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Literature summary extracted from

  • Lu, W.; Yao, X.; Ouyang, P.; Dong, N.; Wu, D.; Jiang, X.; Wu, Z.; Zhang, C.; Xu, Z.; Tang, Y.; Zou, S.; Liu, M.; Li, J.; Zeng, M.; Lin, P.; Cheng, F.; Huang, J.
    Drug repurposing of histone deacetylase inhibitors that alleviate neutrophilic inflammation in acute lung injury and idiopathic pulmonary fibrosis via inhibiting leukotriene A4 hydrolase and blocking LTB4 biosynthesis (2017), J. Med. Chem., 60, 1817-1828 .
    View publication on PubMed

Application

EC Number Application Comment Organism
3.3.2.6 drug development Drug repurposing of histone deacetylase inhibitors that alleviate neutrophilic inflammation in acute lung injury and idiopathic pulmonary fibrosis via inhibiting leukotriene A4 hydrolase and blocking LTB4 biosynthesis Mus musculus
3.3.2.6 drug development drug repurposing of histone deacetylase inhibitors that alleviate neutrophilic inflammation in acute lung injury and idiopathic pulmonary fibrosis via inhibiting leukotriene A4 hydrolase and blocking LTB4 biosynthesis. Inhibiting LTB4 biosynthesis and subsequently neutrophilic inflammation may provide a potential strategy for the treatment of acute lung injury (ALI) and idiopathic pulmonary fibrosis (IPF) Homo sapiens
3.4.11.6 drug development Drug repurposing of histone deacetylase inhibitors that alleviate neutrophilic inflammation in acute lung injury and idiopathic pulmonary fibrosis via inhibiting leukotriene A4 hydrolase and blocking LTB4 biosynthesis Homo sapiens

Crystallization (Commentary)

EC Number Crystallization (Comment) Organism
3.3.2.6 enzyme in complex with inhibitors SAHA or M344, X-ray diffraction structure determination and analysis Homo sapiens
3.3.2.6 enzyme in complex with inhibitors SAHA or M344, X-ray diffraction structure determination and analysis Mus musculus
3.4.11.6 enzyme in complex with inhibitors SAHA or M344, X-ray diffraction structure determination and analysis Homo sapiens

