maximum [mM] | Substrate | Comment | Organism | Structure |
|---|---|---|---|---|---|---|
| 1.14.99.66 | 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 | Homo sapiens | |
| 1.14.99.66 | 0.00446 | - |
[histone H3]-N6,N6-L-dimethyllysine4-1-21 | recombinant enzyme, pH 7.5, 25°C | Homo sapiens | |
| 1.14.99.66 | 0.00446 | - |
H3K4me2 1-21 peptide | pH 7.5, 25°C, recombinant N-terminally truncated KDM1A | Homo sapiens | |
| 1.14.99.66 | 0.00814 | - |
H3K4me2 1-21 peptide | pH 7.5, 25°C, recombinant N-terminally truncated KDM1A-CoREST-C complex | Homo sapiens | |
| 1.14.99.66 | 0.00814 | - |
[histone H3]-N6,N6-L-dimethyllysine4-1-21 | recombinant enzyme, presence of activator CoREST, pH 7.5, 25°C | Homo sapiens | |
| 1.14.99.66 | 0.00889 | - |
H3K4me2 1-21 peptide | pH 7.5, 25°C, recombinant N-terminally truncated KDM1A-CoREST-Linker complex | Homo sapiens | |
| 1.14.99.66 | 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 | Homo sapiens |
Localization
| EC Number | Localization | Comment | Organism | GeneOntology No. | Textmining |
|---|---|---|---|---|---|
| 1.14.11.65 | nucleus | - |
Homo sapiens | 5634 | - |
| 1.14.99.66 | nucleus | - |
Homo sapiens | 5634 | - |
Natural Substrates/ Products (Substrates)
| EC Number | Natural Substrates | Organism | Comment (Nat. Sub.) | Natural Products | Comment (Nat. Pro.) | Rev. | Reac. |
|---|---|---|---|---|---|---|---|
| 1.14.11.65 | histone H3 N6,N6-dimethyl-L-lysine9 + 2-oxoglutarate + O2 | Homo sapiens | - |
histone H3 N6-methyl-L-lysine9 + succinate + formaldehyde + CO2 | - |
? |  |
| 1.14.11.65 | histone H3 N6-methyl-L-lysine9 + 2-oxoglutarate + O2 | Homo sapiens | - |
histone H3 L-lysine9 + succinate + formaldehyde + CO2 | - |
? | |
| 1.14.11.65 | additional information | Homo sapiens | KDM1A catalyzes the oxidative demethylation of histone H3K4me1/2 and H3K9me1/2 as well as non-histone substrates | ? | - |
? | |
| 1.14.11.65 | [histone H3]-N6,N6-dimethyl-L-lysine 9 + 2-oxoglutarate + O2 | Homo sapiens | - |
[histone H3]-N6-methyl-L-lysine 9 + succinate + formaldehyde + CO2 | - |
? | |
| 1.14.11.65 | [histone H3]-N6-methyl-L-lysine 9 + 2-oxoglutarate + O2 | Homo sapiens | - |
[histone H3]-L-lysine 9 + succinate + formaldehyde + CO2 | - |
? | |
| 1.14.99.66 | [histone H3]-N6,N6-dimethyl-L-lysine 4 + 2-oxoglutarate + O2 | Homo sapiens | - |
[histone H3]-N6-methyl-L-lysine 4 + succinate + formaldehyde + CO2 | - |
? | |
| 1.14.99.66 | [histone H3]-N6-methyl-L-lysine 4 + 2-oxoglutarate + O2 | Homo sapiens | - |
[histone H3]-L-lysine 4 + succinate + formaldehyde + CO2 | - |
? | |
Organism
| EC Number | Organism | UniProt | Comment | Textmining |
|---|---|---|---|---|
| 1.14.11.65 | Homo sapiens | O60341 | - |
- |
| 1.14.99.66 | Homo sapiens | O60341 | - |
- |
Substrates and Products (Substrate)
| EC Number | Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
|---|---|---|---|---|---|---|---|
| 1.14.11.65 | histone H3 N6,N6-dimethyl-L-lysine9 + 2-oxoglutarate + O2 | - |
Homo sapiens | histone H3 N6-methyl-L-lysine9 + succinate + formaldehyde + CO2 | - |