Inhibitors

EC Number Inhibitors Comment Organism Structure
3.3.2.6 (S)-2-((2S,3R)-3-amino-2-hydroxy-4-phenylbutanamido)-4-methylpentanoic acid
-
 Homo sapiens
3.3.2.6 (S)-2-((2S,3R)-3-amino-2-hydroxy-4-phenylbutanamido)-4-methylpentanoic acid
-
 Mus musculus
3.3.2.6 3-[methyl[3-[4-(phenylmethyl)phenoxy]propyl]amino]-propanoic acid
-
 Homo sapiens
3.3.2.6 3-[methyl[3-[4-(phenylmethyl)phenoxy]propyl]amino]-propanoic acid
-
 Mus musculus
3.3.2.6 4-(dimethylamino)-N-[7-(hydroxyamino)-7-oxoheptyl]benzamide enzyme binding structure, overview Homo sapiens
3.3.2.6 4-(dimethylamino)-N-[7-(hydroxyamino)-7-oxoheptyl]benzamide markedly diminishes early neutrophilic inflammation in mouse models of ALI and IPF under a clinical safety dose, enzyme binding structure, overview Mus musculus
3.3.2.6 abexinostat
-
 Homo sapiens
3.3.2.6 abexinostat
-
 Mus musculus
3.3.2.6 belinostat
-
 Homo sapiens
3.3.2.6 belinostat
-
 Mus musculus
3.3.2.6 CUDC-101
-
 Homo sapiens
3.3.2.6 CUDC-101
-
 Mus musculus
3.3.2.6 entinostat
-
 Homo sapiens
3.3.2.6 entinostat
-
 Mus musculus
3.3.2.6 givinostat
-
 Homo sapiens
3.3.2.6 givinostat
-
 Mus musculus
3.3.2.6 JNJ-26481585
-
 Homo sapiens
3.3.2.6 JNJ-26481585
-
 Mus musculus
3.3.2.6 mocetinostat
-
 Homo sapiens
3.3.2.6 mocetinostat
-
 Mus musculus
3.3.2.6 additional information drug repurposing of histone deacetylase (HDAC) inhibitors that alleviate neutrophilic inflammation in acute lung injury and idiopathic pulmonary fibrosis via inhibiting leukotriene A4 hydrolase and blocking LTB4 biosynthesis, overview. Analysis of potential inhibitors of LTA4H across a panel of 18 HDAC inhibitors, using enzymatic assay, thermofluor assay, and X-ray crystallographic investigation. Detailed mechanisms of down-regulation of proinflammatory cytokines by SAHA or M344 are determined in vivo. Cotreatment of N-(6-(2-aminophenylamino)-6-oxyhexyl)-4-methylbenzamide and (S)-2-((2S,3R)-3-amino-2-hydroxy-4-phenylbutanamido)-4-methylpentanoic acid synergistically represses the migration of neutrophil and LTB4-induced neutrophil migration is not affected by these treatments. Molecular modelling of HDAC inhibitors against LTA4H hydrolase and aminopeptidase Homo sapiens
3.3.2.6 additional information drug repurposing of histone deacetylase (HDAC) inhibitors that alleviate neutrophilic inflammation in acute lung injury and idiopathic pulmonary fibrosis via inhibiting leukotriene A4 hydrolase and blocking LTB4 biosynthesis, overview. Analysis of potential inhibitors of LTA4H across a panel of 18 HDAC inhibitors, using enzymatic assay, thermofluor assay, and X-ray crystallographic investigation. Detailed mechanisms of down-regulation of proinflammatory cytokines by SAHA or M344 are determined in vivo. Cotreatment of N-(6-(2-aminophenylamino)-6-oxyhexyl)-4-methylbenzamide and (S)-2-((2S,3R)-3-amino-2-hydroxy-4-phenylbutanamido)-4-methylpentanoic acid synergistically represses the migration of neutrophil and LTB4-induced neutrophil migration is not affected by these treatments. Molecular modeling of HDAC inhibitors against LTA4H hydrolase and aminopeptidase Mus musculus