? | |
| 1.14.11.65 | histone H3 N6-methyl-L-lysine9 + 2-oxoglutarate + O2 | - |
Homo sapiens | histone H3 L-lysine9 + succinate + formaldehyde + CO2 | - |
? | |
| 1.14.11.65 | additional information | KDM1A catalyzes the oxidative demethylation of histone H3K4me1/2 and H3K9me1/2 as well as non-histone substrates | Homo sapiens | ? | - |
? | |
| 1.14.11.65 | additional information | the enzyme also catalyzes the demethylation of histone H3 N6,N6-dimethyl-L-lysine4 and histone H3 N6-methyl-L-lysine4. Histone H3 is the preferred histone substrate of KDM1A compared to histones H2A, H2B, and H4. KDM1A likely contains a histone H3 secondary specificity element on the enzyme surface that contributes significantly to its recognition of substrates and products. 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 | Homo sapiens | ? | - |
? | |
| 1.14.11.65 | additional information | the bifunctional enzyme catalyzes the demethylation of H3K4me2/me1 (EC 1.14.99.66) and H3K9me2/me1, 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 | Homo sapiens | ? | - |
? | |
| 1.14.11.65 | [histone H3]-N6,N6-dimethyl-L-lysine 9 + 2-oxoglutarate + O2 | - |
Homo sapiens | [histone H3]-N6-methyl-L-lysine 9 + succinate + formaldehyde + CO2 | - |
? | |
| 1.14.11.65 | [histone H3]-N6-methyl-L-lysine 9 + 2-oxoglutarate + O2 | - |
Homo sapiens | [histone H3]-L-lysine 9 + succinate + formaldehyde + CO2 | - |
? | |
| 1.14.99.66 | H3K4me2 1-21 peptide + 2-oxoglutarate + O2 | - |
Homo sapiens | H3K4me1 1-21 peptide + succinate + formaldehyde + CO2 | - |
? | |
| 1.14.99.66 | 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 | Homo sapiens | ? | - |
? | |
| 1.14.99.66 | [histone H3]-N6,N6-dimethyl-L-lysine 4 + 2-oxoglutarate + O2 | - |
Homo sapiens | [histone H3]-N6-methyl-L-lysine 4 + succinate + formaldehyde + CO2 | - |
? | |
| 1.14.99.66 | [histone H3]-N6,N6-L-dimethyllysine4-1-21 + O2 + 2 H2O | substrate is a dimethylated peptide corresponding to the first 21 amino acids of the N-terminal tail of histone H3 | Homo sapiens | [histone H3]-L-lysine4-1-21 + 2 formaldehyde + 2 H2O2 | - |
? | |
| 1.14.99.66 | [histone H3]-N6-methyl-L-lysine 4 + 2-oxoglutarate + O2 | - |
Homo sapiens | [histone H3]-L-lysine 4 + succinate + formaldehyde + CO2 | - |
? | |
Subunits
| EC Number | Subunits | Comment | Organism |
|---|---|---|---|
| 1.14.11.65 | More | 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 TalphaB) that form a coiled coil and extend approximately 100 A from the AOD | Homo sapiens |
| 1.14.11.65 | More | 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) | Homo sapiens |
| 1.14.99.66 | More | 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) | Homo sapiens |
Synonyms
| EC Number | Synonyms | Comment | Organism |
|---|---|---|---|
| 1.14.11.65 | AOF2 | - |
Homo sapiens |
| 1.14.11.65 | BHC110 | - |
Homo sapiens |
| 1.14.11.65 | KDM1A | - |
Homo sapiens |
| 1.14.11.65 | KIAA0601 | - |
Homo sapiens |
| 1.14.11.65 | LSD1 | - |
Homo sapiens |
| 1.14.11.65 | lysine-specific demethylase 1A | - |