3.3.2.6 N-(6-(2-aminophenylamino)-6-oxyhexyl)-4-methylbenzamide
-
 Homo sapiens
3.3.2.6 N-(6-(2-aminophenylamino)-6-oxyhexyl)-4-methylbenzamide
-
 Mus musculus
3.3.2.6 panobinostat
-
 Homo sapiens
3.3.2.6 panobinostat
-
 Mus musculus
3.3.2.6 pracinostat
-
 Homo sapiens
3.3.2.6 pracinostat
-
 Mus musculus
3.3.2.6 resminostat
-
 Homo sapiens
3.3.2.6 resminostat
-
 Mus musculus
3.3.2.6 rocilinostat
-
 Homo sapiens
3.3.2.6 rocilinostat
-
 Mus musculus
3.3.2.6 scriptaid
-
 Homo sapiens
3.3.2.6 scriptaid
-
 Mus musculus
3.3.2.6 suberanilohydroxamic acid enzyme binding structure, overview Homo sapiens
3.3.2.6 suberanilohydroxamic acid markedly diminishes early neutrophilic inflammation in mouse models of ALI and IPF under a clinical safety dose, enzyme binding structure, overview Mus musculus
3.3.2.6 trichostatin A
-
 Homo sapiens
3.3.2.6 trichostatin A
-
 Mus musculus
3.3.2.6 tubacin
-
 Homo sapiens
3.3.2.6 tubacin
-
 Mus musculus
3.3.2.6 Valproate
-
 Homo sapiens
3.3.2.6 Valproate
-
 Mus musculus
3.4.11.6 (S)-2-((2S,3R)-3-amino-2-hydroxy-4-phenylbutanamido)-4-methylpentanoic acid
-
 Homo sapiens
3.4.11.6 3-[methyl[3-[4-(phenylmethyl)phenoxy]propyl]amino]-propanoic acid
-
 Homo sapiens
3.4.11.6 4-(dimethylamino)-N-[7-(hydroxyamino)-7-oxoheptyl]benzamide enzyme binding structure, overview Homo sapiens
3.4.11.6 abexinostat
-
 Homo sapiens
3.4.11.6 belinostat
-
 Homo sapiens
3.4.11.6 CUDC-101
-
 Homo sapiens
3.4.11.6 entinostat
-
 Homo sapiens
3.4.11.6 givinostat
-
 Homo sapiens
3.4.11.6 JNJ-26481585
-
 Homo sapiens
3.4.11.6 mocetinostat
-
 Homo sapiens
3.4.11.6 additional information drug repurposing of histone deacetylase (HDAC) inhibitors that alleviate neutrophilic inflammation in acute lung injury and idiopathic pulmonary fibrosis via inhibiting leukotriene A4 hydrolase and blocking LTB4 biosynthesis, overview. Analysis of potential inhibitors of LTA4H across a panel of 18 HDAC inhibitors, using enzymatic assay, thermofluor assay, and X-ray crystallographic investigation. Detailed mechanisms of down-regulation of proinflammatory cytokines by SAHA or M344 are determined in vivo. Cotreatment of N-(6-(2-aminophenylamino)-6-oxyhexyl)-4-methylbenzamide and (S)-2-((2S,3R)-3-amino-2-hydroxy-4-phenylbutanamido)-4-methylpentanoic acid synergistically represses the migration of neutrophil and LTB4-induced neutrophil migration is not affected by these treatments. Molecular modeling of HDAC inhibitors against LTA4H hydrolase and aminopeptidase Homo sapiens
3.4.11.6 N-(6-(2-aminophenylamino)-6-oxyhexyl)-4-methylbenzamide
-
 Homo sapiens
3.4.11.6 panobinostat
-
 Homo sapiens
3.4.11.6 pracinostat
-
 Homo sapiens
3.4.11.6 resminostat
-
 Homo sapiens
3.4.11.6 rocilinostat
-
 Homo sapiens
3.4.11.6 scriptaid
-
 Homo sapiens
3.4.11.6 suberanilohydroxamic acid enzyme binding structure, overview Homo sapiens
3.4.11.6 trichostatin A
-
 Homo sapiens
3.4.11.6 tubacin
-
 Homo sapiens
3.4.11.6 Valproate
-
 Homo sapiens