Homo sapiens |
| 1.14.11.65 | p110b | - |
Homo sapiens |
| 1.14.99.66 | KDM1A | - |
Homo sapiens |
| 1.14.99.66 | LSD1 | - |
Homo sapiens |
| 1.14.99.66 | lysine-specific demethylase 1A | - |
Homo sapiens |
Temperature Optimum [°C]
| EC Number | Temperature Optimum [°C] | Temperature Optimum Maximum [°C] | Comment | Organism |
|---|---|---|---|---|
| 1.14.11.65 | 25 | - |
assay at | Homo sapiens |
| 1.14.99.66 | 25 | - |
assay at | Homo sapiens |
Turnover Number [1/s]
| EC Number | Turnover Number Minimum [1/s] | Turnover Number Maximum [1/s] | Substrate | Comment | Organism | Structure |
|---|---|---|---|---|---|---|
| 1.14.99.66 | 0.1 | - |
[histone H3]-N6,N6-L-dimethyllysine4-1-21 | recombinant enzyme, pH 7.5, 25°C | Homo sapiens | |
| 1.14.99.66 | 0.1 | - |
H3K4me2 1-21 peptide | pH 7.5, 25°C, recombinant N-terminally truncated KDM1A | Homo sapiens | |
| 1.14.99.66 | 0.157 | - |
H3K4me2 1-21 peptide | pH 7.5, 25°C, recombinant N-terminally truncated KDM1A-CoREST-Linker complex | Homo sapiens | |
| 1.14.99.66 | 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 | Homo sapiens | |
| 1.14.99.66 | 0.159 | - |
H3K4me2 1-21 peptide | pH 7.5, 25°C, recombinant N-terminally truncated KDM1A-CoREST-C complex | Homo sapiens | |
| 1.14.99.66 | 0.159 | - |
[histone H3]-N6,N6-L-dimethyllysine4-1-21 | recombinant enzyme, presence of activator CoREST, pH 7.5, 25°C | Homo sapiens |
pH Optimum
| EC Number | pH Optimum Minimum | pH Optimum Maximum | Comment | Organism |
|---|---|---|---|---|
| 1.14.11.65 | 7.5 | - |
assay at | Homo sapiens |
| 1.14.99.66 | 7.5 | - |
assay at | Homo sapiens |
Cofactor
| EC Number | Cofactor | Comment | Organism | Structure |
|---|---|---|---|---|
| 1.14.11.65 | FAD | dependent on | Homo sapiens | |
| 1.14.11.65 | FAD | dependent on, required for catalysis. THe FAD is noncovalently bound at the amine oxidase domain (AOD) | Homo sapiens | |
| 1.14.99.66 | FAD | dependent on, required for catalysis. THe FAD is noncovalently bound at the amine oxidase domain (AOD) | Homo sapiens | |
Ki Value [mM]
| EC Number | Ki Value [mM] | Ki Value maximum [mM] | Inhibitor | Comment | Organism | Structure |
|---|---|---|---|---|---|---|
| 1.14.11.65 | additional information | - |
additional information | kinetic analysis of full-length histone products against KDM1A | Homo sapiens | |
| 1.14.11.65 | 0.0000189 | - |
histone H3 | pH 7.5, 25°C, recombinant enzyme | Homo sapiens | |
| 1.14.11.65 | 0.00177 | - |
H3 1-21 peptide | pH 7.5, 25°C, recombinant enzyme | Homo sapiens | |
| 1.14.11.65 | 0.0018 | - |
peptide H31-21 | pH 7.5, 25°C | Homo sapiens | |
| 1.14.11.65 | 0.00189 | - |
histone H3 | pH 7.5, 25°C | Homo sapiens | |
| 1.14.99.66 | 0.0000189 | - |
histone H3 | pH 7.5, 25°C | Homo sapiens | |
| 1.14.99.66 | 0.0000189 | - |
histone H3 | pH 7.5, 25°C, recombinant enzyme | Homo sapiens | |
| 1.14.99.66 | 0.00177 | - |
histone H3-1-21 | pH 7.5, 25°C | Homo sapiens | |
| 1.14.99.66 | 0.00177 | - |
histone H3 1-21 peptide | pH 7.5, 25°C, recombinant enzyme | Homo sapiens |
IC50 Value