Metals/Ions

EC Number Metals/Ions Comment Organism Structure
3.3.2.6 Zn2+ zinc metalloenzyme, enzyme LTA4H folds into three domains and creates a deep cleft harboring the catalytic Zn2+ site, forming the active site with an L-shaped hydrophobic pocket deep into the protein Homo sapiens
3.3.2.6 Zn2+ zinc metalloenzyme, enzyme LTA4H folds into three domains and creates a deep cleft harboring the catalytic Zn2+ site, forming the active site with an L-shaped hydrophobic pocket deep into the protein Mus musculus
3.4.11.6 Zn2+ zinc metalloenzyme, enzyme LTA4H folds into three domains and creates a deep cleft harboring the catalytic Zn2+ site, forming the active site with an L-shaped hydrophobic pocket deep into the protein Homo sapiens

Natural Substrates/ Products (Substrates)

EC Number Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
3.3.2.6 leukotriene A4 + H2O Homo sapiens
-
 leukotriene B4
-
 ?
3.3.2.6 leukotriene A4 + H2O Mus musculus
-
 leukotriene B4
-
 ?

Organism

EC Number Organism UniProt Comment Textmining
3.3.2.6 Homo sapiens P09960
-
-
3.3.2.6 Mus musculus P24527
-
-
3.4.11.6 Homo sapiens P09960
-
-

Source Tissue

EC Number Source Tissue Comment Organism Textmining
3.3.2.6 neutrophil
-
 Homo sapiens
-
3.3.2.6 neutrophil
-
 Mus musculus
-
3.4.11.6 neutrophil
-
 Homo sapiens
-

Substrates and Products (Substrate)

EC Number Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
3.3.2.6 leukotriene A4 + H2O
-
 Homo sapiens leukotriene B4
-
 ?
3.3.2.6 leukotriene A4 + H2O
-
 Mus musculus leukotriene B4
-
 ?
3.3.2.6 additional information the aminopeptidase binding site shares a similar structure to LTA4H at its ligand binding sites Homo sapiens ?
-
 ?
3.3.2.6 additional information the aminopeptidase binding site shares a similar structure to LTA4H at its ligand binding sites Mus musculus ?
-
 ?
3.4.11.6 additional information the aminopeptidase binding site shares a similar structure to LTA4H (EC 3.3.2.6) at its ligand binding sites Homo sapiens ?
-
 ?

Subunits

EC Number Subunits Comment Organism
3.3.2.6 More LTA4H folds into three domains and creates a deep cleft harboring the catalytic Zn2+ site, forming the active site with an L-shaped hydrophobic pocket deep into the protein Homo sapiens
3.3.2.6 More LTA4H folds into three domains and creates a deep cleft harboring the catalytic Zn2+ site, forming the active site with an L-shaped hydrophobic pocket deep into the protein Mus musculus
3.4.11.6 More LTA4H folds into three domains and creates a deep cleft harboring the catalytic Zn2+ site, forming the active site with an L-shaped hydrophobic pocket deep into the protein Homo sapiens

Synonyms

EC Number Synonyms Comment Organism
3.3.2.6 leukotriene A4 hydrolase
-
 Homo sapiens
3.3.2.6 leukotriene A4 hydrolase
-
 Mus musculus
3.3.2.6 LTA4H
-
 Homo sapiens
3.3.2.6 LTA4H
-
 Mus musculus
3.3.2.6 More see also EC 3.4.11.6 Homo sapiens
3.4.11.6 Aminopeptidase
-
 Homo sapiens
3.4.11.6 More see also EC 3.3.2.6 Homo sapiens

IC50 Value

EC Number IC50 Value IC50 Value Maximum Comment Organism Inhibitor Structure
3.3.2.6 0.00068
-
 pH and temperature not specified in the publication Homo sapiens 4-(dimethylamino)-N-[7-(hydroxyamino)-7-oxoheptyl]benzamide
3.3.2.6 0.00068
-
 pH and temperature not specified in the publication Mus musculus 4-(dimethylamino)-N-[7-(hydroxyamino)-7-oxoheptyl]benzamide
3.3.2.6 0.00765
-
 pH and temperature not specified in the publication Homo sapiens suberanilohydroxamic acid
3.3.2.6 0.00765
-
 pH and temperature not specified in the publication Mus musculus suberanilohydroxamic acid
3.3.2.6 0.01
-
 above, pH and temperature not specified in the publication Homo sapiens trichostatin A
3.3.2.6 0.01
-
 above, pH and temperature not specified in the publication Mus musculus trichostatin A
3.3.2.6 0.01
-
 above, pH and temperature not specified in the publication Homo sapiens Valproate
3.3.2.6 0.01
-
 above, pH and temperature not specified in the publication Mus musculus Valproate
3.3.2.6 0.01
-
 above, pH and temperature not specified in the publication Homo sapiens tubacin
3.3.2.6 0.01
-
 above, pH and temperature not specified in the publication Mus musculus tubacin
3.3.2.6 0.01
-
 above, pH and temperature not specified in the publication Homo sapiens JNJ-26481585
3.3.2.6 0.01
-
 above, pH and temperature not specified in the publication Mus musculus JNJ-26481585
3.3.2.6 0.01
-
 above, pH and temperature not specified in the publication Homo sapiens belinostat
3.3.2.6 0.01
-
 above, pH and temperature not specified in the publication Mus musculus belinostat
3.3.2.6 0.01
-
 above, pH and temperature not specified in the publication Homo sapiens entinostat
3.3.2.6 0.01
-
 above, pH and temperature not specified in the publication Mus musculus entinostat
3.3.2.6 0.01
-
 above, pH and temperature not specified in the publication Homo sapiens scriptaid
3.3.2.6 0.01
-
 above, pH and temperature not specified in the publication Mus musculus scriptaid
3.3.2.6 0.01
-
 above, pH and temperature not specified in the publication Homo sapiens panobinostat
3.3.2.6 0.01
-
 above, pH and temperature not specified in the publication Mus musculus panobinostat
3.3.2.6 0.01
-
 above, pH and temperature not specified in the publication Homo sapiens mocetinostat
3.3.2.6 0.01
-
 above, pH and temperature not specified in the publication Mus musculus mocetinostat
3.3.2.6 0.01
-
 above, pH and temperature not specified in the publication Homo sapiens resminostat
3.3.2.6 0.01
-
 above, pH and temperature not specified in the publication Mus musculus resminostat
3.3.2.6 0.01
-
 above, pH and temperature not specified in the publication Homo sapiens abexinostat
3.3.2.6 0.01
-
 above, pH and temperature not specified in the publication Mus musculus abexinostat
3.3.2.6 0.01
-
 above, pH and temperature not specified in the publication Homo sapiens CUDC-101
3.3.2.6 0.01
-
 above, pH and temperature not specified in the publication Mus musculus CUDC-101
3.3.2.6 0.01
-
 above, pH and temperature not specified in the publication Homo sapiens givinostat
3.3.2.6 0.01
-
 above, pH and temperature not specified in the publication Mus musculus givinostat
3.3.2.6 0.01
-
 above, pH and temperature not specified in the publication Homo sapiens N-(6-(2-aminophenylamino)-6-oxyhexyl)-4-methylbenzamide
3.3.2.6 0.01
-
 above, pH and temperature not specified in the publication Mus musculus N-(6-(2-aminophenylamino)-6-oxyhexyl)-4-methylbenzamide
3.3.2.6 0.01
-
 above, pH and temperature not specified in the publication Homo sapiens pracinostat
3.3.2.6 0.01
-
 above, pH and temperature not specified in the publication Mus musculus pracinostat
3.3.2.6 0.01
-
 above, pH and temperature not specified in the publication Homo sapiens rocilinostat
3.3.2.6 0.01
-
 above, pH and temperature not specified in the publication Mus musculus rocilinostat
3.4.11.6 0.0003
-
 pH and temperature not specified in the publication Homo sapiens 4-(dimethylamino)-N-[7-(hydroxyamino)-7-oxoheptyl]benzamide
3.4.11.6 0.00167
-
 pH and temperature not specified in the publication Homo sapiens suberanilohydroxamic acid
3.4.11.6 0.0044
-
 pH and temperature not specified in the publication Homo sapiens scriptaid
3.4.11.6 0.01
-
 above, pH and temperature not specified in the publication Homo sapiens trichostatin A
3.4.11.6 0.01
-
 above, pH and temperature not specified in the publication Homo sapiens Valproate
3.4.11.6 0.01
-
 above, pH and temperature not specified in the publication Homo sapiens tubacin
3.4.11.6 0.01
-
 above, pH and temperature not specified in the publication Homo sapiens JNJ-26481585
3.4.11.6 0.01
-
 above, pH and temperature not specified in the publication Homo sapiens belinostat
3.4.11.6 0.01
-
 above, pH and temperature not specified in the publication Homo sapiens entinostat
3.4.11.6 0.01
-
 above, pH and temperature not specified in the publication Homo sapiens panobinostat
3.4.11.6 0.01
-
 above, pH and temperature not specified in the publication Homo sapiens mocetinostat
3.4.11.6 0.01
-
 above, pH and temperature not specified in the publication Homo sapiens resminostat
3.4.11.6 0.01
-
 above, pH and temperature not specified in the publication Homo sapiens abexinostat
3.4.11.6 0.01
-
 above, pH and temperature not specified in the publication Homo sapiens CUDC-101
3.4.11.6 0.01
-
 above, pH and temperature not specified in the publication Homo sapiens givinostat
3.4.11.6 0.01
-
 above, pH and temperature not specified in the publication Homo sapiens N-(6-(2-aminophenylamino)-6-oxyhexyl)-4-methylbenzamide
3.4.11.6 0.01
-
 above, pH and temperature not specified in the publication Homo sapiens pracinostat
3.4.11.6 0.01
-
 above, pH and temperature not specified in the publication Homo sapiens rocilinostat