| EC Number | IC50 Value | IC50 Value Maximum | Comment | Organism | Inhibitor | Structure |
|---|---|---|---|---|---|---|
| 1.14.11.65 | 0.000153 | - |
pH 7.5, 25°C, recombinant enzyme | Homo sapiens | histone H3 | |
| 1.14.11.65 | 0.00484 | - |
pH 7.5, 25°C | Homo sapiens | peptide H31-21 | |
| 1.14.11.65 | 0.00484 | - |
pH 7.5, 25°C, recombinant enzyme | Homo sapiens | H3 1-21 peptide | |
| 1.14.99.66 | 0.000153 | - |
pH 7.5, 25°C, recombinant enzyme | Homo sapiens | histone H3 | |
| 1.14.99.66 | 0.0048 | - |
pH 7.5, 25°C | Homo sapiens | histone H3-1-21 | |
| 1.14.99.66 | 0.00484 | - |
pH 7.5, 25°C, recombinant enzyme | Homo sapiens | histone H3 1-21 peptide |
General Information
| EC Number | General Information | Comment | Organism |
|---|---|---|---|
| 1.14.11.65 | additional information | KDM1A likely contains a histone H3 secondary specificity element on the enzyme surface that contributes significantly to its recognition of substrates and products. The active site is too sterically restricted to encompass the minimal H3 21-mer peptide substrate footprint | Homo sapiens |
| 1.14.11.65 | additional information | although the active site is expanded compared to that of members of the greater amine oxidase superfamily, it is too 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 | Homo sapiens |
| 1.14.11.65 | physiological function | the enzyme catalyzes the oxidative demethylation of histone H3K4me1/2 and H3K9me1/2 repressing and activating transcription, respectively. Although the enzyme itself is sufficient for demethylation of peptide and histone substrates, activity toward nucleosomes in vitro is regulated by its interaction with CoREST, the minimal portion of which contains the linker and SANT2 domain or possibly the SANT1 domain | Homo sapiens |
| 1.14.11.65 | 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 | Homo sapiens |
| 1.14.99.66 | 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 | Homo sapiens |
| 1.14.99.66 | 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 | Homo sapiens |
kcat/KM [mM/s]
| EC Number | kcat/KM Value [1/mMs-1] | kcat/KM Value Maximum [1/mMs-1] | Substrate | Comment | Organism | Structure |
|---|---|---|---|---|---|---|
| 1.14.99.66 | 17.66 | - |
H3K4me2 1-21 peptide | pH 7.5, 25°C, recombinant N-terminally truncated KDM1A-CoREST-Linker complex | Homo sapiens | |
| 1.14.99.66 | 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 | Homo sapiens | |
| 1.14.99.66 | 19.5 | - |
[histone H3]-N6,N6-L-dimethyllysine4-1-21 | recombinant enzyme, presence of activator CoREST, pH 7.5, 25°C | Homo sapiens | |
| 1.14.99.66 | 19.53 | - |
H3K4me2 1-21 peptide | pH 7.5, 25°C, recombinant N-terminally truncated KDM1A-CoREST-C complex | Homo sapiens | |
| 1.14.99.66 | 22.42 | - |
H3K4me2 1-21 peptide | pH 7.5, 25°C, recombinant N-terminally truncated KDM1A | Homo sapiens | |
| 1.14.99.66 | 22.5 | - |
[histone H3]-N6,N6-L-dimethyllysine4-1-21 | recombinant enzyme, pH 7.5, 25°C | Homo sapiens |
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