General Information

EC Number General Information Comment Organism
3.3.2.6 malfunction LTB4 levels are persistently elevated in bronchoalveolar lavage fluid (BALF) of lipopolysaccharide (LPS)-induced ALI, and the leukotriene levels in pulmonary edema fluid are significantly higher in ALI patients compared to control patients with hydrostatic pulmonary edema. In addition, LTB4 level is increased in lung homogenates, and BALF of patients with IPF and the level of LTB4 correlate with the extent of fibrosis in histological sections Homo sapiens
3.3.2.6 additional information LTA4H folds into three domains and creates a deep cleft harboring the catalytic Zn2+ site, forming the active site with an L-shaped hydrophobic pocket deep into the protein Homo sapiens
3.3.2.6 additional information LTA4H folds into three domains and creates a deep cleft harboring the catalytic Zn2+ site, forming the active site with an L-shaped hydrophobic pocket deep into the protein Mus musculus
3.3.2.6 physiological function leukotriene A4 hydrolase (LTA4H) is a bifunctional enzyme that exhibits LTA4H and aminopeptidase activities, it is a key enzyme in the biosynthesis of leukotriene B4 (LTB4). LTA4H is well-known to regulate chemotactic activity of human neutrophils. LTB4 is secreted by neutrophils at inflammation sites in response to formyl peptides, playing an important role in neutrophil activation and migration to formyl peptides Homo sapiens
3.3.2.6 physiological function leukotriene A4 hydrolase (LTA4H) is a key enzyme in the biosynthesis of leukotriene B4 (LTB4) Mus musculus
3.4.11.6 malfunction LTB4 levels are persistently elevated in bronchoalveolar lavage fluid (BALF) of lipopolysaccharide (LPS)-induced ALI, and the leukotriene levels in pulmonary edema fluid are significantly higher in ALI patients compared to control patients with hydrostatic pulmonary edema. In addition, LTB4 level is increased in lung homogenates, and BALF of patients with IPF and the level of LTB4 correlate with the extent of fibrosis in histological sections Homo sapiens
3.4.11.6 additional information LTA4H folds into three domains and creates a deep cleft harboring the catalytic Zn2+ site, forming the active site with an L-shaped hydrophobic pocket deep into the protein Homo sapiens
3.4.11.6 physiological function leukotriene A4 hydrolase (LTA4H) is a bifunctional enzyme that exhibits LTA4H and aminopeptidase activities, it is a key enzyme in the biosynthesis of leukotriene B4 (LTB4). LTA4H is well-known to regulate chemotactic activity of human neutrophils. LTB4 is secreted by neutrophils at inflammation sites in response to formyl peptides, playing an important role in neutrophil activation and migration to formyl peptides Homo sapiens